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CLINICAL PRACTICE GUIDELINE LYHE-005 Version 1

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Acute Lymphoblastic Leukemia

Effective Date: July, 2016

The recommendations contained in this guideline are a consensus of the Alberta Provincial Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a

review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct

care.


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Table of Contents

SUMMARY OF RECOMMENDATIONS ............................................................................................................ 5

OVERVIEW ..................................................................................................................................................... 9

GUIDELINES METHODOLOGY ........................................................................................................................ 9

PATHOGENESIS ........................................................................................................................................... 10

CLINICAL MANIFESTATIONS, DIAGNOSIS AND WORK-UP .......................................................................... 10

Recommendations: ......................................................................................................................... 11

CLASSIFICATION AND PROGNOSTICATION ................................................................................................. 12

Classification of ALL................................................................................................................................. 12

Prognostic Factors in ALL ........................................................................................................................ 14

Clinical Prognostic Factors: ................................................................................................................. 14

Age, Gender and ethnicity: ............................................................................................................. 14

White Blood Cell Count: .................................................................................................................. 15

Immunophenotype ............................................................................................................................. 15

Cytogenetic Studies............................................................................................................................. 16

Molecular Studies ............................................................................................................................... 18

Gene Expression Profiling ................................................................................................................... 20

BCR-ABL like ALL: ............................................................................................................................ 20

Early T-cell precursor acute lymphoblastic leukaemia (ETP – ALL): ................................................ 20

Other Factors ...................................................................................................................................... 21

Epigenetic changes in ALL: .............................................................................................................. 21

Pharmacogenetics and pharmacogenomics: .................................................................................. 21

Pre-treatment risk stratification ............................................................................................................. 23


TREATMENT APPROACHES IN ALL .............................................................................................................. 26

Adult Multidrug regimens ....................................................................................................................... 26

The M.D. Anderson Model ...................................................................................................................... 29

The pediatric approach ........................................................................................................................... 29

PROVINCIAL RECOMMENDATIONS FOR TREATMENT OF ALL .................................................................... 33


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Adolescents and Young Adults (AYA) ...................................................................................................... 33

Recommendations for patients AYA: .............................................................................................. 34

Patients aged 35 (40) – 60 ...................................................................................................................... 34


Patients aged over 60 ............................................................................................................................. 35


SPECIAL TOPICS IN THE MANAGEMENT OF ALL ......................................................................................... 36

Philadelphia Chromosome or BCR-ABL Positive ALL ............................................................................... 36


Role of allogeneic stem cell transplantation........................................................................................... 39

Ph-/BCR-ABL- ALL ................................................................................................................................ 39


Role of SCT in patients with Ph/BCR-ABL positive ALL ........................................................................ 41


Role of Cranial Radiation ......................................................................................................................... 42


Role of MRD assessments in the management of patients with ALL ..................................................... 44


Supportive Care .......................................................................................................................................... 46

Follow-up .................................................................................................................................................... 47

REFERENCES ................................................................................................................................................ 48

APPENDIX A ................................................................................................................................................. 63

Original DFCI protocol 91-01 (used for paediatric patients)(Barry, et al 2007) ...................................... 63

APPENDIX B ................................................................................................................................................. 64

Canadian NCIC DFCI AL.4 Trial (DeAngelo, et al 2015) ........................................................................... 64

APPENDIX C ................................................................................................................................................. 65

Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Storring, et al 2009) for Philadelphia

Chromosome/BCR-ABL1 negative adult patients aged <60 years old .................................................... 65


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Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Martell, et al 2013) for Philadelphia

Chromosome/BCR-ABL1 negative adult patients aged >60 years old .................................................... 66

APPENDIX D ................................................................................................................................................. 67

Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol for Philadelphia Chromosome/BCR-

ABL1 positive adult patients aged <60 years old (Thyagu, et al 2012) ................................................... 67

Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Martell, et al 2013) for Philadelphia

Chromosome/BCR-ABL1 positive adult patients aged >60 years old ..................................................... 67


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SUMMARY OF RECOMMENDATIONS

1. Diagnosis and Work-up

1.1. All patients suspected of leukemia should undergo bone marrow studies

incorporating morphological assessment, immunophenotyping, cytogenetic +/- FISH

and molecular evaluation.

1.1.1. For B-cell ALL, results of BCR-ABL by PCR or t(9;22) by cytogenetics/FISH

should be available within 5 days as this will influence the induction treatment

regimen used.

1.1.2. Patients with failed cytogenetics for B-cell ALL should have molecular/FISH

testing for BCR-ABL (if not yet done) and MLL rearrangement.

1.2. If bone marrow studies are not feasible peripheral blood should be sent for

immunophenotyping, cytogenetics and molecular studies.

1.3. Patients for whom anthracycline based treatment is contemplated should receive a

cardiac evaluations e.g. MUGA scan or echocardiogram or cardiac MRI.

1.4. Transplant – eligible patients and their siblings should be HLA typed.

2. Classification and Prognostication:

2.1. Patients should be classified as having B-cell or T-cell ALL based upon

immunophenotyping results.

2.2. Pre-treatment risk stratification should be ascertained for all patients using age,

WBC and cytogenetics/FISH and/or molecular studies.

2.3. Post-treatment risk stratification should include the outcomes of minimal residual

disease assessment using either flow cytometry or PCR.

3. Treatment:

3.1. Eligible adults under age 60 with Ph/BCR-ABL negative ALL should be treated with

a pediatric-based protocol.

3.1.1. In Alberta the standard regimen is the modified Dana Farber Cancer Institute

(DFCI) protocol.

3.1.2. Patients with co-morbidities may be treated with a ‘less toxic’ regimen.

3.2. Medically fit adults above age 60 with Ph/BCR-ABL negative ALL should be treated

with curative intent.


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3.2.1. The Princess Margaret Hospital modified DFCI protocol for adults above age

60 has produced favourable results in this population compared to other

regimens and may be used.

3.3. Patients over age 75, or those age 60-75 with major co-morbidities precluding

intensive chemotherapy, should be considered for palliative chemotherapy with

corticosteroids and vincristine +/- low- dose asparaginase.

4. Special Topic in the Management of ALL:

4.1. Philadelphia chromosome/BCR-ABL positive ALL:

4.1.1. No TKI has been clearly shown to be superior upfront. As most studies have

assessed high does imatinib (600 – 800mg) we recommend that it be used

first line

4.1.1.1. Patients with intolerance to, or not achieving an adequate response to,

imatinib should be switched to a second generation TKI such as

dasatinib

4.1.1.2. Ponatinib should be used in patients with a T315I mutation

4.1.1.3. For patients with CNS diseae at diagnosis dasatinib should be used

upfront.

4.1.2. Ph/BCR-ABL positive patients under age 60-65 should be treated with a BCR-

ABL tyrosine kinase inhibitor (TKI) combined with induction and post-

remission therapy.

4.1.2.1. A tyrosine kinase inhibitor together with the DFCI protocol may be

used. Asparaginase should be deleted due to increased toxicity when

used concurrently with TKI.

4.1.2.2. A less intensive induction regimen with corticosteroids, vincristine and

TKI can be used as it is produces higher CR rates due to lower

induction mortality.

4.1.3. Patients with Ph/BCR-ABL positive ALL over age 65, or those with major co-

morbidities precluding transplant, should be treated with corticosteroids and

TKI +/- vincristine as induction.

4.1.3.1. Post-induction therapy should be individualized based on patient

tolerance but should include a TKI combined with some chemotherapy.

TKIs should be continued indefinitely.

4.1.4. Individualized quantitative BCR-ABL monitoring is recommended in all

patients.


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4.2. Role of allogeneic stem cell transplantation:

4.2.1. Allogeneic HSCT should not be routinely performed in patients with Ph/BCR-

ABL negative ALL in CR-1, unless there are high risk features such as:

a) t(4;11) with MLL rearrangement

b) high baseline WBC (>30 x109/L for B-ALL or >100 x10

9/L for T-ALL)

c) lack of attainment of CR with first induction

d) persistent minimal residual disease (MRD) positivity e.g. at the end

of intensification.

4.2.1.1. There is no clear evidence that other cytogenetic abnormalities or

specific cell surface markers constitute high risk features when using a

pediatric-based regimen

4.2.1.2. It is also not clear whether patients with a high-risk feature at baseline

who achieve MRD negativity after induction therapy require a

transplant

4.2.2. Ph/BCR-ABL positive patients up to age 65 should be considered for

allogeneic HSCT in CR-1.

4.2.2.1. If an HLA matched related or unrelated donor is unavailable, patients

achieving molecular negativity by PCR can be continued on post-

induction chemotherapy together with TKI without a transplant.

4.2.2.2. Patients should be closely monitored for disease progression with

serial PCR testing.

4.3. Cranial Radiation:

4.3.1. Given recent data, cranial radiation may be omitted for CNS prophylaxis.

Patients should receive 11 -12 lumbar punctures as noted in the DFCI

protocol.

4.4. Role of MRD assessments in the management of Ph/BCR-ABL negative

patients with ALL:

4.4.1. Ph/BCR-ABL negative patients should have MRD assessments following

induction chemotherapy.

4.4.1.1. MRD positive patients should receive individualized treatment which

may consist of:

a) Continuing DFCI protocol

b) Additional high-dose chemotherapy or immunotherapy with

an intent to achieve MRD negativity. There is insufficient


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evidence to recommend a specific treatment approach to

achieve this.

4.4.2. If persistently MRD positive, patients should be referred for allogeneic SCT.

4.5. Refractory ALL:

4.5.1. Transplant eligible patients should be treated with a non-cross resistant re-

induction chemotherapy regimen or immunotherapy (if available).

4.5.2. Immunotherapy is recommended for patients who have failed two different

chemotherapy regimens.

4.5.3. Transplant eligible patients should be considered for allogeneic HSCT.


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OVERVIEW

Acute Lymphoblastic Leukemia (ALL) is a highly aggressive hematological - malignancy

resulting from the proliferation and expansion of lymphoid blasts in the blood, bone marrow

and other organs (Bassan and Hoelzer 2011). ALL occurs with a bimodal distribution with

an early peak in children 4 – 5 years old followed by a second peak at ~ 50 years of age

(Fullmer, et al 2010) with the worldwide incidence being ~ 1 – 4.75/100,000 individuals with

a male:female prevalence of roughly 1·3:1 (Bassan and Hoelzer 2011). It is the most

common childhood acute leukemia accounting for ~ 80% of the pediatric leukemias but

contributing to only 20% of adult leukemias. Although significant progress has been made in

treating adult ALL the overall survival amongst adults 18 to 60 years old is only 35% in

contrast to childhood ALL in which overall survival at five years is more than 80% (Bassan

and Hoelzer 2011).

Over the past two decades the treatment of adult ALL has changed significantly with the

introduction of paediatric protocols for the treatment of adolescents and young adults, the

addition of tyrosine kinase (TKI) inhibitors for the treatment of Philadelphia positive/BCR-

ABL positive ALL, a reevaluation of the role of allogeneic stem cell transplantation for

standard risk ALL patients, the incorporation of minimal residual diseae into risk

assessments and most recently the introduction of novel agents such blinatumomab and

chimeric antigen receptor – T cell therapy for relapsed/refractory ALL.

GUIDELINES METHODOLOGY

In these clinical practice guidelines we review the literature to highlight the important

diagnostic criteria for adult ALL, the work-up and risk-stratification necessary prior to

initiating treatment and the treatment of various subgroups of patients. We further review

some special topics in the management of patients with ALL. Lastly, we make

recommendations for the province of Alberta on the management of patients with ALL.

These guidelines are based on electronic search of the PubMed database using the term

Acute Lymphoblastic Leukemia. The search results were narrowed by selecting studies in

humans published in English. Clinical trials, practice guidelines, systematic reviews and

metaanalysis were evaluated. American Society of Clinical Oncology, American Society of

Hematology and European Society of Hematology abstracts were also reviewed.


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This first iteration of the guideline is to be reviewed reviewed by the Alberta Provincial

Hematology Tumour Team members of which include hematologists, medical oncologists,

radiation oncologists, nurses, hematopathologists, and pharmacists.

PATHOGENESIS

ALL is thought to arise from interactions between exogenous or endogenous exposures,

genetic susceptibility, and chance. Infection was the first suggested causal exposure for

childhood acute lymphoblastic leukemia (Ward 1917). After the Hiroshima and Nagasaki

atomic detonations, ionizing radiation quickly became established as an exposure leading to

childhood ALL (Preston, et al 1994). Chromosomal translocations occurring in utero during

fetal hematopoiesis have been suggested as the primary cause for pediatric ALL while

postnatal genetic events are considered secondary contributors (Greaves, et al 2003,

Inaba, et al 2013). Many of these chromosomal rearrangements disrupt genes that regulate

normal haematoopoiesis and lymphoid development (eg, RUNX1, ETV6), activate

oncogenes (eg, MYC), or constitutively activate tyrosine kinases (eg, ABL1). Patients with

trisomy 21, Klinefelter’s syndrome and inherited diseases with excessive chromosomal

fragility such as Fanconi’s anemia, Bloom’s syndrome and ataxia-telangiectasia have a

higher risk of developing ALL (Jabbour, et al 2005). However, in the majority of ALL patients

no gross chromosomal alteration is noted suggesting that additional submicroscopic genetic

alterations likely contribute to leukaemogenesis (Inaba, et al 2013). Genome-wide

association studies of childhood ALL (Inaba, et al 2013) have noted common allelic variants

in IKZF1, ARID5B, CEBPE, and CDKN2A which have been significantly and consistently

associated with childhood ALL (Inaba, et al 2013). Others have investigated the

associations of genetic polymorphisms in folate pathway and DNA repair genes with

susceptibility to ALL (Goricar, et al 2015). Although several genetic alterations have well

established roles in leukaemogenesis (eg, activating mutations in NOTCH1) the roles of

many others remains elusive.

CLINICAL MANIFESTATIONS, DIAGNOSIS AND WORK-UP

Clinical manifestations of ALL are highly variable. At presentation patients may have a

multitude of constitutional symptoms, easy bruising, bleeding, dyspnea, dizziness, and

infections due to anemia, thrombocytopenia and neutropenia. Extremity and joint pain may

be the only presenting symptoms in some patients (Alvarnas, et al 2015).

Lymphadenopathy, splenomegaly and/or hepatomegaly are seen on phycial examination in

approximately 20% of patients (Alvarnas, et al 2015). Abdominal masses from

gastrointestinal involvement or chin numbness from cranial nerve involvement may be seen


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but are more suggestive of mature B-ALL. Less than 10% of patients have symptomatic

central nervous system (CNS) involvement. T-lineage ALL with a mediastinal mass can

cause stridor and wheezing, pericardial effusions, and superior vena cava syndrome.

Testicular involvement is rare in adults (Faderl, et al 2010).

The diagnosis of ALL begins with an evaluation of the peripheral blood film which may

identify the presence of blasts. Patients presenting with only a mediastinal mass or

lymphadenopathy may require a tissue biopsy. All patients should have a bone marrow

examination. As per the 2008 WHO classification, in contrast to myeloid malignancies, there

is no agreed-upon lower limit for the percentage of blasts required to establish a diagnosis

of lymphoblastic leukemias (Swerdlow, et al 2008). Despite this, some guidelines suggest

that the diagnosis of ALL requires demonstration of > 20% blasts in the bone marrow

aspirate/biopsymaterial (Alvarnas, et al 2015). By convention the term lymphoma is used

when the process is confined to a mass lesion with no or minimal evidence of peripheral

blood and bone marrow involvement. Based on morphologic, genetic and

immunophenotypic features, lymphoblastic lymphoma is indistinguishable from ALL.

The assessment of immunophenotype by flow cytometry is essential and part of the World

Health Organization Classification of Neoplastic Diseases of Hematopoietic and Lymphoid

Tissues (Faderl, et al 2010). The initial immunophenotyping panel should be comprehensive

enough to establish a leukemia associated phenotype (LAP) to allow for use in minimal

disease monitoring (MRD). Cytogenetic examination with examination of metaphases

and/or fluorescence in situ hybridization (FISH) is crucial (eg, for BCR-ABL and MLL-AF4)

particularly in cases in which cytogenetics are unavailable or have failed. Screening by

polymerase chain reaction (PCR) for the BCR-ABL transcripts is also essential as it

significantly impacts treatment. Some labs also evaluate blast cells with molecular methods

for the detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR)

rearrangements (Faderl, et al 2010) however this is not routinely performed within Alberta. If

bone marrow transplant is a consideration tissue typing of both the patient and siblings

should also be performed at diagnosis. If there are no HLA-matched siblings, consideration

should be given to prompt initiation of an unrelated donor search.

Recommendations: The intiail work-up of patients with ALL should include a thorough

history and physical examination as well as baseline laboratory investigations including

complete blood count, chemistry with extended electrolytes, tests of renal and liver function

including amylase and lipase, a disseminated intravascular coagulation panel, a tumour

lysis panel. Cardias imaging e.g. echocardiogram, multigated acquisition (MUGA) scan or

cardiac MRI should be undertaken for all patients due to the use of anthracyclines.


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Bone marrow studies or peripheral blood studies incorporating, as noted above,

immunophenotyping, cytogenetics, and molecular studies should be completed. Ideally

results of BCR-ABL testing should be available prior to the initiation of treatment, and if

delayed, should be available within 5 days. Lastly, patients eligible for allogeneic stem cell

transplantation, and their siblings should have human leukocyte antigen (HLA) typing

performed.

CLASSIFICATION AND PROGNOSTICATION

Classification of ALL

Classification of ALL relies heavily on morphological, immunophenotypic, cytogenetics and

molecular markers. According to the WHO 2008 classification three broad groups can be

distinguished: Precursor B-cell ALL, mature B-cell ALL and T-cell ALL. These guidelines

will focus on Precursor B-cell ALL and T-cell ALL. Precursor B-cell ALL can be

subclassified as: B-lymphoblastic lymphoma/leukemia not otherwise specified (B-cell ALL

NOS) and B – lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

(Table 1). B-cell ALL NOS may be further divided into early Pre-B ALL, common ALL and

Pre-B ALL.

Precursor T-cell ALL may be subclassified as Early T-cell ALL (Pro-T- cell ALL and Pre-T-

cell ALL), cortical (or thymic) T-cell ALL and medullary (or mature) T-cell ALL. One study

noted that cortical T-cell ALL represented 56% of T-cell ALL cases, medullary T-cell ALL

represented 21% of cases and early T-cell ALL represented 21% of cases. Recently, a

distinct subtype of early T-cell ALL termed early T-cell precursor (ETP) has been identified

with unque biologic and clinical characteristics.

Table 1: WHO (2008) Immunophenotypic classification of ALL (Swerdlow, et al 2008)

ALL - Subtype Characteristics

B-Cell ALL NOS

Early Pre-B ALL/pro B-ALL CD19+, cCD79a+, cCD22+, nuclear TdT positive, CD10-

Common ALL CD10 (CALLA)

Pre-B ALL Cytoplasmic IgM, CD19+, CD79a+, CD22+, CD10+

B-ALL with recurrent


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cytogenetic abnormalities

t(9;22)(q34;q11.2); BCR-ABL1 CD10, CD19, TdT positive, May express CD13/CD33. CD25 highly associated with t(9;22). p190 transcript (most childhood cases) p210 transcript (50% of adult cases)

t(v;11q23); MLL Most common leukemia in infants. Short latency period. High WBC, CNS involvement. Pro-B immunophenotype CD19+, CD10 –ve, CD24 –ve, CD15+ve Neuroglial antigen-2 (NG2) relatively specific.

t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)

Rare in adulthood CD19+ve, CD10+ve, CD34 +ve (commonly) May have near or complete absence of CD9/CD220/CD66c Myleoid antigens (CD13) frequently expressed. ?necessary but sufficient for leukemic translocation?

Hyperdiploidy >50 and usually <66 chromosomes without structural abnormalities. Non-random: chromosomes 21, X, 14 and 4 most common; chromosomes 1, 2 and 3 being the least common. CD19+ve, CD10+. CD34+ (most cases) CD45 –ve (often) Patients with T-ALL should not be considered part of this group.

Hypodiploidy < 44 – 46 chromosomes. Structural abnormalities are uncommon. CD19+, CD10+ Diagnosis may be missed by standard karyotyping due to endoduplication.

t(5;14)(q31;q32);IL3-IGH Constitutive expression of IL-3 gene. Associated with eosinophilia which is reactive and not part of the leukemic clone. Diagnosis may be based on immunophneotype and genetic findings even if the bone marrow blast count is low. CD19+, CD10+

t (1;19)(q23;p13.3);E2A-PBX1 (TCF3 – PBX1)

CD19+, CD10+, cytoplasmic M heavy chain. Strong expression of CD9 Lack of CD34 or very limited CD34 expression.

T-Cell ALL

Precursor T- ALL CD1a, CD2, CD3, CD4, CD5, CD7 and CD8. CD7 and cCD3 are most often positive. CD3 is lineage specific CD4 /CD8 are frequently co-expressed;


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CD10 may be positive; CD79a (10% of cases) CD13/CD33 (19-32% of cases).

Pro T-cell ALL cCD3+, CD7+, CD2-,CD1a-, CD34+/-; CD4-, CD8-

Pre T-cell ALL cCD3+, CD7+, CD2+, CD1a-, CD34+/-; CD4-, CD8-

Cortical T-cell ALL cCD3+, CD7+, CD2+, CD1a+, CD34-; CD4+, CD8+

Medullary T-cell ALL cCD3+, CD7+, CD2+, CD1a-, CD34-, sCD34+; CD4+ or CD8+

Early T-cell Precursor* Absence of CD1a/CD8, weak expression of CD5 Presence of 1 or more myeloid or stem cell markers (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65)

*Not part of the WHO 2008 claissification.

Prognostic Factors in ALL

Prognostic models for ALL have been refined continuously with improvements in therapy

rendering some prognostic variables invalid (Faderl, et al 2010). The following represent

clinical, cytogenetic and important molecular risk factors. It is important to note that many of

these factors were defined using adult –based protocols and more studies are needed to

evaluate their significance with pediatric based protocols.

Clinical Prognostic Factors:

Age, Gender and ethnicity: Age is an important prognostic factor in ALL. In children age

(infant or ≥10 years old) is an unfavourable risk group especially those younger than 6

months old (Inaba, et al 2013, Jeha and Pui 2009). Regardless of the treatment protocol

utilized older adults are regarded as a prognostically unfavorable group. One study noted

that the outcomes of patients aged over 55 had a probability of survival of 20% at 3 years

while others have noted that patients over the age of 35 have poorer outcomes (Hoelzer, et

al 1988, Kantarjian, et al 2004, Lazarus, et al 2006, Marks, et al 2009, Rowe, et al 2005).

Rrecent data suggests that adolescents and young adults benefit with improved overall

survival if treated according to pediatric protocols (Bassan and Hoelzer 2011). Several

studies have suggested that the influence of age may relate to the increased prevalence of

poor-risk features while others have suggested that it is independent of cytogenetic and

molecular aberrations (Arico, et al 2000, Jeha 2009). The ability to tolerate chemotherapy

likely plays an important role (Goldstone, et al 2008, Larson, et al 1998, Rowe, et al 2005).

Toegther with age, male gender and race (Hispanic or of African descent) have been

considered negative prognostic factors in pediatric ALL (Inaba, et al 2013). Racial

differences in prognosis have been linked to socioeconomic factors but also to differences

in genomic variations. For example, germline single nucleotide polymorphisms of PDE4B

and ARID5B are associated with Native American genetic ancestry and somatic CRLF2

were over-represented in children with a Hispanic background.


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White Blood Cell Count: In children, a presenting leucocyte count (≥50 × 10⁹ /L) has been

associated with a worse prognosis (Jeha and Pui 2009) however, in many, but not all adult

studies of ALL, high-risk ALL has been defined as WBC ≥ 30 x 109/L for B-cell ALL and

≥100x109/L for T-cell ALL (Bassan and Hoelzer 2011, Hoelzer, et al 1988, Lazarus, et al

2006, Marks, et al 2009, Rowe, et al 2005). Although most early studies identifying this

factor used adult-based protocols, subgroup analyses in larger studies show that these

continue to be important prognostic factors with pediatric-inspired regimens (Boissel, et al

2003, Brandwein 2011). In their study of the DFCI protocol in adults a high WBC (>30 x

109/L for Pre-B ALL or >100 x 10

9/L for T-ALL) was associated with inferior RFS and OS

(Storring, et al 2009). The role of age and WBC was questiond by the Southwest Oncology

Group (SWOG) who noted that in a multivariate model which included age, WBC and

cytogenetics that only cytogenetics was a significanct independent factor for relapse-free

and overall survival overshadowing age and WBC (Pullarkat, et al 2008).

Immunophenotype

The SEER database demonstrated a better prognosis with B cell as compared with T cell

immunophenotype in patients < age 20 years; while in patients ≥ 20 years of age, T cell

immunophenotype was more favorable (Lukenbill and Advani 2013). This was confirmed in

a metanalysis by Kako et al. of published studies from January 1998 to March 2013 to

compare the outcomes of chemotherapy for T- and B- lineage ALL and noted superior

survival in patients with T-lineage ALL compared to those with B-lineage ALL although the

inclusion of patients with Ph+ ALL likely influenced the results (Kako, et al 2015).

Amongst adults T-cell ALL accounts for 14–22% of adult ALL (Boucheix, et al 1994) and is

thought to be of favourable prognosis. In both the LALA 87 and the UKALL/EGOG 2993

trial, T-ALL was associated with male gender, age <35 - 39 years old, CNS involvement and

a high WBC count. The LALA-87 investigators also noted a higher incidence of a

mediastinal mass and anemia (Boucheix, et al 1994, Marks, et al 2009). In this study for

patients age <40 treated with chemotherapy alone 3 year DFS was superior in the group

with a T-cell phenotype relative to a B-ALL phenotype (59% vs. 20%). No difference in DFS

was seen in patients with B- or T- ALL patients treated with allo- or auto – HSCT (Boucheix,

et al 1994). Similaly, Both Rowe et al. and Larson et al. noted that improved OS in patients

with T-cell antigen expression relative to B-lineage antigents (Larson, et al 1998, Rowe, et

al 2005). Kantarjian et al. using Hyper-CVAD noted similar results (Kantarjian, et al 2004).

Using the pediatric Dana Farber Cance Institute (DFCI) protocol a trend toward improved

clinical outcomes was observed in adolescents (Stock, et al 2008) and adults (Brandwein

2011, Storring, et al 2009) with T-ALL. The GRAALL study group (Huguet, et al 2009) noted

that when using a pediatric protocol at 42 months, EFS was estimated to be 62% (95% CI,


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50% to 72%) in T-ALL patients and 52% (95% CI, 42% to 59%) in BCP-ALL patients ( P =

.09 by log-rank test). Within the T-cell ALL subset the prognosis is worse for pro-, pre- and

mature-T subtypes (CD1a-, CD3-/CD3+) compared with the CD1a+ cortical/thymic

phenotype. The early T-cell precursor ALL which retains stem cell-like features is

associated with a dismal prognosis with conventional chemotherapy (Coustan-Smith, et al

2009) in both adult and pediatric T-ALL (Chiaretti, et al 2011).

As noted above, several studies have suggested that patients with B-cell phenotype fare

worse than those with T-ALL. Patients with a CD10-negative pro-B phenotype are

considered as high-risk particularly when associated with t(4;11)/abn q23 (Bassan and

Hoelzer 2011, Brandwein 2011). The pre-B subtype expressing cytoplasmic heavy chains

has a bad outlook when harboring MLL rearrangements. The CD20 antigen is expressed in

nearly half of B-cell ALL and its impact on clinical outcomes is controversial. Maury et al.

when using the pediatric GRAALL 2003 protocol in adults aged 15-60 years old with Ph-

negative ALL noted that CD 20 expression did not influence achievement of complete

remission but was associated with a higher cumulative incidence of relapse (CIR) and lower

EFS at 42 months (42% vs. 29%) in patients with a WBC ≥ 30 ×109/L (P=0.006). Thomas

et al. also noted an inferior survival in CD20 positive patients using the adult-based hyper-

CVAD protocol (Thomas, et al 2009). In contrast, a retrospective analysis by the Princess

Margaret Hospital groups in adult patients, most of whom had received a pediatric-based

regimen, did not find any association between CD20 expression and outcome (Chang, et al

2010) and in-fact there appeared to be a trend towards a favourable EFS in those showing

CD20 positivity. Craddock et al. noted that CD13 positivity was an independent poor

prognostic indicator for OS, EFS and RFS in a cohort of patients treated with the DFCI

protocol. The prognostic value of CD13 was primarily seen in patients with normal or

intermediate risk cytogenetics.

Cytogenetic Studies

Karyotype is an important prognostic factor with a number of cytogenetic abnormalities

being associated with altered prognosis in ALL (Table 2). The frequency of cytogenetic

aberrations varies between adult and childhood ALL and may partially explain the

differences in clinical outcomes between patient populations (Alvarnas, et al 2015). Whether

cytogenetic abnormalities will continue to remain important with the increasing use of

pediatric protocols in adult patients remains unknown (Storring, et al 2009).

The Philadelphia chromosome derives its name from the city where it was first described in

the leukemia cells of a CML patient (Nowell and Hungerford 1960). Ninety percent of

pediatric Ph+ ALL patients have the classic ALL-type p190 translocation (Bernt and Hunger


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2014). The BCR-ABL1 translocation is present in approximately 8–10% of adolescents and

is the most frequent and clinically relevant structural abnormality in adult ALL (15% to 30%)

(Faderl, et al 2010) with the frequency increasing with age and being high as 50% in the

elderly. Until recently the BCR – ABL1 marked the most unfavourable subgroup of adult

ALL. Although CR rate was 75%- 80% median DFS was about 10 months and 5-year

survival below 10-20% using chemotherapy alone (Brandwein 2011, Fielding, et al 2009,

Gupta, et al 2004). Larson et al noted that in the CALGB 8811 clinical trial the detection of

the t(9;22) has a statistically significant adverse effect on survival. Only 16% of those with

either a Ph chromosome or a BCR-ABL rearrangement were estimated to survive for 3

years, compared with 62% of those who were negative by both genetic tests (P< .001)

(Larson, et al 1995). Most studies, however, demonstrate a survival advantage with HSCT

compared to chemotherapy alone (Brandwein 2011, Fielding, et al 2009, Gupta, et al 2004).

Combinations of tyrosine kinase inhibitors (TKIs) with chemotherapy have produced

promising results but their impact on long-term DFS remains unclear.

The t(4;11) is present in up to 60 % of infants younger than 12 months but is rarely

observed in adult patients. When rearranged, the MLL gene has been found to be

associated with inferior RFS and OS in adult patients when using a paediatric protocol

(Storring, et al 2009). The t(1;19) is present in 30% of childhood ALL. Jeha et al. evaluated

the impact of contemporary therapy on the outcome of children with t(1;19)/TCF3/PBX1

treated at St Jude Children's Research Hospital. Although, patients had comparable EFS

patients and a lower cumulative incidence of any hematological relapse, a multivariate

analysis revealed that the t(1;19) was an independent risk factor for isolated CNS relapse

(Jeha, et al 2009). Garg et al. also noted that adults treated with Hyper CVAD had a

significantly better CRD and OS compared with all other patients combined and compared

individually with patients who had Philadelphia chromosome-positive, t(4;11), and

lymphoma-like abnormalities (deletion 6q, addition q14q, t[11;14], and t[14;18]). They

concluded that adults with ALL and t(1;19) had an excellent prognosis when receiving the

hyper-CVAD regimen (Garg, et al 2009). However, Foa et al. found that this abnormality is

frequently associated with early treatment failure. They recommended that E2A-PBX1+

adult ALL should be considered for intensified treatment strategies (Foa, et al 2003). The

t(12;21) abnormality leading to ETV6-RUNX1 fusion is detectable in about 25 % of children

and 3 % of adults with B-ALL. Patients generally have a favorable prognosis (Iacobucci, et

al 2012b, Romana, et al 1995).

Hyperdiploidy (>50 chromosomes) is seen in approximately 25% - 30% of paediatric cases

and 7% of adults and represents the most common chromosomal abnormality in children. It

is associated with a favourable prognosis regardless of age and leukocyte count at


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presentation.(Look, et al 1985, Paulsson, et al 2015, Trueworthy, et al 1992). Its

characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18

and 21, with individual trisomies or tetrasomies being seen in over 75% of cases. The

individual structural abnormalities do not appear to influence outcome in patients with

hyperdiploidy except for the t(9;22), which is associated with a poor prognosis (Raimondi, et

al 1996). The favourable prognosis may reflect an increased propensity of these cells to

undergo apoptosis (Jeha and Pui 2009). In contrast, approximately 5 % to 6 % of ALL

patients, independent of age, have the loss of various chromosomes, resulting in a

hypodiploid clone with fewer than 44 – 46 chromosomes. These patients generally have a

poor prognosis, especially those with near-haploid and low-hypodiploid clones (Iacobucci, et

al 2012b, Jeha and Pui 2009, Nachman, et al 2007). Recent data suggest that complex

karyotypes (≥ five chromosomal abnormalities) occur more frequently with increasing age

and may be associated with inferior survival (Brandwein 2011, Marks 2010, Marks, et al

2009, Moorman, et al 2007a).

Intrachromosomal amplification of chromosome 21 (iAMP21) occurs at an incidence up to 2

% in older children with B-cell precursor ALL (Harrison, et al 2005) and is defined by at

least three copies of the RUNX1 gene (Children's Oncology Group, COG, definition for

iAMP21). iAMP21 has been shown to be linked to a dismal outcome when patients are

treated with standard therapy, because it is associated with an increased risk of both early

and late relapses (Attarbaschi, et al 2008, Iacobucci, et al 2012b, Moorman, et al 2007b,

Rand, et al 2011).

Molecular Studies

Molecular genetics has identified several gene mutations, translocations and amplifications

that may have prognostic significance in ALL. IKZF1 encodes IKAROS and over the last 5

years has been established as one of the most clinically relevant tumor suppressors in ALL.

It is a DNA-binding zinc finger transcription factor that regulates the development and

function of the immune system and acts as a master regulator of normal hematopoietic

differentiation and proliferation, particularly in lymphoid lineage (Iacobucci, et al 2012a).

Deletion of a single IKZF1 allele or mutations of a single copy of IKZF1 were first detected

in 15 % of pediatric B-cell ALL and in more than 80 % of Ph+ ALL cases, either de novo

Ph+ ALL or chronic myeloid leukemia at progression to lymphoid blast crisis suggesting a

critical role in the pathogenesis of Ph+ ALL (Bernt and Hunger 2014, Iacobucci, et al 2009,

Martinelli, et al 2009, Mullighan, et al 2008). Incidence in adults is about 50% in B-cell ALL

and about 65% when BCR-ABL positive. Recent data further suggest that together with

Ph+ve ALL, mutations in IKZF1 are also a hallmark of ‘BCR–ABL1-like ALL’ (Inaba, et al

2013). Alteration of the IKAROS gene is associated with increased risk of treatment failure


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and relapse in both BCR–ABL1-positive and BCR–ABL1-negative disease independent of

commonly used risk stratification features such as age, sex, white cell count, and levels of

minimal residual disease (MRD) (Beldjord, et al 2014, Martinelli, et al 2009)

PAX5 encodes a transcription factor known as B-cell specific activator protein, that plays a

key role in B-cell commitment by activating essential components of the B-cell receptor

signaling and repressing the transcription of genes necessary for T-lymphopoiesis

(Busslinger 2004). Monoallelic deletion of PAX5 have been observed in about 30 % of

children and adults (Iacobucci, et al 2010, Mullighan, et al 2007) and have been

demonstrated to not influence treatment outcome (Iacobucci, et al 2010, Iacobucci, et al

2012b, Mullighan, et al 2009b). The CDKN2A/B locus encodes for the INK4-class cyclin

dependent kinase inhibitors p15INK4B, p16INK4A and for p14ARF. CDKN2A and CDKN2B

deletions have been identified in 29 % and 25 % of BCR-ABL1-positive ALL patients,

respectively (Iacobucci, et al 2011). The association with prognosis is still controversial

(Heyman, et al 1996, Iacobucci, et al 2011, Iacobucci, et al 2012b).

Four independent groups in late 2009 and early 2010 identified that up to 50 % of BCR-

ABL1-like ALL cases have dysregulated expression of CRLF2, the gene encoding the

cytokine receptor-like 2 factor (Hertzberg, et al 2010, Mullighan, et al 2009a, Russell, et al

2009, Yoda, et al 2010). Overall aberrant expression of CRLF2 was found in 12.5 % to 15

% of B-ALL that lacks typical chromosomal rearrangements (Hertzberg, et al 2010,

Mullighan, et al 2009a, Russell, et al 2009, Yoda, et al 2010) and in in 50–60 % of Down

Syndrome (DS) associated ALL, suggesting that CRLF2 overexpression is especially

relevant to tumorigenesis in patients with trisomy 21 (Hertzberg, et al 2010, Mullighan, et al

2009a, Yoda, et al 2010). Patients with CRLF2 rearrangements had extremely poor

treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3%

relapse-free survival at 4 years)(Harvey, et al 2010).

Mutations of NOTCH1, a transmembrane receptor-encoding gene that regulates normal T-

cell development, have been detected in in about 60% of T-ALL (Ferrando 2010). Early

studies on the prognostic significance of NOTCH1 activation in paediatric T-ALL showed

that NOTCH1 mutations are not associated with poor outcome and suggested that in fact

they could be associated with good prognosis (Beldjord, et al 2014, Breit, et al 2006,

Clappier, et al 2010, Ferrando 2010, Kox, et al 2010, van Grotel, et al 2006, Yuan, et al

2015). Similarly discrepant results were obtained in adult T-ALL patients where an analysis

by Asnafi and colleagues and Yuan et al. showed better rognosis for patients with NOTCH1

and/or FBXW7 mutations (Asnafi, et al 2009, Yuan, et al 2015) but this could not be

validated in a series of 88 patients treated in the MRC UKALLXII/ECOGE2993 protocol


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(Mansour, et al 2009) or by the Zhu et al who in fact noted that Chinese adult TALL patients

with mutated NOTCH1 had poorer survival compared with those with wild-type NOTCH1

(Zhu, et al 2006). Overall these studies seem to suggest that NOTCH activation is

associated with improved early therapeutic response. However, this early benefit translates

into improved overall survival only in some series, most probably as a result of differences

in therapy (Ferrando 2010).

Gene Expression Profiling

BCR-ABL like ALL: Mullighan and colleagues identified some patients with Ph-negative

ALL which had a gene expression profile almost identical to Ph+ ALL and which were

termed Ph-like ALL (Abutalib, et al 2009, Mullighan, et al 2007, Mullighan, et al 2009b). This

gene-signature has been noted in approximately 15% of cases of B-cell ALL. Genetic

alterations of activating kinases or cytokine receptor signaling are commonly observed in

addition to frequent deletions of IKZF1 (Abutalib, et al 2009, Boer, et al 2015, Mullighan, et

al 2007, Mullighan, et al 2009b). Some studies have found higher levels of MRD after

induction therapy while others have noted intermediate minimal residual disease levels at

the end of induction therapy (Boer, et al 2015). Similar to Ph-positive ALL, the 5-year DFS

in this population is estimated to be 60% (Alvarnas, et al 2015). Interstingly, in the Total

Therapy XV study, BCR- ABL1-like cases were responsive to increased treatment intensity,

showing similar outcomes to other B-cell ALL cases.

Early T-cell precursor acute lymphoblastic leukaemia (ETP – ALL): ETP – ALL

accounts for 12% of paediatric T-ALL. It is an aggressive leukaemia characterised by an

immature immunophenotype with lack of CD1a and CD8 expression and weak CD5 (<75%

lymphoblasts) expression (Rothenberg, et al 2008) and aberrant expression of myeloid and

stem cell markers (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65) on at least 25%

of lymphoblasts (Alvarnas, et al 2015). ETP – ALL has a distinct gene expression profile.

The long-term response to therapy is one of the worst among recognized high-risk forms of

childhood ALL, equal or inferior to that of BCR-ABL+ ALL or infant ALL with MLL gene

rearrangement (Coustan-Smith, et al 2009). In one study, the 10 year OS was 19%

compared with 84% in the non-ETP ALL (Coustan-Smith, et al 2009). Zhang et al have

suggested that the mutational spectrum in ETP-ALL is similar to myeloid tumours with high

frequency of activating mutations in the cytokine receptor and RAS signaling pathways

including NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, raising the possibility

that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL

(Zhang, et al 2012).


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Other Factors

Epigenetic changes in ALL: Epigenetic changes, including hypermethylation of tumor-

suppressor genes or microRNA genes and hypomethylation of oncogenes, are common

and have been identified in up to 80% of patients (Faderl, et al 2010, Garcia-Manero, et al

2009, Roman-Gomez, et al 2009, Roman-Gomez, et al 2007). Gabriel et al. revealed that

ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation and

TCF3-PBX1 and high hyperdiploidy was associated with hypomethylation (Gabriel, et al

2015). The clinical impact of alterations in epigenetic genes is just beginning to be

understood. Kaplan-Meier analysis shows that T-ALL expressing EZH2 had a lower

probability of disease-free survival (DFS) compared to T-ALL negative for EZH2 (23 % vs

100 %) (D'Angelo, et al 2015).

Pharmacogenetics and pharmacogenomics: Genome-wide analyses have identified

specific gene signatures which may be prognostically relevant when associated with drug

resistance e.g. polymorphism of genes metabolizing thiopurines, methotrexate, and

cytarabine all of which have been associated with variable treatment response and are a

mechanisms of drug resistance (Bassan and Hoelzer 2011). Rocha et al noted that the

glutathioneS-transferasel1(GSTM1) non-null genotype was associated with a higher risk of

recurrence, which was increased further by the thymidylate synthetase (TYMS) 3/3

genotype. Others have observed that hyperdiploid cells accumulate more methotrexate

polyglutamates as they possess extra copies of the gene encoding reduced folate carrier,

an active transporter of methotrexate. Hareedy et al found significant associations between

variants in genes coding for enzymes and transporters related to the 6-mercaptopurine

pathway and clinical outcomes as well as hematological toxicity (neutropenia,

agranulocytosis and leukopenia) in pediatric patients with acute lymphoblastic leukemia

(Hareedy, et al 2015). The membrane transporter P-glycoprotein, encoded by the ABCB1

gene, influences the pharmacokinetics of anti-cancer drugs. Gregers et al. noted statistically

significant association between ABCB1 polymorphisms, efficacy and toxicity in the

treatment of ALL (Gregers, et al 2015).

Table 2: Prognostic Factors in ALL

Abnormality Clinical Impact

Notes

Cyto-Genetics

Philadelphia Chromosome Poor prognostic 8-10% of adolescents. 15-30% adults. 50% elderly.


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indicator

MLL Rearrangements Poor prognostic indicator

Significance in adult patients using paediatric protocols? Immature immunophenotype, B-cell lineage, co-expression of myeloid antigens and high leukocyte counts.

t(1;19) [TCF3-PBX1] Poor prognostic indicator

30% of childhood ALL; Adverse prognosis can be overcome with intensive chemotherapy in adults and children, increased risk of CNS relapse (Jeha 2009). Adults treated with Hyper CVAD had better CRD and OS compared with all other patients (Garg, et al 2009).

t(12;21)[ETV6- RUNX 1] Favourable prognosis

Detectable in about 18-25% of children and 1-3% of adults.

iAMP of chromosome 21 Poor prognosis 2% of older children with B-ALL.

Hyperdiploidy Favourable prognosis

25-30% of cases; nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21; The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis.

Hypodiploidy Poor prognosis

5-6% of ALL patients; near haploid and low-hypodiploid have the worst prognosis.

Complex Karyotype Poor prognosis More than 5 chromosomal abnormalities.

Molecular Genetics

IKZF1 mutations Poor prognosis Most commonly present in BCR-ABL + ALL or BCR-ABL like ALL.

PAX5 No effect on treatment outcomes

30% of adults and paediatric patients.

CDKN2A/B Prognosis uncertain

CDKN2A – 29% of BCR-ABL positive patients CDKN2B – 25% of BCR-ABL positive patients

CRLF2 Extremely poor outcomes.

12.5% - 15% of B-ALL in patients lackingtypical rearrangements; 5060% down syndrome ALL. 50% concomitant mutations in JAK ½.

NOTCH Improved prognosis

Most common alteration in TALL; 60% of T-ALL Maybe associated with FBXW7 mutations – which may worsen survival.

Molecular Profiling

BCR-ABL Like ALL Poor prognosis 15% of B-cell ALL.


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May be responsive to treatment intensity

Early T-cell phenotype Poor Prognosis Distinct gene-expression profile. Lack of CD1a, CD8 and weak CD5 expression. Long-term response to therapy one of the worst in childhood ALL.

Other Prognostic Factors

Epigenetics Unknown prognostic significance

Up to 80% of patients; Unclear clinical implications. T-ALL expressing EZH2 had a lower probability of DFS compared to T-ALL negative for EZH2

Pharmacogenomics

Determine response to drugs and toxicities of ALL therapy. GlutathioneS-transferase 1 phenotype associated with higher risk of recurrence. Hyperdiploid cells accumulate more MTX and have increased toxicity. Variants in genes encoding enzymes and transporters related to the 6-MP pathways influence toxicity. Variants of ABCB1 (P-glycoprotein) maybe associated toxicity and efficacy.

Pre-treatment risk stratification

Over the past twenty years there has been continued debate regarding the risk stratification

of patients with ALL with different groups using the above clinical, immunophenotype,

cytogenetics and molecular tests to variably group patients into those that are standard risk,

high risk or very high risk of having a leukemia relapse (reviewed by Bassan and Hoelzer,

Table 3).

Given the poor prognosis of patients with Ph+ve ALL the initial risk stratification for all

patients should be based on the presence or absence of t(9;22)/BCR-ABL1. Amongst Ph-ve

patients the NCCN considers those with hypodiploidy (<44 chromosomes), t(v;11q23)/MLL

rearrangements or complex karyotype (≥5 chromosomal abnormalities) has high risk

(Alvarnas, et al 2015).


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Although the NCCN guidelines caution against using the WBC alone to classify patients as

high-risk (Alvarnas, et al 2015), studies using paediatric protocols in adolescents and young

adults have shown that age > 35-45 and a WBC > 30 for B-cell ALL and >100 for T-cell ALL

continue to be important risk factors. The role of cytogenetics and molecular mutations

however is less clear. Amongst Ph-ve patients there was no difference in OS amongst

standard risk and high risk patients receiving the paediatric GRAALL-2003 protocol

(Huguet, et al 2009). Similarly, Brandwein et al. noted that only age and WBC were

important variables for OS (Brandwein, et al 2014). In their most recent study the GRAALL

group noted that only Abn.14q32/IGH mutations were associated with poor EFS amongst

patients with B-cell ALL while del (17p), t(10;11)/PICALM-MLLT10 and complex karyotype

were assocuiated with poor event-free survival in T-cell ALL. Thus, given the increasing

use of paediatric protocols in adolescents and adults, the role of traditional pre-treatment

risk factors (Table 3) needs to be readdressed.

Table 3: Pre-treatment risk stratification factors in ALL patients treated with ‘adult’ chemotherapy regimens (Bassan and Hoelzer 2011)

Study Group

Age WBC Immunophenotype Cytogenetics Others Definition of Risk Group

GMALL (Hoelzer, et al 1988)

>35 >30 B-cell, CD10-ve CR>4 weeks

SR = 0 HR = 1-3

MSKCC (Gaynor, et al 1988)

>60 >20 B-Cell Ph+ CR > 5 weeks

SR = 0 IR = CR> 5 weeks plus 1 HR >1

CALGB (Larson, et al 1995)

>60 >30 Ph+, t(4;11) L3, Med - SR = 0-1 HR = 2-4

GIMEMA (Annino, et al 2002)

>30 >50 Ph+ Prephase

JALSG (Takeuchi, et al 2002)

>30 >30 Ph+ SR = 0 IR = 1 HR = 2/Ph+

MDACC (Kantarjian, et al 2004)

- >50 Ph+ ECOG 3-4, L2, d14 BM+

SR = 0-1 IR = 2-3 HR >3

GOELAMS (Hunault, et al 2004)

>35 >30 B-Cell Ph+, t(4;11), (t1;19) CR > 1c SR = 0 HR1 = 1-2 HR2 = 2-3

LALA (Thomas, et al 2004b)

- >30 Myeloid Markers Cd10 and CD20 negativity

Ph+, t(4;11), 11q23, (t1;19)

CR > 1c, CNS +

SR = 0 HR ≥ 1, Ph+, CNS+

PETHEMA (Ribera, et al 2005)

30-50 >25 Ph+, t(4;11), 11q23, (t1;19)

SR = 0 HR ≥ 1


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MRC-ECOG (Goldstone, et al 2008)

>35 >30 (B-Cell) >100 (T-Cell)

Ph+ SR = 0 HR ≥ 1

HOVON (Cornelissen, et al 2009)

- >30 (B-Cell) >100 (T-Cell)

Ph+, t(4;11), t(1;19) CR > 4 weeks

SR = 0 HR ≥ 1

GMALL (Gökbuget, et al 2007)

15 -55 >30 (B-Cell)

Pro-B Early/Mature T

Ph+, t(4;11) CR > 3 weeks

SR = 0 MRD-HR ≥1, MRD + VHR = Ph+

NILG (Bassan, et al 2009)

- >30 (B-Cell) >100 (T-Cell)

Pro-B Early/Mature T

Ph+, t(4;11), adverse cytogenetics

CR > 1c SR = MRD –HR = MRD + VHR = Ph+, t(4;11)+

SR – Standard Risk; HR – High Risk; IR – Intermediate Risk; VHR – Very High Risk; CR – Complete Remission; ECOG – Eastern Cooperative Oncology Group; Ph – Philadelphia; 1c – 1 cycle of chemotherapy; BM – Bone Marrow; MRD – Minimal Residual Disease

Table 4: Pre-treatment risk stratification factors in ALL patients treated with ‘paediatric’ chemotherapy regimens.

Study Group

Age WBC Immunophenotype Cytogenetics Others Definition of Risk Group

FRALLE 93 (Boissel, et al 2003)

>15 >50 t(9;22), t(4;11); Hypodiploidy, Tetraploidy, slow response to prednisone/chemotherapy

SR = 0 HR ≥ 1

DCOG (de Bont, et al 2004)

t(9;22), MLL rearrangements, slow response to induction

Not specified

DFCI - 91 – 01 (Barry, et al 2007)

<2 or >9

>20 T-cell Ph+, Mediastinal mass, CNS leukemia,

SR = 0 HR ≥ 1

DFCI – 95 – 01 (Barry, et al 2007)

<1 or >10

>50 T-cell Ph+, Mediastinal mass, CNS leukemia,

SR = 0 HR ≥ 1

PETHEMA (Ribera, et al 2008)

>30 - t(9;22), t(1;19), t(4;11), MLL rearrangements.

SR = 0 HR ≥1

GRAALL (Huguet, et al 2009)

>30 – B-cell

CNS involvement t(4;11) orMLL-AF4 fusion

transcript, t(1;19) and/or E2A-PBX1 fusion transcript, low hypodiploidy (30 to 39 chromosomes or DNA index 0.85),

SR = 0 HR ≥1


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near-triploidy (60 to 78 chromosomes or DNA index of 1.30 to 1.69). CsR and/or ChR, absence of CR after the first induction course, Ph+

DFCI (Storring, et al 2009)

≥35 >30 B-Cell >100 T- Cell

MLL Not specified

DFCI (Brandwein, et al 2014)

≥34 >30 B-Cell >100 T – Cell

Not specified

DFCI (DeAngelo, et al 2015)

≥35 B-Cell

≥35 B-Cell ≥100 T-Cell

MLL, Ph+, Not specified

SR – Standard Risk; HR – High Risk; IR – Intermediate Risk; VHR – Very High Risk; CR – Complete Remission; ECOG – Eastern Cooperative Oncology Group; Ph – Philadelphia; 1c – 1 cycle of chemotherapy; BM – Bone Marrow

Recommendations: All patients should be classified as having B-cell or T-cell ALL based

upon immunophenotyping results. Although many of the above noted prognostic factors are

beyond the scope of routine clinical laboratories, all patients, should undergo cytogenetic

evaluation and if unsuccessful FISH for the determination of the most clinically significant

abnormalities in particular BCR-ABL and MLL gene rearrangements. There is no convincing

evidence that other cytogenetic abnormalities or cell surface markers add to risk-

stratification when using paediatric or paediatric inspired protocols. Given the increasing

recognization of minimal residual assessments, all patients should have

immunophneotyping performed. This can be used to guide post induction treatment.

TREATMENT APPROACHES IN ALL

In general, the treatment of ALL is complex consisting of several different chemotherapy

cycles and, for some patients, stem-cell transplantation (Bassan and Hoelzer 2011). A

number of different approaches have been used as discussed below.

Adult Multidrug regimens

Starting in the 1960s, researchers at St. Jude Children’s Research Hospital designed

combination therapies of available anti-leukemia drugs that were delivered in a sequence of

extended courses of therapy (Faderl, et al 2010). Since then several multidrug

combinations have been developed centered on a vincristine, prednisone, and

anthracycline combination, with or without asparaginase and cyclophosphamide. This

concept was modified in children to the Berlin-Frankfurt Munster (BFM) ALL model and


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later, by Hoelzer et al., to adult ALL (Hoelzer, et al 1984, Hoelzer, et al 1988). Studies using

this approach are presented in Table 5. Despite variations in chemotherapy regimens,

variable use of allogeneic SCT or auto SCT the 5 year overall survivals ranged from 35 –

60% in various subgroups with induction mortality ranging of 5-10%.

Table 5: Outcomes of patients with adult multiagent chemotherapy

Study Group

Number Age Outcomes

Number Range Complete Remission

Mortality Overall Survival

CALGB (Larson, et al 1998)

197 Age< 30 = 94% Age< 30 = 1% Age< 30 = 69% at 3 years

Age 30 - 60= 85% Age 30 - 60= 8%

Age 30 - 60= 39% at 3 years

Age >60 - 39% Age >60 - 50% Age >60 - 17% at 3 years

Combined - 85% Combined - 9% Combined - 9%

Median = 36 months

Median = NR for those in CR

UKALL XII/ECOG 2993 (Rowe, et al 2005)

1521 91% 38% at 5 years

41 % at 5 years - Ph negative

25% at 5 years - Ph positive

GMALL (Hoelzer, et al 1988)

368 73.90% 11.10% Median = 27.5 months

5 Year 39% ± 6%

Median = 58.4 months in CR

5 year - 49% ± 7%.

MSKCC (Gaynor, et al 1988)

199 > 15 82% 9.50% Median - 30.7 months

5 year - 37%

Gimema (Annino, et al 2002)

794 12 - 59.9 82% 7% Median - 25 months

53% with salvage regimen

9 year survival - 27%


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Median time from 2nd randomization --> 48 months;

8 year survival from 2nd randomization --> 38%

Consolidation + Maintenance at 8 year = 38%

Just Maintenance = 37%

JALSG (Takeuchi, et al 2002)

263 15 - 59 78% 6% Age < 30 = 47.5% at 6 years; Age 30-60 = 21.4%

CR < age 40 --> OS not different between allo BMT vs. Chemotehray

CR - all ages --> OS not different between allo BMT vs. Chemotherapy

LALA – 94 (Thomas, et al 2004a)

922 72% 4% Standard Risk ALL --> Median - 37.8 months

Standard Risk ALL --> OS at 3 years 50%

Standard Risk ALL --> OS at 5 years 44%

High risk group (with allo SCT) --> median OS --> NR

High risk group (with allo SCT) --> 5-year --> 51%

Pethema (Ribera, et al 2005)

222 82% 6% Median OS --> 23 months

5 year overall survival --> 34%

Median OS --> 24 months (Ph-positive excluded)

5 year OS - 35% (Ph - positive excluded).

UK ALL (Goldstone, et al 2008)

1929 15 - 59 5 years was 39%

43% for patients that were Ph chromosome negative.

PH -ve: 5 years 53% with donor

Ph - ve: 45% years without donor

High risk - donor - 41%

High risk - no donor - 35%

Standard risk - donor - 62%

Standard Risk - no donor - 52%


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MDACC (Kantarjian, et al 2004)

288 15-92 92% 5% Median survival - 32 months

5 year survival - 38%

T-AlL 5 year survival - 48%

B- Cell ALL 5 year survival- 36%

The M.D. Anderson Model

The second treatment model pioneered at the M.D. Anderson cancer centre consists of

hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone,

alternating with high-dose methotrexate and cytarabine (Hyper–CVAD). The regimen

consists of a total of eight courses: four courses of hyper-CVAD (courses 1, 3, 5, and 7)

alternate with four courses of MTX and HIDAC (courses 2, 4, 6, and 8) (Garcia-Manero and

Kantarjian 2000, Kantarjian, et al 2000). In the original report the mortality was 6% and the

overall CR rate was 91%. The estimated median survival time was 35 months with a 5-year

estimated survival of 39%. Younger age was associated with better survival (age <30 had

estimated 5-year survival rate of 54% vs. age > 60 estimated 5-year survival rate of 25%). In an

updated report of patients aged 15 – 92 years old, the CR rate for patients age ≤30 years

was 99% and for patients age ≥60 years 80%, mostly because of a higher induction

mortality. (Kantarjian, et al 2004). The addition of rituximab was associated with CCR and

OS rates of 60% and 58%, respectively. Treatment with Rituximab–hyper-CVAD was

associated with improvement in 3-year CRD rates compared with hyper-CVAD (78% vs.

53%). In patients age < 60 improvements in 3-year OS (75% v47%; P 0=.003) rates

favoring rituximab were observed (Thomas, et al 2010).

The pediatric approach

A third approach that is rapidly being used worldwide is the adoption of pediatric protocols

or “pediatric inspired”regimens particularly for adolescents and young adults variably

defined as patients 15 to 35-45 years old (Bassan and Hoelzer 2011, Douer 2012). These

regimens have common features, including significantly increasing the non-

myelosuppressive agents such as vincristine and steroids, using much higher cumulative

doses of asparaginase for prolonged asparagine depletion, and administering very early

and extended intrathecal methotrexate together with high-dose systemic methotrexate.

Several studies from Europe and the USA reported that pediatric inspired approaches are

feasible in adolescents and adults (Table 6 and 7). These studies have shown that

prolonged administration of non-myelosupressive agents such as asparaginase, vinca

alkaloids and steroids is feasible and tolerated in a substantial portion of adults.


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Table 6: Outcomes of adolescents and young adults treated on paeditric protocols

Study Number Age Outcomes

Range Complete Remission

Mortality Overall Survival

Combined

LALA 94 vs. FRALLE- 93 (Boissel, et al 2003)

FRALLE - 77

15 - 20 FRALLE - 94% FRALLE - 5 year OS - 78% ± 11%; 5 year DFS - 72%, 5 year EFS - 67%; 5-year RFS --> 77%

LALA - 107

LALA - 83% LALA - 5 year OS - 45%; 5 year DFS- 49%; 5 year EFS - 41%; 5-year RFS --> 49%

B-CELL : FRALLE - 98%

B-CELL : LALA - 91%

DCOG vs. HOVON (de Bont, et al 2004)

DCOG – 47

DCOG - 15 - 18

DCOG - 98% DCOG - 15 - 18 - 4% (5 years TRM)

DCOG - 15 - 18 - 5 year OS - 79 % - 5; 5 year DFS - 71 %; 5 year EFS - 69%; 5 year CIR - 27%

HOVON - 44

HOVON - 15 -20

HOVON 15-18 - 91%

HOVON - 15-18 - 25% - (5 year TRM)

HOVON - 15-18 - 5 year OS - 38% ; 5 year DFS - 37 %; 5 year EFS - 34%; 5 year CIR - 55%

HOVON 19- 20 - 90%

HOVON - 19 - 20 21% (5 year TRM)

HOVON - 19 - 20 - 5 year OS - 45% ; 5 year DFS - 38 %; 5 year EFS - 34%; 5 year CIR - 50%

UKALL vs ALL97

(Ramanujachar, et al 2007)

UKALL - 67

15-17 ALL97 - 98% ALL97 - 5 year - 71%; 5 year - EFS - 69%

ALL97 - 61

UKALL - 94% UKALL - 5 year - 56%; 5 year EFS - 49%

DFCI (Barry, et al 2007)

DFCI - 51 15 - 18 94% 5 year OS - 81%; 5 year DFS - 78%

PETHEMA (Ribera, et al

Age 15 - 18 = 35

15 - 30 Age 15 - 18 --> 94%

Age 15 - 18 --> 1 out of 35 patients

Age 15 - 18 --> 6 years - 77%; 6 year EFS - 60%


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2008)

Age 18 - 30 = 46

Age 18 - 30 --> 100%

Age 18 - 30 --> 0/46 patients

Age 18 - 30 --> 6 years - 63%; 6 years - 63%

CCG vs. CALGB (Stock, et al 2008)

CCG - 197 16 20 CCG - 90% CCG - 7 year - 67%; 7 year EFS - 63%

CALGB - 124

16 - 20 CALGB - 90% CALGB - 7 year - 46%; 7 year EFS - 34%

CCG age 16 - 17 7 year EFS - 64%

CALGB age 16 - 17 7 year EFS - 55%

CCG age 18 - 20 7 year EFS - 57%

CALGB age 16 - 17 7 year EFS - 29%

CCG 1961 (Nachman, et al 2007)

262 16 -21 5-year overall survival - 77.5%; 5-year EFS - 71.5%

St. Jude XV (Pui, et al 2011)

45 on XV study

15 - 18 5-year overall survival - 87.9%; 5 yearsEFS - 86.4%

Table 7: Outcomes of adult patients using paediatric protocols

Study Number Age Outcomes Range Median Complete

Remission Mortality Overall Survival

GRAALL vs. LALA - 94 (Huguet, et al 2009)

GRAALL - 225 15 - 55 31 GRAALL - 93.5%

GRAALL - 6% GRAALL: OS 3.5 years --> 61%; EFS - 57%; CIR - 31%

LALA - 712 15 -55 29 LALA - 88% LALA - 4.5% LALA: OS 3.5 years --> 41%; EFS - 33%; CIR - 55%

GRAALL Age 15 - 45: OS 3.5 years - 64%; EFS - 58%

GRAALL Age 46 - 60: OS 3.5 years - 47%; EFS - 46%

DFCI (Storring, et al 2009)

DFCI - 85 18 - 60 37 < 35 = 98% 0% age < 35 3 year OS - 67%

> 35 yo --> 81%

8% age - 36-49 5 Year OS - 63%


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Combined - 89%

73% age >50 DFCI Age 18 - 35: 3 year OS - 83%; RFS - 77%

DFCI Age 35 - 60: 3 year OS - 52%; RFS - 60%

DFCI Age 18 - 35: 5 year OS - 80%

DFCI Age 35 - 60: 5 year OS - 50%

DFCI (Brandwein, et al 2014)

Age 17 - 60 --> 156

17 - 60 37 17 - 34 = 99%

Age 17 - 34 5 year OS = 80%

34 - 50 = 87%

Age 34 - 50 5 year OS= 50%

17 - 34 --> 73 50 - 60 = 90%

Age 50 - 60 5 year OS= 62%

34 - 50 --> 54 Combined - 93%

Combined 5 year OS - 66%; 5 Year DFS - 70%

50 - 60 --> 29 age < 34 and low WBC (n = 57): 85% (71–93%)

age <34 and high WBC (n = 15): 57% (28–78%)

age > 34 and low WBC (n = 73): 57% (44–68%)

age > 34 and high WBC (n = 10): 30% (7–58%)

DFCI (Martell, et al 2013)

51 60 - 79 65 BCR - ABL Positive --> 81%

20% BCR - ABL Positive --> 47.3 % at 5 years

(12>70) BCR - ABL Negative --> 71%

BCR - ABL Negative --> 40.5% at 5 years

Combined - 75%

DFCI (DeAngelo, et al 2015)

92 18-50 28 85% 1/92 patients 4 Year OS 67%; DFS - 69%; EFS - 58%

18-29 48 16/18 = 89% T-cell

Age 18 - 29: 4 Year OS - 68%; DFS - 70%; EFS - 55%

30-50 44 62/74 = 84 % B- cell

Age 30 - 50: 4 Year OS - 65%; DFS - 67%; EFS - 61%

T-cell ALL: 4 year OS - 76%; DFS - 87%; EFS - 77%

14/18 = 78% Ph - +ve

Ph -ve/B-cell: 4 Year OS - 68%; DFS - 66%; EFS - 57%

64/74 = 86% Ph - -ve

Ph +ve/B-cell: 4 year OS - 53%; DFS - 54%; EFS - 42%

WBC < 20: 4 year OS - 80

WBC > 20: 4 year OS - 45%


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DFCI (Fathi, et al 2014)

30 51-72 58 age > 50 = 67%

Age > 50 = 10% 62% at 1 year; < 20% at 3 years (based on survival curve)

PROVINCIAL RECOMMENDATIONS FOR TREATMENT OF ALL

Adolescents and Young Adults (AYA)

Adolescents and young adults have been variably defined as those aged 15 – 35 (40) years

old. A multitude of accumulating evidence suggests that this group of patients is best

treated with a pediatric or a pediatric inspired protocol. Ram et al. conducted a systematic

review of 11 studies that compared adult and pediatric protocols (Ram, et al 2012). Overall,

all-cause mortality, relapse rates and non-relapse mortality were lower in the pediatric

groups whereas CR rates and EFS were higher in the pediatric groups. It is important to

note that in many of these studies the median age ranged from 12.9 – 31 with only two

studies including patients over age 55 (Table 2).

Boissel and colleagues compared the outcomes of adolescents aged 15 – 20 years of age

treated with the adult LALA -94 vs. the peadiatric FRALLE-93 protocol (Boissel, et al 2003).

The LALA-94 trial included 100 patients (median age 17.9 years) and the FRALLE-93 trial

included 77 patients (median 15.9 years) 15- 20 years of age. The CR rate was significantly

higher in the FRALLE-93 trial (94 %) than the LALA-94 trial (83 %). The 5 year-EFS was

also worse in the LALA-94 trial (67 %) compared to 41 % in the FRALLE-93 trial. In the

Dutch study by de Bont and colleagues (de Bont, et al 2004) adolescents aged 10 – 20

years old were treated with the Dutch Childhood Oncology Group (DCOG) or adult Dutch-

Belgian Hemato-Oncology Cooperative Study Group (HOVON) adult protocol. For 15–18-

year-old adolescents, the 5- year event-free survival (EFS) when treated on pediatric

protocols was 69%, which is significantly higher than when treated on adult protocols (34%).

Stock and colleagues (Stock, et al 2008) assessed the outcomes of 321 adolescents and

young adults ages 16 – 20 years treated on either the paediatric Children’s Cancer Group

(CCG) protocols (N= 197, median age 16) or the CALGB group protocols ( N= 124, median

age 19). EFS at 7 years for the 25 CALGB patients aged 16 to 17 years was 55% which

was not different that the CCG patients (P =.49). Interstingly, 18-20 year olds treated with

the CALGB protocol fared significantly worse compared to 18-20 year olds treated with the

CCG protocol (7 year EFS 29% vs. 57%). More frequent and earlier CNS prophylaxis was


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incorporated into the CCG trials leading to a lower CNS relapse rate of 1.4% in the CCG

arm and 11 % in the CALGB arm.

In the most recent study the GRAALL study group evaluated the outcomes of 225 adult

patients aged 15 to 60 treated with the GRAALL-2003 protocol and compared the outcomes

with 712 patients aged 15 – 55 treated on the adult LALA-94 protocol. The overall CR rate

for the 225 GRAAL-2003 treated patients was 93.5% with 6% induction mortality. A

significantly longer OS was observed in patients aged 15 - 45 at 42 months when treated

with the GRAALL-2003 protocol. Storring and colleagues also assessed the outcomes of

adults treated with the modified DFCI paediatric regimen (Storring, et al 2009). Between

2000 and 2006 85 adults aged 18 -60 (median age 37) with BCR-ABL negative ALL were

treated. CR was achieved in 89% of cases. Of these, only age predicted for achievement

of CR. For patients aged ≤35 years, the complete response rate was 98% (41/42). For

patients age < 35 the median 3 year RFS was 77% and the median 3 year OS was 83%.

Recommendations for patients AYA: Nonwithstanding the potential barriers to

administration of a paediatric protocol, we recommend that all adolescents and young

adults patients be treated with a paediatric protocol. In Alberta, as in many other Canadian

centres, the standard regimen is the modified Dana Farber Cancer Institute (DFCI) protocol.

The original DFCI protocol is shown in Appendix A. The modified AL.4 protocol used in

National Cancer Institute of Canada ALL study is shown in Appendix B. The modified

protocol as used by the Princess Margaret Hospital (PMH) is shown in Appendix C.

Patients with co-morbidities, felt to be inelgigible for the full protocol, may require

modifications to mimimize toxicity.

Patients aged 35 (40) – 60

The use of pediatric protocols for the treatment of adolescents has inspired some groups to

explore the use of pediatric protocols in older adults however the data are not clear whether

this represents a significant difference relative to adult protocols. When using the paediatric

GRAALL-2003 protocol improvemnets in EFS and OS were noted at 42 months but only for

patients <age 45 (Huguet, et al 2009). Similarly, Storring and colleagues, when using a

modified DFCI paediatric regimen (Storring, et al 2009) for adults aged 18 -60 noted that the

complete response rate decreased with increasing age – from 86% for patients aged 36–49

years, to 73% for patients aged ≥ 50 years. In addition, there was a trend for an increase in

induction mortality by age: 0% for age ≤ 35 years, 8% for age 36–49 years, and 20% for

age ≥ 50 years. In addition, age >35 was significantly associated with inferior 3 year - OS

(83% vs. 52%). In an updated analsysis, Brandwein et al. assessed the outcomes of 156

adults with BCR-ABL negative ALL treated with a modified DFCI. Again, the CR rate


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decreased with increasing age. The CR rate amongst those age <34 was 99% while for

those age 34-50 the CR rate was 87% and those aged 50-60 was 90%. The 5 year OS

amongst patients aged <34 was 80% while those for patients aged 34-50 was 50% and

those aged 50-60 was 62%. Whether the decreased rate of survival seen in patients aged

34-50 was due to an increased use of allo- SCT in this age group is unknown. DeAngelo

and colleagues recently presented the results of their studies on the use of the DFCI

protocol for patients 18-50 years old. They found no statistically significant difference in the

outcomes for patients that were 18-29 years old or those that were 30-50 years old in terms

of 4 years DFS ( 70 vs. 67%), 4 year EFS (55 vs. 61%) or 4 year OS (68 vs. 65%).

Recommendations: These data suggest that although results in patients 30-60 years old

may be inferior to those in adolescents and young adults a use of a pediatric protocol may

benefit these patients with 3-5 year OS improving from an historic 35-40% to 50-70%. The

lower OS observed in some studies may be related to the preferential use of allo-SCT in

this cohort of patients. Nonetheless, we recommend that patients in this age range

continue to be treated with the DFCI protocol (Appendix A-C).

Patients aged over 60

The outcome of patients above age 60 treated with standard ALL chemotherapy has been

generally poor. Larson et al. using the CALGB 8811 protocol noted a 3 year OS of only 17%

with a median survival of only 1 month (Larson, et al 1995). Brandwein et al. noted similar

results when using a multitude of different adult based chemotherapy regimens (Brandwein,

et al 2005). In their study the 3 year OS was only 18.4%. Using the HyperCVAD protocol

Kantarjian et al. noted a 5 year OS of 17% (Kantarjian, et al 2004). Thus, it appears that

the majority of older patients with ALL will succumb to their disease although some older

patients may remain long-term survivors.

Whether a paediatric inspired regimen might benefit this older subset of patients was

investigated by Martell et al. who evaluated the outcomes of 51 patients treated with a

modified DFCI paediatric regimen at the PMH (Appendix B) (Martell, et al 2013).

Modifications from the full-dose DFCI 91-01 protocol during induction included the

substitution of dexamethasone for two 4-d pulses instead of daily prednisone, reduction of

the methotrexate dose from 4 g/m2 to 40 mg/m2, reduction in the asparaginase dose from

25 000 to 12 000 iu/m2 and removal of one vincristine dose. In the CNS prophylaxis phase

cranial radiation was removed. In the intensification phase seven cycles were given instead

of 10, the dexamethasone dose was reduced to 6 mg PO BID and the asparaginase

reduced to 6000 iu/m2 from 12500 iu/m

2. In the maintenance phase parenteral

methotrexate was switched to oral, and the dexamethasone dose was again reduced from 6


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mg/m2 BID to 6 mg PO BID. For patients who developed progressive grade ≥2 neuropathy,

intravenous vinblastine 10 mg was substituted for vincristine. Median age was 65 (60 – 79),

12 patients were over the age of 70, 35 patients were BCR-ABL negative and 16 were BCR

– ABL positive. CR rate was 75% for the entire cohort with 20% induction mortality.

Interestingly CR rate was 81% in BCR – ABL positive patients and 71% in BCR – ABL1

negative patients. The estimated 5-year OS was 40.5% for the BCR-ABL1 negative

patients, and 47.3% for the BCR-ABL1+ patients but there was no significant difference in

OS between these two groups. The estimated 5-year OS for BCR-ABL1 negative patients

presenting with low WBC (defined as <30 x 109/L for B-ALL or <100 x 10

9/L for T-ALL) was

44.3% respectively.

Recommendations: Given that some medically fit patients above age 60 may be cured of

ALL we recommend that eligible patients over age 60 be treated with curative intent

therapy. Although, there are no randomised studies, based upon data from the PMH group,

the modified DFCI provides superior results relative to historical controls. We therefore

recommend that the modified DFCI protocol be used for older patients with ALL (Appendix

C).

Patients over age 75 or or those age 60-75 with major co-morbidities precluding intensive

chemotherapy should be considered for palliative chemotherapy with corticosteroids and

vincristine +/- low- dose asparaginase. Such patients should continue to receive central

nervous system prophylaxis and may benefit from incorporatio of a ‘CNS phase’. Patients

not tolerating DFCI type ‘intensification’ may be moved directly to the DFCI ‘maintenance’

phase.

SPECIAL TOPICS IN THE MANAGEMENT OF ALL

Philadelphia Chromosome or BCR-ABL Positive ALL

Tyrosine kinase inhibitors (TKI’s) have become the standard of care for Ph+/BCR-ABL+

ALL and have led to improvements in the outcomes for all age groups (Bassan and Hoelzer

2011). The earliest TKI used in ALL was imatinib. Although, differing chemotherapy regimes

and schedules of imatinib have been assessed all showed improvements in overall survival

and reduction in the relapse rate (Delannoy, et al 2006, Lee, et al 2005, Wassmann, et al

2006). In thre first large study done by the French GRAAPH-2003 group, the combination of

matinib with induction and post-remission therapy (de Labarthe, et al 2007) led to higher

estimated OS (65% vs. 39%), lower CIR (30% vs. 49%) and improved DFS (51% vs. 31%)

at 18 months in comparison to historical controls treated with the LALA-94 protocol. An


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Italian study also reported 5-year OS of 38% and DFS of 39% with imatinib combined with

chemotherapy and again these results were significantly superior to a historical cohort

receiving chemotherapy alone (Bassan, et al 2010). In the large UKALL/ECOG2993 trial

investigators reported an improved post-induction CR rate with imatinib, improved 4 year

OS, EFS and a considerable reduction in relapse risk in the imatinib cohort (Fielding, et al

2014). Lastly, The M.D. Anderson group also combined imatinib with their standard hyper-

CVAD protocol and reported CR rates of 93% as well as results that were substantially

superior to their retrospective results with chemotherapy (Thomas, et al 2004a).

Second and third generation TKI’s have also been assessed in Ph+ ALL (Foa, et al 2011,

Jabbour, et al 2015, Ottmann, et al 2007a, Talpaz, et al 2006). Kim et al evaluated the

outcomes of Nilotinib with multiagent chemotherapy for adult patients with newly diagnosed

Ph+ve ALL. After achieving CR, subjects received either 5 courses of consolidation,

followed by 2-year maintenance with nilotinib, or allo-HCT. Amongst the 90 evaluable

subjects the CR rate was 91%, the 2-year RFS was 72% and the 2-year OS was 72%.

Unlike nilotinib, dasatinib has the ability to peneterate the CNS. Single agent dasatinib is

associated with short-term cytogenetic remission and median replase freee survivals of only

3.3 months. Studies of dasatinib in combination with chemotherapy, however, have been

associated with excellent response rates approaching 100% with minimal toxicity (Foa, et al

2011) (Abutalib, et al 2009). Ponatnib was evaluated in Ph+/BCR-Abl+ by Jabbour and

colleagues for patients with previously untreated Ph +ve ALL or those who had received

fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors.

Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously each

subsequent cycle of hyper-CVAD. Patients in complete remission received maintenance

with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by

ponatinib indefinitely. The 2-year EFS rate was 81% (95% CI 64-90) for the 37 patients

enrolled in the study (Jabbour, et al 2015).

Several investigators have combined TKI’s with paediatric based regimens used for the

treatment of adult patients. Thyagu et al. evaluated the outcomes of 32 ALL patients age

18-60 with Philadelphia positive ALL treated between 2001 and December 2008 with

imatinib. Ninety-four percent of patients (94%) achieved a CR and, of the 28 patients

proceeding to intensification therapy, 16 received a HSCT. The 3-year OS was 56% in the

transplanted group vs. 50% in the non-transplanted group (Thyagu, et al 2012). They also

noted increased rates of peripheral neuropathy, ileus, myopathies, deconditioning,

infections and abnormal liver enzymes in a high proportion of patients. Therfore, a number

of modifications were made to the original DFCI protocol (Thyagu, et al 2012). Using an

unmodified DFCI protocol, Deangelo et al. reported similar results amongst 18 Ph +ve


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patients treated with imatinib 11 of whom went on to transplant. The 4 year DFS was 54%

and 4 year OS was 53% (DeAngelo, et al 2015). Martell et al. also treated 16 BCR-ABL

positive patients aged 62 – 75 with a modified DFCI protocol together with imatinib. The CR

rate was 81% with an induction mortality of 19% and the estimated 5-year OS was 47.3%

for the BCR-ABL1+ patients (Martell, et al 2013).

More recently, monotherapy with TKI has been explored in several studies particularly in

elderly patients, who had an extremely poor outcome with chemotherapy alone. Ottmann et

al evaluated imatinib monotherapy in 27 patients older than 55 years of age, and observed

CR in 26 patients and a partial remission in the remaining patient (Ottmann, et al 2007b).

Vignetti et al. treated patients aged 61 to 83 years with Ph-+ ALL with a 45-day induction of

imatinib 800 mg daily plus prednisone (40 mg/m2 daily). Post-remission therapy was not

specified. All 29 assessable patients (100%) experienced a CR. At 12 months, the OS and

DFS probabilities were 74% and 48%, respectively (Vignetti, et al 2007). Chalandon et al.

conducted a randomised controlled trial comparing high dose imatinib combined with

reduced-intensity chemotherapy (Arm A) to standard imatinib/hyperCVAD (Arm B) in 268

adults with Ph+ve ALL. With fewer induction deaths, the CR rate was higher in arm A than

in arm B (98% vs 91%) whereas the MMolR rate was similar in both arms (66% vs 64%)

(Chalandon, et al 2015).

Foa et al. evaluated a similar regimen consisting of dasatinib (70 mg twice daily for 84 days)

together with prednisone 60 mg/m2 daily for 32 days plus two doses of intrathecal

methotrexate in untreated patients with Ph +ve ALL (Foa, et al 2011). Post remission

therapy was not defined with two patients receiving no further therapy, 19 continuing on TKI

only (16 dasatinib, 2 imatinib and 1 imatinib-dasatinib), 10 receiving intensive chemotherapy

with TKI, 4 having an auograft and 18 receiving an allogeneic HSCT. Overall, 53 patients

aged 24 – 76 were treated. A CR rate of 100% was seen with 92.5% by day 22 and no

deaths occurred during induction. Of the patients that had MRD measured by PCR 10

achieved levels lower than 10-3

and 8 had a complete molecular remission. Twenty-three

patients relapsed after completing induction with 12/17 relapsing patients showing a T315I

mutation. This trial demonstrated impressive remission rates for dasatinib and steroids only

but at the same time underscored the importance of adding intensive chemotherapy and/or

HSCT to maintain durable remissions.

Recommendations: All patients with Ph+/BCR-ABL+ve ALL should receive TKI. No TKI

has shown to be superior. As in most studies, we recommend the use of high dose imatinib

(600- 800 mg) as first line therapy. Patients with documented T315I BCR-ABL mutations

should be treated with ponatinib.


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Ph+/BCR-ABL+ve ALL patients under age 60-65 should be treated with a TKI together with

induction and post-remission therapy. Given data indicating increased toxicity of

asparaginase and vincristine with TKI the modified DFCI protocol as outlined in Appendix D

may be used.

Given recent studies showing higher remission rates and decreased mortality using

steroids, TKI +/- vincristine during induction, this combination may be preferred in some

cases, however, such patients require additional intensive chemotherapy to maintain a

durable remission (Appendix D).

Patients above age 65, particularly, those with co-morbidities, poor performance status or

ineligible for SCT should be treated with steroid and TKI +/- vincristine. Post induction

therapy should be individualized based upon patient tolerance. Patients should continue

TKI indefinitely.

Quantitattive BCR-ABL monitoring should be performed in all patients. Patients with

inadequate response or loss of response may be switched to an alternative TKI or require

additional treatments.

Role of allogeneic stem cell transplantation

Ph-/BCR-ABL- ALL

In the largest adult ALL trial to date (MRC-ECOG UKALLXII/E2993) patients in first

complete remission < 50 years were assigned to alloHCT if they had a compatible sibling

donor while others were randomized to consolidation/maintenance therapy for 2.5 years or

to autologous transplant and no further therapy. Patients were considered to be high-risk if

they had age >35, WBC >30,000/ mL for B-lineage or WBC >100,000/mL for T-ALL,

Philadelphia chromosome positivity, t(4;11), t(8;14), complex karyotype, low hypodiploidy or

triploidy. All other patients were considered standard risk. In a donor versus no-donor

analysis, patients with a sibling donor had improved OS than those with no donor (53% vs.

45%). In the standard risk group, the OS at 5 years was 62% for patients with a donor

compared to 52% for patients with no donor (P=.02). In contrast, for high-risk patients OS

was 41% for those with a donor vs. 35% for those without a donor (p=0.2) likely due to the

high nonrelapse mortality. The 10 year relapse rate was substantially lower in patients with

a donor (24% for standard risk and 37% for high-risk) versus those without a donor (49%

standard risk and 37% high-risk). (Goldstone, et al 2008). The Spanish PETHEMA group

reported similar findings in their cohort of high-risk patients defined as those with age 30-50

years old, WBC count >25,000/ mL, Ph +ve, t(4;11)/other 11q23 rearrangements, or t(1;19)


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(Ribera, et al 2005). In contrast, data from two French studies both reported that there was

an advantage for high-risk patients having a donor (Thiebaut, et al 2000, Thomas, et al

2004b).

A meta-analysis of 7 studies that included 1274 patients also noted improvements in overall

survival for patients with donors relative to those in the no-donor groups undergoing

allogeneic stem-cell transplantation. When only high-risk patients were analyzed, the

survival advantage was greater (Yanada, et al 2006). More recently, Gupta et al. conducted

a meta-analysis using individual patient data from a total of 20 trials that included a donor

no-donor comparison. Overall survival at 5 years was significantly better in the donor arm

(49.9% vs 42.7%, p=.003). However, because TRM was much higher in those age >35

both in the donor and no-donor arms there was no difference in OS in this age group.

Interestingly, unlike in previous studies and using standardized defintions of high/standard

risk, there was no evidence that survival differed by risk category. It was therefore

concluded that patients age<35 benefit from an allo-SCT regardless of risk group.

Furthermore, by reducing TRM, RIC has the potential to extend the benfit of allo-SCT to

those age>35.

Despite the above data, it remains unclear whether adult patients treated with paediatric

protocols would gain a benefit from SCT. In their study of a 156 BCR-ABL –ve patients

treated with the DFCI protocol the 5 year OS amongst patients receiving an allogeneic SCT

was 44% while for those not undergoing a SCT the survival was 74% with the difference

possibly related to transplant related mortality. Seftel and colleagues compared 422 Ph-ve

ALL patients aged 18-50 years with 108 patients reciving DFCI chemotherapy. Expectedly,

treatment related mortality was higher in those reciving a SCT (37% vs. 6%). At 4 years, the

incidence of relapse was similar for those receiving SCT and chemotherapy (24% vs. 23%),

however, both DFS and OS were improved for those receiving chemotherapy alone (40%

vs. 71% for DFS and 45% vs. 73% for OS) (Seftel, et al 2015). Dhedin and colleagues

further assessed the the role of allogeneic stem cell transplantation in Ph-ve ALL adult

patients with at least 1 conventional high-risk factor treated with the paediatric inspired

GRAALL 2003 and 2005 protocols (Dhedin, et al 2015). In all, 522 patients age 15 to 55

years old were candidates for SCT in first complete remission. Among these, 282 (54%)

received a transplant in first complete remission while 240 (46%) did not. As with previous

studies, the lower CIR observed in the SCT was counterbalanced by a higher NRM. When

analyzing SCT in CR1 as a time-dependent event RFS and OS were not significantly

improved in the SCT cohort. No significant effect of SCT on RFS was noted in patients

younger or older than age 45 or on any prespecified baseline risk factor. RFS and OS were

significantly longer, however, in patients who presented with morphologic poor early BM


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blast clearance or in late CR patients. Furthermore, SCT was associated with longer RFS

in patients with postinduction minimal residual disease (MRD) >10-3

but not in good MRD

responders.

Recommendations: These data suggest that most patients with Ph-/BCR-ABL -ve ALL

treated with a paediatric protocol will not benefit from an allogeneic SCT, we therefore

recommend, that such patients not proceed with allo SCT. Given that patients with MLL

rearrangements remain a high-risk group with pediatric based regimens (Storring, et al

2009) SCT may be a reasonable recommendation for younger ALL patients with this

abnormalities. Higher WBC and failure to achieve a complete remission after the first

induction cycle are generally considered high risk features. Transplantation is also

recommended for these patients.

Although, emerging data suggests that patients that are MRD +ve may benefit from an

allogeneic SCT, the role of MRD in guiding SCT decision is not well defined. All patients

with persistent MRD positivity, however, should be considered for transplant. It is not clear,

however, whether patients with a high-risk feature at baseline who achieve MRD negativity

after induction therapy require a transplant thus this should be an individualized decision.

Role of SCT in patients with Ph/BCR-ABL positive ALL

The UKALLXII/ECOG 2993 study evaluated the outcome of allo-SCT in Ph+/BCR-ABL+

patients younger than 55 years of age achieving complete remission with an adult ALL

protocol. Of the 267 patients, 76 (28%) proceeded to alloHSCT in first CR (45 with cells

from a sibling and 31 with cells from a MUD) whereas 86 received chemotherapy alone.

The median EFS for all 267 Ph+ patients was 9 months and the median OS was 13 months.

At 10 years, OS was 39% for sib alloHSCT, 31% for MUD alloHSCT, and 13% for

chemotherapy. Comparing the outcome after any alloHSCT with the outcome after

chemotherapy alone, OS, EFS, and RFS were all significantly superior for patients receiving

any alloHSCT over those receiving chemotherapy alone. Whereas the leading cause of

death in chemotherapy treated patients was relapse, the leading cause of death after

transplantation was TRM, which was 27% after sib HSCT and 39% after MUD HSCT

(Fielding, et al 2009).

Lmited information is available comparing adult Ph+ patients receiving a paediatric protocol

with those undergoing an allo SCT. Thyagu et al. treated 32 patients with Ph+ ALL with

DFCI protocol together with imatinib. Of the 28 patients proceeding to intensification

therapy, 16 underwent an allo-SCT. The 3 year OS was 56% in the transplanted group and

50% in the non-transplanted group (Thyagu, et al 2012). Recent studies in the pediatric


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setting noted that children receiving intensive multidrug chemotherapy with imatinib had a

survival higher than 80% compared to 35% in historical controls, and even better than

related or unrelated HSCT (>60%). In the recent US Children’s’ Oncology Group study, the

outcomes at 3 years were not significantly different for those treated with chemotherapy

plus imatinib compared with those assigned to alloHSCT (Schultz, et al 2014). However,

limited patient numbers precluded rigorous subgroup analysis.

Recent studies in adults are also demonstrating the impact of molecular status on relapse

risk in Ph+ ALL. The MD Anderson Cancer Center (Ravandi, et al 2013) found that

molecular positivity at a variety of time points was associated with a significantly higher

cumulative incidence of relapse. The French GRAAPH study (Chalandon, et al 2015) found

that the benefit of allo-HCT in CR1 was restricted to patients who were molecularly positive

post-induction chemotherapy. In contrast, a study using nilotinib plus chemotherapy (Kim, et

al 2015) found that overall survival was superior in patients undergoing HSCT regardless of

MRD status; however, 60% of patients achieving molecular negativity remained free of

relapse at 30 months without a transplant. Taken together, these data suggest that some

patients who achieve MRD negativity early on may remain relapse-free with continuing

chemotherapy + TKI, potentially sparing them the toxicity associated with a higher risk

transplant.

Recommendations: Despite growing data from the paediatric literature questioning the

need for alloSCT in the TKI era, we recommend that all eligible Ph/BCR-ABL positive

patients with an HLA matched donor be referred for alloSCT. If an HLA matched related or

unrelated donor is unavailable, patients achieving molecular negativity by PCR can be

continued on post-induction chemotherapy + TKI indefinitely without a transplant. For

patients with persistent molecular positivity, consideration should be given to switching to a

more potent TKI such as dasatinib, and consideration should also be given to alternative

donor alloSCT (e.g. haploidentical related or cord blood), due to the high risk of relapse.

Role of Cranial Radiation

CNS involvement at the time of presentation is uncommon in adults with ALL being reported

in 5% to 7% of patients (Jabbour, et al 2010). Before the use of central nervous system

(CNS) prophylaxis, the CNS was the most frequently reported site of initial recurrence in

children with ALL, accounting for up to 75% of cases (Jabbour, et al 2010). Similarly,

amongst adults with ALL, CNS recurrence occurs in approximately 30% of those in a

hematological remission. (Bassan and Hoelzer 2011)Aur et al. published the results of St.

Jude Total Study V in 1971 demonstrating that 2,400 cGy cranial radiation and five doses

of intrathecal methotrexate greatly diminished CNS relapse resulting in the first cures of


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childhood ALL (Winick 2015). Subsequently, widespread incorporation of CNS prophylaxis

led to the largest single “step up” in 10-year survival from approximately 20% to 60%

among those diagnosed from 1970 to 1972 versus 1972 to 1975 (Winick 2015). Given the

significant risk of CNS relapse current adult and paediatric protocols incorporate CNS

prophylaxis with both systemic and intrathecal chemotherapy and/or radiation. CNS

prophylaxis may be incorporated into induction, consolidation, maintenance or in all three

phases of treatment.

Cranial irradiation is an effective form of CNS-directed treatment, but its effectiveness is

offset by substantial rates of secondary neoplasms, endocrinopathies, growth impairment,

neurocognitive dysfunction, and neurotoxic effects. Amongst the paediatric population, Pui

et al. found that prior cranial radiation was associated with a 20.9% cumulative risk of

second neoplasms at 20 years in addition to a higher mortality and a greater likelihood of

being unemployed when compared to an age matched general population (Winick 2015).

Subsequently, multiple trials compared CNS prophylaxis using intrathecal chemotherapy

and/or intravenous methotrexate with cranial radiation. These trials demonstrated the

efficacy of IT/IV therapy without cranial radiation leading to use of cranial irradiation for

patients at especially high risk of CNS relapse and elimination of cranial radiation for infants

or very young children, irrespective of their presenting features (Jeha and Pui 2009). More

recently, in the St Jude Total XV and Dutch Childhood Oncology Group acute lymphoblastic

leukaemia-9 protocols cranial irradiation is replaced by triple intrathecal chemotherapy with

methotrexate, hydrocortisone, and cytarabine for all newly diagnosed patients. The 5 year

cumulative risk of isolated CNS relapse was 2·7% with the St Jude and 2·6% with the Dutch

Childhood Oncology Group protocol similar to the relapse rates observed with prophylactic

cranial irradiation (1·5–4·5%). In the largest study to date Vora and colleagues (Vora, et al

2016) obtained data on 16623 patients aged 1 to 18 years old treated between 1996 and

2007 by 10 coperative groups. In their analysis cranial radiation was associated with a

reduced risk of relapse but only in patients with overt CNS disease at time of presentation.

In other patients there was no difference in CNS relapse between those that received and

did not receive cranial radiation. These data suggest that, in the context of a paediatric

protocol prophylactic cranial irradiation can be safely omitted in patients in the context of

effective intrathecal and systemic chemotherapy.

Recommendations: Given the above data we recommend that cranial irradiation not be

used for CNS prophylaxis in patients receiving a pediatric protocol such as the DFCI if

intrathecal or systemic chemotherapy is used.


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Role of MRD assessments in the management of patients with ALL

Based upon the paediatric literature a number of studies over the past 15 years have

explored the role of minimal residual disease (MRD) in adult patients with ALL. Most of

these have suggested that MRD may be the single most important factor predicting clinical

outcomes (Faderl, et al 2010). Most of our current knowledge about MRD derives from

studies in childhood ALL. However, a number of investigators have described in differences

in pattern and dynamics of clearance of MRD between adult and childhood ALL as well as

between B- and T- cell ALL. Foroni et al. noted that MRD decreased faster in children than

in adults particularly in the first 6 months of CR (Foroni, et al 1997) while Parekh et al. noted

that MRD clearance was slower with T-ALL (Parekh, et al 2015). In the adult setting, a

study by Bruggemann and colleagues measured MRD at 9 different time points ranging

from 11 days post-induction upto to 52 weeks post induction (Bruggemann, et al 2006).

Interestingly, only a minority of patinets were had undectatable MRD at day +11 while at 6

weeks approximately 50% had undectable MRD suggesting that at early time points the

majority of adults have detectable MRD.

Several groups have explored the prognostic value of MRD in adult ALL patients.

Bruggman and colleagues noted that a combination of MRD measurements at day 11, day

24 and 16 weeks could classify patients into those with a low likelihood of ALL relapse

(MRD –ve at day 11 and day 24), high likelihood of relapse (MRD + at week 16) or

intermediate risk of relapse (all others) (Bruggemann, et al 2006). Similar findings were

noted by Bassan and colleagues who measured MRD at week 10 and week 22 post

induction chemotherapy (Bassan, et al 2009). Regardless of whether they were SR, HR or

VHR by traditional criteria, patients who were MRD negative had significantly better DFS

relative to those that were MRD positive.

Whether treatment intensification can negate the negative effects of residual diseae has

also been investigated by several investigators. Bassan and colleagues assessed MRD at

week, week 16 and week 22 (Bassan, et al 2009). Patients that were MRD negative or with

unknown MRD status but standard risk by traditional criteria received maintenance

treatment only while patients that were MRD positive or with unknown MRD but high risk or

very high risk by traditional criteria received an allogeenic SCT or autologous blood stem

cell harvest/reinfusion with subsequent maintenance therapy. MRD positive patients

receiving either SCT or intensive chemotherapy had improvements in DFS with no

significant difference between those that received SCT and intensive chemotherapy.

Moreover, patients who became MRD negative had improved DFS relative to those who

remained MRD positive. Similar, results were noted by Gokbuget et al. where 5 year CCR

improved for MRD positive patients undergoing an allo SCT (Gokbuget, et al 2012). Riberia


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and colleagues noted that allo SCT in MRD –ve patients was unnecessary and

counterproductive as it led to worse DFS and overall survival both in the whole series and

an intention to-treat-analysis (Ribera, et al 2014). Although Dhedin and colleagues, when

using a paediatric protocol, found no utility overall for early SCT, they did note that patients

who were MRD +ve and received a SCT faired better in both RFS and OS when

transplanted(Dhedin, et al 2015).

Although chemotherapy and alloSCT can both lead to an MRD negative state both can be

associated with significant morbidity and mortality. Blinatumomab is a bispecific antibody

that was first investigated in adult B-precursor ALL patients in hematological remission but

having detectable MRD despite induction/consolidation or those with molecular relapse after

at least three cycles of chemotherapy. Patients received up to two cycles of blinatumoma

induction and those achieving molecular complete remission received up to three additional

consolidation cycles. Of 20 evaluable patients (out of 21), 16 (80%) responded with

negative MRD at the end of the first cycle, including 12 patients who had persistent MRD

after previous induction and consolidation including patients with t(4;11) translocation or

with Ph+ ALL. After a median observation time of 405 days, 16 out of 20 patients were in

an ongoing hematologic remission. Eight patients proceeded to allogeneic HSCT with no

differences in RFS for those patients proceeding to transplant versus those who did not:

65% versus 60%, respectively (Topp, et al 2011). In an open label multicentre phase II

study of patients in haematological remission but who remained MRD positive after three

chemotherapy cycles blinatumomab was able to induce a complete MRD negative state in

approximately 80% of patients regardless of gender, age or initial MRD(Goekbuget, et al

2014, Gökbuget, et al 2015). Thus, although, blinatumomab provides an chemotherapy

free approach to reducing MRD the long term impact of this strategy remains unknown.

Whether the impact of MRD on clinical outcomes is similar with a paediatric porotol was

investigated by Beldjord et al. The assessed 423 adult patients with Ph-negative ALL

treated with a paediatric protocol (Beldjord, et al 2014). MRD1 was evaluated at 6 weeks

after induction initiation and MRD2 after the first consolidation phase i.e. 12 weeks after

induction initiation. As expected, MRD2 and MRD1 levels strongly correlated in this cohort.

Overall, 265 patients achieved a MRD response at MRD1, 57 achieved it at MRD2 only,

and 49 did not achieve it at either time-point. At 5 years, CIR was estimated at 24.7% in

patients who reached a MRD level lower than 10-4 at MRD1, while it was 56.0% in those

who reached this level at MRD2 only or never reached it, respectively. The value of

traditional risk factors was examined in this population of patients treated with a pediatric-

inspired protocol, first in univariable analysis and then in multivariable analysis, against

MRD1 response. Based on multivariate analysis, MLL gene rearrangement, IKZF1 gene


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deletion, and MRD1 level ≥10-4 were significant factors in BCP-ALL patients whereas a

high-risk genetic profile and MRD1 level ≥10-4 were significant in T-ALL patients. Based on

these results, high-risk patients could be defined as patients with MRD1 level ≥10 -4; and/or

unfavorable genetics, defined as: 1) t(4;11) translocation or other MLL gene rearrangement

and/or IKZF1 gene deletion in BCP-ALL; and 2) no NOTCH1/FBXW7 mutation and/or N/K-

RAS mutation and/or PTEN alteration in T-ALL patients. MRD level seemed to be the

predominant predictor in BCP-ALL patients with the risk further refined by genetic features.

In contrast, in T-ALL patients the oncogenetic classification seemed to be the predominant

predictor, further refined by MRD response. In both lineages, patients with high-risk genetic

characteristics and poor MRD1 response experienced a worse outcome. Without SCT

censoring the single conventional factor that remained of significant value in this study was

the presence of MLL rearrangement, including the recurrent t(4;11) chromosomal

translocation.

Recommendations: Taken together these data suggest that the evaluation of MRD

provides independent prognostic information in children and adults with ALL. There is

convincing evidence in pediatric and adult ALL that a high level of MRD at the end of

induction therapy is associated with a higher relapse rate (Abutalib, et al 2009).

Furthermore, the continuous detection of high levels of MRD during consolidation and

maintenance therapy, the re-emergence, or increase in MRD levels all seem to herald

relapse. In contrast, declining or negative MRD results are associated with a favorable

prognosis. We therefore recommend that all patients have MRD ascertained at the end of

induction and following consolidative chemotherapy. Patients with persistent MRD should

be considered for treatment intensification with allo-SCT, additional chemotherapy or

blinatumomab treatment. However, the best time-point for clinical decision makine is

unknown.

Supportive Care Supportive care remains an important aspect of the care of the ALL patient throughtout all

phases of treatment. All patients should be transfused packed red blood cells as per

institutional guidelines and particularly for symptomatic anemia. Similarly, platelets should

be transfused to maintain platelet counts > 10 x 109/L. All patients receive prophylaxis, and

if indicated, treatment for tumour lysis syndrome with allopurinol and/or rasburicase during

induction therapy. Dissemintaed intravascular coagulation should be treated aggressively

with clotting factor replacement. Patients with signs and symptomns of febrile neutropenia

should be managed with broad spectrum antibiotics and intensive care support as


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necessary. As corticosteroids may mask fevers in such patients, broad spectrum antibiotics

should be instituted for clinical suspicion of sepsis (e.g. unexplained hypotension) even in

the absence of fever. Antifungal prophylaxis against Candida is recommended during

induction due to the risk of Candida septicemia.

Clinicans should be continuously aware of both the short- and long-term consequences of

potential toxicities associated with specific agents used in ALL and use prevention,

treatment or dose adjustment as necessary:

1. Steroids may lead to hyperglycemia or gastrointestinal reflux in the acute setting

whereas patients are at risk for osteoporosis, osteonecrosis or avascular necrosis and

pnueumocystis jirvocii infections with long-term use. Patients should be treated with

calcium, vitamin D, bisphosphonates and pneumocystis prophylaxis.

2. Asparaginase has been associated with hypersensitivity reactions, hyperglycemia,

coagulopathy, hepatotoxicity, and/or pancreatitis. Liver function tests should be

performed regularly and patients should be monitoried for clinical signs/symptoms of

pancreatitis. Anticoagulation prophylaxis with adjusted dose low-molecular weight

heparin during the intensification phase of the DFCI protocol should be considered due

to the high risk of VTE (25-30%), and patients should be closely monitored for clinical

signs of VTE.

3. Vincristine can cause neuropathies including peripheral neuropathy and ileus. Patients

with progressive peripheral neuropathy should be switched to vinblastine (6mg/m2 to a

maxiumum of 10mg/dose).

4. Other drugs: Doxorubicin may lead to cardiomyopathy while methotrexate can lead to

hepatotoxicity. Patients requiring tyrosine kinase inhibitors may encounter a variety of

general and TKI specific side-effects.

Follow-up For patients with ALL the highest risk of relapse remains within the first two years following

completion of chemotherapy. Patients should have monthly blood work for the first 2-3

years and every three months thereafter until 5 years. Patients with concerning laboratory

features or clinical signs and symptoms for ALL relapse should be evaluated with repeat

bone marrow studies.


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APPENDIX A

Original DFCI protocol 91-01 (used for paediatric patients)(Barry, et al 2007)

Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 1.5 mg/m2/dose IV, maximum

2 mg, days 3, 10, 17, 24; prednisone 40 mg/m2/d IV/PO for 28 days; doxorubicin 30 g/m2/dose IV, days 1 and 2 methotrexate 4 g/m2 IV for one dose on day 3 IT cytarabine, dosed by age, one dose on day 0 IT cytarabine, dosed by age, one dose on day 17

CNS Therapy 3 Weeks SR girls: IT methotrexate/cytarabine for 4 doses during 2 weeks, then every 18 weeks SR boys and all HR patients: cranial XRT 18 Gy, randomly assigned to hyperfractionated (0.9 Gy bid) or conventional (1.8 Gy daily) with IT methotrexate/cytarabine for 4 doses during 2 weeks

Intensification Every 3 weeks for 30 weeks

SR: vincristine (2 mg/m2 IV every 3 weeks, maximum 2 mg); dexamethasone 6 mg/m2/d PO for 5 days; methotrexate 30 mg/m2 IV or IM every week; mercaptopurine,randomly assigned to high-dose 1,000 mg/m2 IV for 20 hours, weeks 1 and 2) or conventional 50 mg/m2/d PO for 14 days Asparaginase, randomly assigned to PEG 2,500 IU/m2 IM every 2 weeks for 15 doses or E. coli 25,000 IU/m2 IM every week for 30 doses HR: same as SR patients except dexamethasone 18 mg/m2/d PO for 5 days; no methotrexate; doxorubicin 30 mg/m2 IV every 3 weeks, to total cumulative dose 360 mg/m2, randomly assigned to continuous infusion during 48 hours versus IV bolus

Continuation Every 3 weeks until 2 years of continuous complete remission

SR: vincristine 2 mg/m2 IV every 3 weeks, maximum 2 mg; dexamethasone 6 mg/ m2/d PO for 5 days; methotrexate 30 mg/ m2 IV or IM every week; mercaptopurine 50 mg/m2/d PO for 14 days HR: same as SR patients except dexamethasone 18 mg/m2/d PO for 5 days


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APPENDIX B

Canadian NCIC DFCI AL.4 Trial (DeAngelo, et al 2015)

Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 2 mg weekly, days 1, 8, 15 and 22

Prednisone 40 mg/m2/day, days 1 –28 Doxorubicin 30 mg/m2/dose, days 1and 2 Methotrexate 4 g/m2 (8–24 h after doxorubicin) with leucovorin rescue on day 3 E coli L-asparaginase 25 000 IU/m2 IM × 1 dose, day 5 IT cytarabine 50 mg, day 0 (prior to initiation of systemic therapy) IT methotrexate (12 mg)/cytarabine (40 mg) /hydrocortisone (50mg), days 15 and 29

CNS Therapy 3 Weeks Vincristine 2 mg × 1 dose 6-mercaptopurine (6-MP) 50 mg/m2/day orally, × 14 consecutive days Doxorubicin 30 mg/m2 × 1 dose IT methotrexate/cytarabine twice weekly × 4 doses Cranial radiationc


Every 3-week cycles: Vincristine 2 mg, day 1 Dexamethasone 18 mg/m2/day b.i.d., orally, days 1 –5 Doxorubicin 30 mg/m2, day 1 of each cycle to a (cumulative dose 300 mg/m2) 6-MP 50 mg/m2/day orally × 14 consecutive days E. coli asparaginase Individualized dosing: 12 500 IU/m2/dose (starting dose)d Methotrexate 30 mg/m2 i.v. or IM weekly, 1 day after asparaginase (no weekly methotrexate until doxorubicin completed). IT methotrexate/cytarabine/hydrocortisone at start of a cycle IT therapy consisting of methotrexate/cytarabine at start of a cycle every 18 weeks

Continuation Every 3 weeks for 72 weeks

Same as intensification except no asparaginase and dexamethasone dose reduced to 6 mg/m2/day


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APPENDIX C

Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Storring, et al

2009) for Philadelphia Chromosome/BCR-ABL1 negative adult patients aged

<60 years old

Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 2 mg weekly IV, days 1, 8, 15 and 22

Prednisone 40 mg/m2/day PO, days 1 –28 Doxorubicin 30 mg/m2/dose IV, days 1and 2 Methotrexate 4 g/m2 IV (8–24 h after doxorubicin) with leucovorin rescue on day 3 E coli L-asparaginase 25 000 IU/m2 IM × 1 dose, day 5 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a, days 1, 15, 29

CNS Therapy 3 Weeks Vincristine 2 mg IV × 1 dose day 1b

6-mercaptopurine (6-MP) 50 mg/m2/day PO, × 14 consecutive days (day 1 -14) Doxorubicin 30 mg/m2 IV × 1 dose day 1 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a twice weekly × 4 doses


Vincristine 2 mg IV, day 1b

Dexamethasone 9 mg/m2 BID PO, days 1 –5 Doxorubicin 30 mg/m2 IV, day 1 of each cycle to a (cumulative dose 300 mg/m2) 6-MP 50 mg/m2/day PO × 14 consecutive days (days 1-14) E. coli asparaginase 12 500 IU/m2/dose IM day 1, 8 and 15 Methotrexate 30 mg/m2 i.v. or IM weekly, 1 day after asparaginase i.e. day 2, 9, and 16 (after maximum doxorubicin dose completed)

c.

IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a start of a cycle every 18 weeks


Same as intensification except no asparaginase Dexamethasone dose reduced to 6 mg/m2 BID PO Methotrexate 30 mg/m2 i.v. or IM weekly days 1, 8 and 15

c


a at start of a cycle every 18 weeks

aMethotrexate (12mg)/cytarabine (40 mg)/hydrocortisone (15 mg);

bVinblastine 10 mg may be substituted for unacceptable

vincristine toxicity; cMethotrexate may be administered PO


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Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Martell, et al

2013) for Philadelphia Chromosome/BCR-ABL1 negative adult patients aged

>60 years old

Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 2 mg IV weekly, days 1, 8, 15

Dexamethasone 40 mg PO, days 1-4, 9 –12 Doxorubicin 30 mg/m2/dose IV, days 1and 2 Methotrexate 40 mg/m

2 IV, day 3

E coli L-asparaginase 12000 IU/m2 IM, day 4

IT Cytarabine 70 mg, day 1 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a, day 15

CNS Therapy 3 Weeks Vincristine 2 mg IV × 1 dose day 1b

6-mercaptopurine (6-MP) 50 mg/m2/day PO × 14 consecutive days (day 1 -14) Doxorubicin 30 mg/m2 IV × 1 dose day 1 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a twice weekly × 4 doses



Dexamethasone 6 mg BID, orally, days 1 –5 Doxorubicin 30 mg/m2 IV, day 1 6-MP 50 mg/m2/day orally × 14 consecutive days (days 1-14) E. coli asparaginase 6000 IU/m2/dose IM day 1, 8 and 15 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a start of a cycle every 18 weeks



Dexamethasone 6 mg PO BID, days 1 –5 6-MP 50 mg/m2/day PO × 14 consecutive days (days 1-14) Methotrexate 30 mg/m2 PO weekly days 1, 8 and 15 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

a at start of a cycle every 18 weeks

aMethotrexate (12mg)/cytarabine (40 mg)/hydrocortisone (15 mg);

bVinblastine 10 mg may be substituted for unacceptable

vincristine toxicity


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APPENDIX D

Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol for

Philadelphia Chromosome/BCR-ABL1 positive adult patients aged <60 years

old (Thyagu, et al 2012)

Phase of Therapy Time Period Chemotherapy Induction* 28 Days Vincristine 2 mg IV, days 1, 8

a

Vinblastine 10 mg, day 15a

Prednisone 10 mg/m2 PO QID, days 1 –28a

Doxorubicin 30 mg/m2 IV, days 1 and 2 Methotrexate 4 g/m2 IV day 3 (8–24 h after doxorubicin) with leucovorin rescue on day 4

a

IT cytarabine 70 mg, day 1a


b, days 15, 28

a

Imatinib 600 mg, days 1-28a

CNS Therapy* 3 weeks Vinblastine 10 mg IV × 1 dose day 1a

6-mercaptopurine (6-MP) 50 mg/m2/day PO, × 14 consecutive days (day 1 -14) Doxorubicin 30 mg/m2 IV × 1 dose day 1 IT therapy consisting of methotrexate/cytarabine /hydrocortisone

b twice weekly × 4 doses

Imatinib 400 mg daily, days 1-21a

Intensification* Every 3 weeks for 30 weeks

Vinblastine 10 mg IV, day 1a

Dexamethasone 9 mg/m2 BID PO, days 1 –5 Doxorubicin 30 mg/m2 IV, day 1 of each cycle to a (cumulative dose 300 mg/m2) 6-MP 50 mg/m2/day PO × 14 consecutive days (day 1 -14) Methotrexate 30 mg/m2 i.v. or IM weekly, days 1,8 and 15 (after 300 mg/m2 doxorubicin dose completed)

c.


b every 18 weeks

Imatinib 400 mg, days 1-21a

Continuation* Every 3 weeks for 72 weeks


Dexamethasone 6 mg/m2 BID PO, days 1-5

6-MP 50 mg/m2/day PO × 14 consecutive days Methotrexate 30 mg/m2 i.v. or IM weekly days 1, 8 and 15

c


b at start of a cycle every 18 weeks

Imatinib 400mg, days 1-21a

Long Term Maintenance Imatinib 600 mg daily *

Recent modifications from published protocol include elimination of asparaginase from induction and intensification, elimination of cranial radiation from CNS phase of treatment and switch from vincristine to vinblastine in CNS phase, intensification and continuation therapy;

aModified from original published protocol;

bMethotrexate (12mg)/cytarabine (40

mg)/hydrocortisone (15 mg); cMethotrexate may be administered PO


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Princess Margaret Hospital Modified DFCI 91-01/AL.4 protocol (Martell, et al

2013) for Philadelphia Chromosome/BCR-ABL1 positive adult patients aged

>60 years old

Phase of Therapy Time Period Chemotherapy Induction* 28 Days Vincristine 2 mg,, days 1, 8

a

Vinblastine 10 mg, day 15a

Dexamethasone 40 mg PO, days 1-4, 9 –12 Doxorubicin 30 mg/m2 IV days 1and 2 Methotrexate 40 mg/m

2 IV, day 3

IT Cytarabine 70 mg, day 1 IT therapy: methotrexate/cytarabine /hydrocortisone, days 15, 29

a,b

Imatinib 600mg, day 1 -28a

CNS Therapy* 3 Weeks Vinblastine 10 mg IV, day 1a

6-mercaptopurine (6-MP) 50 mg/m2 PO × 14 consecutive days (day 1 -14) Doxorubicin 30 mg/m2 × 1 dose day 1 IT therapy: methotrexate/cytarabine /hydrocortisone

b days 1,4,8,11

Imatinib 400mg, day 1-21

Intensification* Every 3 weeks for 21 weeks


Dexamethasone 6 mg BID PO, days 1 –5 Doxorubicin 30 mg/m2 IV, day 1 6-MP 50 mg/m2/day orally × 14 consecutive days (days 1-14) IT therapy: methotrexate/cytarabine /hydrocortisone

b start of a

cycle every 18 weeks Imatinib 400mg, day 1-21

Continuation* Every 3 weeks for 72 weeks


Dexamethasone 6 mg PO BID, days 1-5 6-MP 50 mg/m2/day orally × 14 consecutive days (days 1-14) Methotrexate 30 mg/m2 i.v. or IM weekly days 1, 8 and 15

c

IT therapy: methotrexate/cytarabine /hydrocortisonea at start of a

cycle every 18 weeks Imatinib 400mg, day 1-21

Alternative Induction #1 (Vignetti, et al 2007) Alternative Induction #2 (Foa, et al 2011) Alternative Induction #3 (Chalandon, et al 2015)

Imatinib 800 mg, days 1-45 Prednisone 40mg/m

2 PO, days 1-45

Post remission therapy not specified Dasatinib 70 BID, days 1-84 Prednisone 60mg/m

2 PO, days 1 – 32

IT chemotherapy, two doses Continue with DFCI intensification post induction Vincristine 2mg IV, day 1,8,15,22 Dexamethasone 40mg/d PO, days 1-2, 8-9, 15-16, 22-23 Imatinib 400 mg BID PO, days 1-28 IT therapy consisting of methotrexate (12mg)/cytarabine (50 mg)/hydrocortisone (15 mg), days 1,8,15 Continue with DFCI intensification post induction

* Recent modifications from published protocol include elimination of asparaginase from induction and intensification, and switch

from vincristine to vinblastine in CNS phase, intensification and continuation therapy; aModified from original published protocol;

bMethotrexate (12mg)/cytarabine (40 mg)/hydrocortisone (15 mg);

cMethotrexate may be administered PO


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