ALL

ACUTE LYMPHOBLASTIC

LEUKEMIA

Alyssa Mellott

LEUKEMIA Systemic disease

Diagnosed based on type of white blood cell affected & speed at which it progresses Acute vs. ChronicMyelogenous vs. Lymphocytic

ALL

ALL Forms in bone marrow

B & T lymphocytes: a mature form of lymphoblasts that are critical to the immune system

3 subtypes 1. Precursor B cell

Adults 2. Mature B cell

Genetic changes 3. Precursor T cell*

Pediatric*

Invades blood & spreads to lymph nodes & lymphoid organs

EPIDEMIOLOGY Most common subtype of leukemia

Most common cancer diagnosed in children

More prominent in:2-10 year oldsWhite peopleMales

ETIOLOGY Family history

Chromosome instability disorders Ex. Down’s Syndrome

Viral infections Ex. Epstein Barr

Radiation exposure Previous radiation or prenatal x-rays

Environmental factors

PRESENTATION Neutropenia

Fever

Malaise

Petechiae

Lymphadenopathy

Hemorrhage

Fatigue

Bone/joint pain

Pallor

Enlarged spleen

PHYSIOLOGY & LYMPHATICS

PHYSIOLOGY & LYMPHATICS Bone marrow produces lymphocytes

ALL: too many lymphocytes & they don’t function properly

Can’t fight infection & overcrowding = less RBC’s & platelets

This causes Bleeding (lack of platelets) Fatigue (lack of RBC’s) Build up of WBC’s in spleen, lymph nodes, & liver =

swelling & discomfort

ALL VS. LYMPHOMA Both can develop from lymphocytes

ALL starts in the bone marrow & can spread to other parts of the body

Lymphoma starts in lymph nodes & other organs & can spread to the bone marrow

TREATMENT Radiation, chemotherapy, & bone

marrow transplant Combination or aloneChemo alone is most common

CHEMOTHERAPY Chemo alone 3 steps

1. Induction: intense 2-3 weeks, goal is remission Agents: doxorubicin, methotrexate, vincristine,

ect.

2. Consolidation: goal to kill remaining cells Agents: same + cytarbine & etoposide

3. Maintenance: goal to reduce risk of leukemia coming back Agents: mercaptopurine & methotrexate tablets

+ vincristine injection

RADIATION THERAPY TBI

Conditioning for bone marrow transplant

1200 cGy6 fractions

German Helmet1800-2400 cGy

Cranial Spinal + German helmetHelmet to 2400 cGySpine to 1500 cGy

Treatment of testis2000-2400 cGyRelapse due to

methotrexateCan be prophylactic

BONE MARROW TRANSPLANT For patients in fair

health Can do lower dose TBI

for weaker patients Chemotherapy can

severely damage normal bone marrow cells Restore bone marrows

ability to make blood Autogeneic vs.

Autologous Severe side effects

TBI: PATIENT EXAMPLE 7 year old male

Presented with lymphadenopathy & petechiae in 2011 ALL

Relapse in 2014

Had chemotherapy & prophylactic cranial radiation to 1200 cGy in 2011 CNS = sanctuary site Remission

Orchiectomy in June 2014 due to relapsed testicular disease Testes = sanctuary site Methotrexate

Started 3 cycles of chemo again Reinduction

Vincristine Steroids Doxorubicin Asparaginase

TBI and testicular boost at MXE in September to prepare for BMT

TBI: PATIENT EXAMPLE TBI

1200 cGy total6 fractions/BID6 mV

Boost to testes1200 cGy total6 fractions/BID12 meV

TBI: PATIENT EXAMPLE

OPTION 1: ANTIBODY THERAPY Antibody therapy

A form of targeted therapy

Radiation and chemotherapy side effects can limit quality of life

Focus on pediatric relapse cases Usually a poor prognosis (~30% in 5 years)

OPTION 1: ANTIBODY THERAPY 1. Monoclonal antibodies

In phase III trial for pediatric ALL

Leukemic blasts express antigens on their surface that can be selectively targeted by monoclonal antibodies

This allows directed delivery of highly potent drugs

Advantages over chemo: Longer circulating half-lives Greater accumulation in tumor cells Fewer systemic side effects

OPTION 1: ANTIBODY THERAPY 2. Antibody-Drug Conjugates (ADC’s)

Next generation of antibodiesBeing tested for ALL & AMLA highly potent cytotoxic agent is bound to

an antibody by a linker, resulting in selective targeting of leukemia cells

3. Bispecific T-Cell Engager (BiTE) Each antibody contains two binding sites

One designed to engage the patient’s own immune system and the other to target malignant cells

OPTION 1:CONCLUSIONS Less severe side effects

More “targeted”

Minimal changes over last 50 years in drugs to induce & maintain remission in pediatric leukemia

Could change routine management of this disease

Cannot not penetrate blood-brain barrier Still a challenge to get these drugs to sanctuary sites

CNS & testes

Still in trials

OPTION 2:PRE-BMT BUSULFAN Busulfan (BU)

Alkylating agent One of most potent anti-leukemia drugs Very toxic to normal bone marrow cells but not

immunosuppressive Need fludarabine to get new stem cells to engraft

Limited toxicity to organs Most common alternative to TBI

Study: childhood leukemia survivors Best conditioning treatment for BMT? TBI 174 patients vs. Busulfan 66 patients

Health status & quality of life? Median follow up = 10.1 years

OPTION 2:CONCLUSIONS

Patients that developed more than three late complications59.2% of TBI

patients 44% of BU

patients

OPTION 2:SIDE EFFECTS

Side Effects BU TBI

Height growth failure

27.3% 49.4%

Overweight* 22.7% 13.8%

Hypothyroidism 15.2% 28.2%

Secondary Tumors

4.5% 11.5%

Gonadal Dysfunction

48.1% 53.9%

Alopecia* 25.8% 2.9%

Cataract 4.5% 51.7%

OPTION 2:CONCLUSIONS Seems to be equally effective

BU replace TBI?Children & TBI

More damaging to physical and mental development (lower IQ)

Higher risk for secondary cancers

Patients considered were all long-term survivorsTBI seems to have more serious side effects

in children

MY OPINION Antibody therapy vs. common

chemotherapy agentsSide effectsRelapse/ALL

Better prognosis?

BU vs. TBI as conditioning for BMTSide effectsLong term quality of lifePediatric development

REFERENCES Bernard F, Auquier P, Michel G, et al. Health status of childhood leukemia

survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study. Bone Marrow Transplantation [serial online]. May 2014;49(5):709-716. Available from: Academic Search Complete, Ipswich, MA. Accessed October 23, 2014.

“Childhood Lymphoblastic Leukemia Treatment.” Cancer.gov. National Cancer Institute, n.d. Web. 30 Oct. 2014. <http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional>.

 Hackworth, Ruth. "Pediatric Tumors." Applied Technical Oncology. Lecture. 2014.

"Intravenous Busulfan Before Stem Cell Transplant." MD Anderson Cancer Center. University of Anderson Texas MD Anderson, n.d. Web. 30 Oct. 2014. <http://www2.mdanderson.org/cancerwise/2010/05/qa-intravenous-busulfan-before-stem-cell-transplant.html>.

"Stem cell transplant for acute lymphocytic leukemia." American Cancer Society. American Cancer Society, n.d. Web. 30 Oct. 2014. <http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/overviewguide/leukemia-all-overview-treating-bone-marrow-stem-cell>.

Vedi A, Ziegler D. Antibody therapy for pediatric leukemia. Frontiers In Oncology [serial online]. April 2014;4:1-10. Available from: Academic Search Complete, Ipswich, MA. Accessed October 27, 2014.