INTERNISTI ED EMATOLOGI A CONFRONTO:

EVIDENCE-BASED MEDICINE NELLA GESTIONE MULTIDISCIPLINARE

DELLA LEUCEMIA LINFATICA CRONICA

STRUMENTI DIAGNOSTICO-TERAPEUTICI NELLA LLC

NELLA REALTA’ AMBULATORIALE QUOTIDIANA:

PRATICA CLINICA, POTENZIALITA’ REALI E TRANSITO VERSO IL FUTURO

Roberta Murru

WHAT HAS CHANGED IN CLL OVER THE LAST 10 YEARS?

1. Better understanding of the biology of the disease; future clinical

implications, maybe actual…

2. Improved prognostic stratification

3. More and more active drugs (new combinations, new drugs)

4. New concepts (definition of molecular responses and MRD - minimal

residual disease - consolidation and maintenance)

5. Impact on survival

CLL is not curable with standard therapies…. ALL PATIENTS PROGRESS AND DIE

BECAUSE OF THE DISEASE OR TREATMENT-RELATED COMPLICATIONS

PATIENT

OVERALL

RESPONSE

OVERALL

SURVIVAL

PROGRESSION

FREE

SURVIVAL

IMPACT OF

PROFESSIONAL

SKILLS

PATIENT

COMPLIANCE

QUALITY OF

LIFE

…..THE SITUATION IN CLL NOW

CLL: MAJOR CAUSE OF DEATH

…even with comorbidities

0

20

40

60

80

100

NO COMORBIDITY COMORBIDITY

Therapy-related

CLL-unrelated

CLL-related

CAUSE OF DEATH

Patients

(%

)

69% 70%

Cramer P, et al. Blood 2006; 108: Abstract 2840.

J Gribben. EHA 2014, oral presentation.

PROGNOSTIC MARKERS IN CLL

J Gribben. EHA 2014, oral presentation.

PRACTICAL USE OF

PROGNOSTIC MARKER AND DIAGNOSTIC TOOLS IN CLL

Rossi D et alii, Blood 2013, 121 (8): 1403-1412.

Integrated mutational and Cytogenetics Analysis identifies Prognostic subgroups in CLL

E’ possibile ottimizzare la

terapia dei pazienti affetti

da LLC?

BACKGROUND

STRUMENTI

DIAGNOSTICI

OUTCOMES

COMPLIANCE

PAZIENTI

REALTA’ LOCALI

INTERVENTI

TERAPEUTICI

ENDPOINT

CANCER is a disease of aging and the population

of older people in the US is growing rapidly…. 35

million people > 65 yrs old….expected to double by

2030 according to the US Census Bureau.

…Oncologists who have cared for older adults

understand that their treatment needs are different

than those of young counterparts….

…they can experience secondary cancers or

memory problems following treatment…..

…As a result, GERIATRIC ONCOLOGY

has become an emerging area of focus.

ASCO News and Forum, 2006

FRA GLI ULTRA65ENNI A LIVELLO NAZIONALE:

- oltre il 8% è confinato in casa

- oltre il 12% presenta limitazioni nello svolgimento di attività quotidiane

- oltre il 18% risulta disabile

- oltre il 40% è affetto da almeno una malattia cronica

- oltre il 68% delle persone disabili presenta almeno 3 malattie croniche

ALCUNI DATI RECENTI….

Fonte: Condizioni di salute, fattori di rischio e ricorso ai servizi sanitari. ISTAT, 2007.

LE PRINCIPALI PAURE DELLE PERSONE ANZIANE

Fonte CENSIS

ETA’

SINDROMI GERIATRICHE

- malnutrizione

- incontinenza

- sordità, riduzione del visus, alterazioni della deambulazione

- assunzione di farmaci

- fragilità

- alterazioni cognitive

- disturbi depressivi

DISABILITA’ - limitazioni nelle attività quotidiane

- autostima

COMORBIDITA’ - patologie cardiovascolari, respiratorie, metaboliche, neurologiche

PROBLEMATICHE NEL PAZIENTE ANZIANO CON MALATTIA EMATO-ONCOLOGICA

LOSS OF ORGAN RESERVE CHRONOLOGIC AGE

FUNCTIONAL STATUS:

PERFORMANCE STATUS,

ADL SCALE, IADL SCALE

COMORBIDITIES

IMMUNE SYSTEM

DEFECTION

BONE MARROW

RESERVE

CAREFUL ASSESSMENT OF THE RISK OF THERAPY

Chronic lymphocytic leukemia in the elderly: who should be treated.

Zent C. ASCO 2010.

BIOLOGICAL

PROGNOSTIC FACTORS

COGNITIVE IMPAIRMENT

DEPRESSIVE DISORDERS

Journal of Clinical Oncology 2013, 31 (29): 3711-3718.

Adapted from: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers.

Hematology 2013.

SELECTED STANDARDIZED TOOLS TO EVALUATE VARIOUS DIMENSIONS OF PATIENT FITNESS

METODO DI DETERMINAZIONE DEL “FITNESS STATUS”

Prevalenza di una valutazione soggettiva basata sull’esperienza

Comportamento sovrapponibile per i 2 target

Le scale CIRS, ECOG e WHO sono i riferimenti più citati fra i criteri definiti utilizzati

MEASUREMENT OF COMORBIDITY:

Cumulative illness rating scale (CIRS)

Linn B, et al. J Am Geriatr Soc 1968; 16:622–626.

Parmelee P, et al. J Am Geriatr Soc 1995; 43:130–137.

CUMULATIVE ILLNESS RATING SCALE (CIRS)

Total Score:

Organ system Score If illness/impairment present, please specify:

Heart

Vascular

Blood pressure

Respiratory

Endocrine/metabolic

Ear/nose/throat

Upper gastrointestinal

Lower gastrointestinal

Liver

Renal

Genitourinary

Musculoskeletal

Neurological

Psychiatric

0: ASSENTE (nessuna compromissione d’organo)

1: LIEVE (compromissione d’organo; non interferisce

con la normale attività; trattamento opzionale; prognosi

eccellente)

2: MODERATO (compromissione d’organo; interferisce

con la normale attività; trattamento necessario; prognosi

buona)

3: GRAVE (compromissione d’organo; produce disabilità;

trattamento non dilazionabile; prognosi non sempre

favorevole)

4: MOLTO GRAVE (compromissione d’organo; mette a

repentaglio la sopravvivenza; trattamento urgente;

prognosi grave)

LE SCALE CITATE DA CHI UTILIZZA CRITERI DEFINITI

CIRS consolidato nella letteratura ematologica e maggiormente utilizzato nella pratica clinica anche per altre patologie (linfomi)

FIT / UNFIT

FIRST-LINE TREATMENT CHOICE FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS:

WHAT DO CLINICIANS CARE ABOUT?

THE CLL FITNESS STUDY

Investigator-driven multicenter retrospective observational non-interventional study

Data collection on the criteria applied in the clinical practice when selecting first-line treatment for CLL

patients and on the outcome in terms of tolerance and toxicities to the initial therapy.

Primary objective: define the most relevant parameters influencing physician’s choice and their

correlation with treatment tolerance “Fitness score” (to be validated in clinical practice)

CLL patients requiring first-line treatment between January 1st, 2009 and December 31, 2010.

Study target population of 700 subjects…. 104 patient records were reported

36 Italian sites with long-standing experience in CLL patient management

MAIN REQUESTED CLINICAL INFORMATION:

anthropologic parameters

global health status

disease information

biological parameters

treatment

follow-up data Scarfò L. et alii. EHA 2014

FIRST-LINE TREATMENT CHOICE FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS:

WHAT DO CLINICIANS CARE ABOUT?

THE CLL FITNESS STUDY

35% of patients enrolled in clinical trials.

Treatment choice based on:

99% age

98% comorbidities

82% functional

80% performance status

79% mental status

68% need for caregiver

65% polypharmacy

39% biological factors (IgVH, FISH and CD38)

From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key

questions and current answers. Hematology 2013.

THE TIGHT LINK BETWEEN EFFICACY AND TOXICITY WITH HISTORICAL CLL THERAPY

DETERMINING THE GOALS OF TREATMENT FOR OLDER PATIENTS WITH CLL

From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.

COMORBIDITY

TOXICITY

COMPLIANCE

SOCIAL FACTORS

THERAPY OF LLC: CRITICISM IN ELDERLY

No unequivocal age cut-off

(treatment dependent)

DOSE REDUCTION

LESS EFFECTIVENESS

1724 studies found for CLL

413 open studies found for CLL therapy

41 studies found for ELDERLY CLL

1650 studies found for CLL therapy

21 open studies found for THERAPY

IN ELDERLY CLL

NEW THERAPEUTIC AGENTS AND THEIR TARGETS IN A CHRONIC LYMPHOCYTIC LEUKEMIA CELL

F1000Prime Reports 2014, 6: 65.

Adapted from: Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies.

Haematology 2013.

POTENTIAL FUTURE STRATEGIES TO ACHIEVE LONG-TERM CONTROL OF CLL

CLL: INCREASE IN CR RATE OVER THE YEARS

Montserrat et alii. Blood 2005, 106: 2226

Rai et al. 2000; Leporrier et al. 2001; Lundin et al. 2002; O’Brien et al. 2001; Bosch et al. 2008; Tam et al. 2008

0

20

40

60

80

Chlorambucil Fludarabine Alemtuzumab CAP CHOP FC FCM FCR

Pe

rce

nt o

f p

atie

nts

CR according to NCI criteria, 1996

INCREASING COMPLETE REMISSIONS...

Anti CD20 di nuova generazione;

inibitori tirosin kinasi, inibitori Bruton kinasi, ......

?

?

?

?

? ?

? ?

? ?

Hematol Oncol 2014, 15 (Epub ahead of print).

Frequency of first line treatment over time (n=620).

Others: regimens with frequency < 5%

Hematol Oncol 2014, 15 (Epub ahead of print).

Frequency of second line treatment

(n= 270)

Martin, et al. Blood. 2012;119:2590-2594.

BCR-Inhibition and Transient Lymphocytosis

Unexpected side effect of BCR inhibitors (SYK, BTK, and PI3K inhibitors):

• Rapid reduction of lymphadenopathy

• Transient lymphocytosis

IBRUTINIB (PCI-32765)

Inhibits BCR-controlled signaling and integrin-

mediated adhesion

Inhibits CXCL12-, CXCL13-, and CCL19-induced

signaling

Overcomes BCR and chemokine-controlled

integrin-mediated retention/homing of CLL cells

Deprives CLL cells of growth- and survival-

supporting lymph node and bone marrow

microenvironment

Particolare attenzione a:

- agenti antiaggreganti e anticoagulanti (intervento chirurgico)

- linfocitosi

- leucostasi

- infezioni

- neoplasie maligne

- interazioni farmacologiche (l’elenco completo degli inibitori, induttori e substrati del citocromo P450 è

disponibile all’indirizzo http://medicine.iupui.edu/clinpharm/ddis/table.aspx)

IBRUTINIB: AVVERTENZE E PRECAUZIONI SPECIALI PER L’USO

FINAL RESULS OF A PHASE I STUDY OF IDELALISIB (GS-1101) A SELECTIVE INHIBITOR OF PHOSPHATIDYLINOSITOL 3-

KINASE p110 Delta (PI3Kδ) IN PATIENTS WITH RELAPSED OR REFRACTORY CLL

Adverse events and selected lab abnormalities

FINAL RESULS OF A PHASE I STUDY OF IDELALISIB (GS-1101) A SELECTIVE INHIBITOR OF PHOSPHATIDYLINOSITOL 3-

KINASE p110 Delta (PI3Kδ) IN PATIENTS WITH RELAPSED OR REFRACTORY CLL

Serious adverse events, leading to study drug discontinuation

SKIN LESIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Cutaneous lesions in up to 25% of patients with chronic lymphocytic leukemia (cutaneous seeding by

leukemic cells - leukemia cutis, LC - and other malignant diseases or non malignant disorders.

Solitary, grouped, or generalized papules, plaques, nodules, or large tumors

Prognosis in CLL patients with LC is rather good and many authors claim that it does not

significantly affect patients' survival.

However, prognosis is poor in patients in whom LC shows blastic transformation (Richter's

syndrome) and when leukemic infiltrations in the skin appear after the diagnosis of CLL.

Secondary cutaneous malignancies are also frequent complications in patients with CLL.

Nonspecific, secondary cutaneous lesions are frequently observed in CLL patients (infectious or

hemorrhagic )

Other secondary lesions present as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, and

paraneoplastic pemphigus

An exaggerated reaction to an insect bite and insect bite-like reactions have been also observed.

Leuk Lymphoma 2007, 48 (5): 855-865.

MANIFESTAZIONI AUTOIMMUNI NON EMATOLOGICHE NELLA LLC

Pemfigo paraneoplastico

Pioderma gangrenoso

Angioedema

Sindrome di Churg-Strauss

Tiroidite autoimmune

Glomerulonefrite

LES

Sindrome di Raynaud

Polineuropatia

Artrite reumatoide

Sindrome di Sjogren

Vasculite

Colite ulcerativa

DIAGNOSI CORRETTA

DIAGNOSI DIFFERENZIALE

SUPPORTIVE CARE CONSIDERATIONS FOR CLL PATIENTS

From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia:

key questions and current answers. Hematology 2013.

Dipartimento di

Oncologia Medica

Struttura Complessa

Ematologia e Centro Trapianti

Programma Trapianti

Accreditato Presidio Ospedaliero

Armando Businco

Centro Riferimento Oncologico Regionale

TRIALS CLINICI IN CORSO

Studio di fase III, multicentrico randomizzato, a tre bracci di trattamento, di comparazione dell’efficacia e della sicurezza di

RO5072759 + chlorambucil (GClb), rituximab + chlorambucil (RClb) o chlorambucil (Clb) in monoterapia in pazienti affetti da

leucemia linfatica cronica non pretrattati, con comorbidità (CLL11 - BO21004).

Studio di fase III randomizzato, in doppio cieco, controllato con placebo, per valutare l’efficacia e la sicurezza di GS-1101

(CAL-101) in combinazione con bendamustina e rituximab per la leucemia linfocitica cronica precedentemente trattata (GS-

US-312-0115).

Studio di fase III MO28543 - multicentrico, in aperto, a braccio singolo, di fase IIIB, per valutare la sicurezza di

obinutuzumab in monoterapia o in associazione a chemioterapia in pazienti affetti da leucemia linfatica cronica non

pretrattata o recidivata/refrattaria.

Studio di fase III multicentrico randomizzato, controllato vs placebo, in doppio cieco, sull’efficacia e sicurezza di

lenalidomide come terapia di mantenimento dopo terapia di prima linea in pazienti ad alto rischio affetti da leucemia linfatica

cronica – CLLM1.

Named Patient Program – NPP - Ibrutinib

TRIALS CLINICI CONCLUSI

Studio di fase III sulla immunochemoterapia con Fludarabina, Ciclofosfamide e Rituximab (FC-R) in confronto

alla sola chemioterapia con Fludarabina e Ciclofosfamide (FC), in pazienti con leucemia linfatica cronica non trattata

in precedenza (CLL8 - ML1710).

Studio multicentrico a braccio singolo, di Bendamustina associata ad Ofatumumab (BendOfa) in pazienti con

leucemia linfatica cronica (LLC) refrattari o ricaduti.

PROSSIMA APERTURA

Studio di fase III multicentrico randomizzato per valutare l’efficacia e la sicurezza di GS-1101 (CAL-101) in

combinazione con bendamustina e rituximab per la leucemia linfocitica cronica in prima linea (GS-US-312-0123).

RICERCA CLINICA

Progetto di ricerca clinica “Rischio evolutivo in pazienti con leucemia linfatica cronica (LLC): ricerca di modello

predittivo”, finanziato dall’Assessorato della Programmazione,– Centro Regionale di Programmazione, Regione

Sardegna, annualità 2012.

Dipartimento di

Oncologia Medica

Struttura Complessa

Ematologia e Centro Trapianti

Programma Trapianti

Accreditato Presidio Ospedaliero

Armando Businco

Centro Riferimento Oncologico Regionale

Journal of Clinical Oncology 2007, 25 (14).