STRUMENTI DIAGNOSTICO-TERAPEUTICI NELLA LLC NELLA REALTA AMBULATORIALE QUOTIDIANA: PRATICA CLINICA, POTENZIALITA REALI E TRANSITO VERSO IL FUTURO

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1 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

2 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

3 ..THE SITUATION IN CLL NOW PROGRESSION FREE SURVIVAL OVERALL RESPONSE OVERALL SURVIVAL PATIENT PATIENT COMPLIANCE QUALITY OF LIFE IMPACT OF PROFESSIONAL SKILLS CLL is not curable with standard therapies. ALL PATIENTS PROGRESS AND DIE BECAUSE OF THE DISEASE OR TREATMENT-RELATED COMPLICATIONS

4 Patients (%) CLL: MAJOR CAUSE OF DEATH even with comorbidities CAUSE OF DEATH Therapy-related % 70% CLL-unrelated CLL-related 0 NO COMORBIDITY COMORBIDITY Cramer P, et al. Blood 2006; 108: Abstract 2840.

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6 PROGNOSTIC MARKERS IN CLL J Gribben. EHA 2014, oral presentation.

7 PRACTICAL USE OF PROGNOSTIC MARKER AND DIAGNOSTIC TOOLS IN CLL J Gribben. EHA 2014, oral presentation.

8 Integrated mutational and Cytogenetics Analysis identifies Prognostic subgroups in CLL Rossi D et alii, Blood 2013, 121 (8):

9 BACKGROUND REALTA LOCALI STRUMENTI DIAGNOSTICI E possibile ottimizzare la terapia dei pazienti affetti da LLC? INTERVENTI TERAPEUTICI OUTCOMES ENDPOINT COMPLIANCE PAZIENTI

10 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

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

12 LE PRINCIPALI PAURE DELLE PERSONE ANZIANE Fonte CENSIS

13 PROBLEMATICHE NEL PAZIENTE ANZIANO CON MALATTIA EMATO-ONCOLOGICA 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

14 CAREFUL ASSESSMENT OF THE RISK OF THERAPY LOSS OF ORGAN RESERVE CHRONOLOGIC AGE BONE MARROW RESERVE FUNCTIONAL STATUS: PERFORMANCE STATUS, ADL SCALE, IADL SCALE IMMUNE SYSTEM DEFECTION COGNITIVE IMPAIRMENT DEPRESSIVE DISORDERS BIOLOGICAL PROGNOSTIC FACTORS COMORBIDITIES Chronic lymphocytic leukemia in the elderly: who should be treated. Zent C. ASCO 2010.

15 Journal of Clinical Oncology 2013, 31 (29):

16 SELECTED STANDARDIZED TOOLS TO EVALUATE VARIOUS DIMENSIONS OF PATIENT FITNESS Adapted from: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.

17 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

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19 MEASUREMENT OF COMORBIDITY: Cumulative illness rating scale (CIRS) CUMULATIVE ILLNESS RATING SCALE (CIRS) Organ system Heart Blood pressure Vascular Respiratory Ear/nose/throat Upper gastrointestinal Lower gastrointestinal Liver Renal Genitourinary Musculoskeletal Endocrine/metabolic Neurological Psychiatric If illness/impairment present, please specify: Score 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; Total trattamento Score: urgente; prognosi grave) Linn B, et al. J Am Geriatr Soc 1968; 16: Parmelee P, et al. J Am Geriatr Soc 1995; 43:

20 LE SCALE CITATE DA CHI UTILIZZA CRITERI DEFINITI CIRS consolidato nella letteratura ematologica e maggiormente utilizzato nella pratica clinica anche per altre patologie (linfomi)

21 FIT / UNFIT

22 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, 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

23 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)

24 THE TIGHT LINK BETWEEN EFFICACY AND TOXICITY WITH HISTORICAL CLL THERAPY From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.

25 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.

26 THERAPY OF LLC: CRITICISM IN ELDERLY COMORBIDITY TOXICITY COMPLIANCE SOCIAL FACTORS No unequivocal age cut-off (treatment dependent) DOSE REDUCTION LESS EFFECTIVENESS

27 1724 studies found for CLL 1650 studies found for CLL therapy 413 open studies found for CLL therapy 41 studies found for ELDERLY CLL 21 open studies found for THERAPY IN ELDERLY CLL

28 NEW THERAPEUTIC AGENTS AND THEIR TARGETS IN A CHRONIC LYMPHOCYTIC LEUKEMIA CELL F1000Prime Reports 2014, 6: 65.

29 POTENTIAL FUTURE STRATEGIES TO ACHIEVE LONG-TERM CONTROL OF CLL Adapted from: Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Haematology 2013.

30 CLL: INCREASE IN CR RATE OVER THE YEARS Montserrat et alii. Blood 2005, 106: 2226

31 Percent of patients INCREASING COMPLETE REMISSIONS CR according to NCI criteria, 1996???? 40 20?????? 0 Chlorambucil Fludarabine Alemtuzumab CAP CHOP FC FCM FCR Anti CD20 di nuova generazione; inibitori tirosin kinasi, inibitori Bruton kinasi,... 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

32 Frequency of first line treatment over time (n=620). Others: regimens with frequency < 5% Hematol Oncol 2014, 15 (Epub ahead of print).

33 Frequency of second line treatment (n= 270) Hematol Oncol 2014, 15 (Epub ahead of print).

34 BCR-Inhibition and Transient Lymphocytosis Unexpected side effect of BCR inhibitors (SYK, BTK, and PI3K inhibitors): Rapid reduction of lymphadenopathy Transient lymphocytosis Martin, et al. Blood. 2012;119: IBRUTINIB (PCI-32765) Inhibits BCR-controlled signaling and integrinmediated 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 survivalsupporting lymph node and bone marrow microenvironment

35 IBRUTINIB: AVVERTENZE E PRECAUZIONI SPECIALI PER L USO 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

36 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

37 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

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41 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):

42 MANIFESTAZIONI AUTOIMMUNI NON EMATOLOGICHE NELLA LLC Pemfigo paraneoplastico Pioderma gangrenoso Angioedema Sindrome di Churg-Strauss Tiroidite autoimmune Glomerulonefrite LES DIAGNOSI CORRETTA DIAGNOSI DIFFERENZIALE Sindrome di Raynaud Polineuropatia Artrite reumatoide Sindrome di Sjogren Vasculite Colite ulcerativa

43 SUPPORTIVE CARE CONSIDERATIONS FOR CLL PATIENTS From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.

44 Dipartimento di Oncologia Medica Struttura Complessa Ematologia e Centro Trapianti Presidio Ospedaliero Armando Businco Centro Riferimento Oncologico Regionale Programma Trapianti Accreditato TRIALS CLINICI IN CORSO Studio di fase III, multicentrico randomizzato, a tre bracci di trattamento, di comparazione dell efficacia e della sicurezza di RO 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 ). Studio di fase III MO 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

45 Dipartimento di Oncologia Medica Struttura Complessa Ematologia e Centro Trapianti Presidio Ospedaliero Armando Businco Centro Riferimento Oncologico Regionale Programma Trapianti Accreditato 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 ). 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.

46 Journal of Clinical Oncology 2007, 25 (14).