REAL LIFE AMBULATORIALE E STUDI CLINICI RANDOMIZZATI NELLA PROGRAMMAZIONE TERAPEUTICA DELLA LEUCEMIA LINFATICA CRONICA.

REAL LIFE AMBULATORIALE E STUDI CLINICI RANDOMIZZATI NELLA PROGRAMMAZIONE TERAPEUTICA DELLA LEUCEMIA LINFATICA CRONICA Roberta Murru Struttura Complessa Ematologia e Centro Trapianti Presidio Ospedaliero Armando Businco, Cagliari

OBINUTUZUMAB OFATUMUMAB IBRUTINIB IDELALISIB J Clin Oncol 2015, 33 (7): 786-809.

US Food and Drug Administration approvals by cancer drug class and year (2014 is trough October) J Clin Oncol 2015, 33 (7): 786-809.

Cheson BD. Blood. 2014, 23: 3368-3370.

CLL: HOMOGENEOUS PHENOTYPE BUT HETEROGENEOUS CLINICAL COURSE Adapted from: Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 2015, 126 (4): 445-453.

Initial Diagnosis: Questions You Will Need to Consider in Clinical Practice 1. What Is The Prognosis? Should You Do Additional Prognostic Testing? 2. When Should Treatment Start? Is Watch And Wait Still Appropriate For Many Patients? 3. What Type Of Therapy Should You Choose? 4. What Is Your Goal Of Therapy? Adapted from: Coutre S. How I treat CLL in 2014. Clinical Care Options - Oncology.

PROGNOSTIC MARKERS IN CLL Adapted from: J Gribben. EHA 2014, oral presentation.

FISH Mutations: Probability of Disease Progression 100 80 Patients Treated (%) 60 40 20 17p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality 0 0 12 24 36 48 60 72 84 96 108 120 132 144156 168 180 Months Döhner H, et al. N Engl J Med. 2000, 343: 1910-1916.

IgVH Mutation Status and Prognosis: patients With Mutated vs Unmutated VH Genes Median survival 8-9 yrs in unmutated vs > 24 yrs in mutated 100 All Patients (N = 84) Patients With Stage- A CLL (n = 62) 100 Surviving (%) 80 60 40 P =.001 Mutated Surviving (%) 80 60 40 P =.0008 Mutated 20 Unmutated 20 Unmutated 0 0 50 100 150 200 250 300 Months 0 0 50 100 150 200 250 300 Months Damle RN, et al. Blood. 1999, 94: 1840-1847. Hamblin TJ, et al. Blood. 1999, 94: 1848-1854.

NOVEL GENE MUTATIONS IN CLL Gaidano G et alii. Molecular pathogenesis of chronic lymphocytic leukemia. J Clin Invest 2012, 122 (10): 3432-3438.

NOVEL GENE MUTATIONS IN CLL Genes With Significant Mutation Frequency TP53 SF3B1 MYD88 ATM FBXW7 NOTCH1 ZMYM3 DDX3X MAPK1 0 4 8 12 N of Mutations per 91 Pts 16 Mutation Mutations % No. of Base Pairs P Value Q Value TP53 15 119,041 <1.0x10-11 <6.3x10-8 SF3B1 15 359,856 <1.0x10-11 <6.3x10-8 MYD88 10 73,805 <1.0x10-11 <6.3x10-8 ATM 9 837,986 2.4x10-9 1.1x10-5 FBXW7 4 225,671 2.0x10-6 7.4x10-3 NOTCH1 4 306,968 3.3x10-6 1.0x10-2 ZMYM3 4 314,226 3.5x10-5 7.4x10-2 DDX3X 3 181,343 1.6x10-5 4.3x10-2 MAPK1 3 89,405 1.9x10-5 4.4x10-2 Number of mutations per gene that were found at a significant frequency, the percentage of patients who had each mutated gene, and for each gene, the total territory in numbers of base pairs with sufficient sequencing coverage across normal and malignant samples from 91 patients. P and Q values were calculated by comparing the probability of the observed constellation of mutations with the background mutation rates across the data set. Wang L, et al. N Engl J Med. 2011;365:2497-2506.

NEXT GENERATION SEQUENCING IN CLL NGS sequencing has highlighted the molecular heterogeneity of CLL Relatively large number of genes recurrently mutated at low frequency and only a few genes mutated in up to 10% to 15% of pts May provide new biomarkers and potential therapeutic targets for the diagnosis and management of the disease Recurrent mutations in CLL. The size of each gene symbol is proportional to the logarithm of the mutational frequency of the corresponding gene. Frequencies have been corrected for gene size and codon composition. Genes mutated in both Adapted from: Quesada V. et alii. BMC Med. 2013;11:124.

Application of genetic biomarkers in CLL ACP- 166 OFATUMUMAB IBRUTINIB ABT- 196 CHLORAMBUCIL IDELALISIB RITUXIMAB OBINUTUZUMAB PROGNOSTICATOR SURVIVAL PREDICTOR TREATMENT TAILORING Factors that provide information on the likely outcome of CLL Factors that provide information on the likely benefit from a specific CLL treatment Adapted from: Italiano A. J Clin Oncol 2011. Delgado J. et alii. Survival analysis in hematologic malignancies: recommendations for clinicians. Haematologica 2014, 99 (9): 1410-1420.

NOTCH1 mutations as predictive marker for no benefit from addition of anti- CD20 MoAb to chemotherapy Adapted from: Stilgenbauer S. et alii. Gene Mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014, 123: 3247-3254.

Pretreatment evaluation of patients with CLL - IWCLL - NCI 2008 - General practice is defined as the use of accepted treatment options for a patient with CLL who is not enrolled in a clinical trial Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute- Working Group 1996 guidelines. Blood 2008; 111: 5446-56

Diagnostic and staging work up in CLL - ESMO 2015 - Eichorst B. et alii. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up. Annals of Oncology 2015, 26 (5): 78-84.

Guidelines recommendations on TP53 lesions in CLL NCI- IWCLL 2008 GUIDELINES In the clinical practice cytogenetics (FISH) del17p- in the peripheral blood lymphocytes is desiderable before treatment Repetition of FISH analyses seems justified before subsequent, second and third line treatment ERIC RECOMMENDATIONS ON TP53 MUTATION ANALYSES TP53 mutations (exons 4-9) should be investigated immediately before treatment decision outside clinical trials in patients requiring terapy who would be eligible to an allogeneic stem cell transplantation or other intensive therapies (es: FCR, Bendamustine + rituximab) Previously treated patients with wild- type TP53 at the time of treatment should be retested when further therapy is needed and results can be expected to influence choice if therapy BRITISH COMMITTEE FOR STANDARDS IN HAEMATOLOGY (BCSH) Patients should be screened for the presence of a TP53 abnormality prior to initial and subsequent treatment. Currently, TP53 loss should be assessed by FISH Patients should also be screened for TP53 mutations when this assay becomes routinely available (grade B2) Hallek M. et alii. Blood 2008, 15, 111 (12): 5446-5456 Oscier D. et alii. Br J Haematol 2012, 159 (5): 541-564 Pospisilova S. et alii. Leukemia 2012, 26 (7): 1458-1461

INDICATIONS FOR TREATMENT IN CLL 1. guidelines should not serve to trigger the initiation of treatment automatically. 2. Indeed, the clinical context of findings is critical. For example, both lymphocyte counts and lymph node size can fluctuate. 3. A finding on a single blood test in a healthy- appearing patient must be interpreted with caution; decisions to treat should be made within the context of analysis of larger trends over time. CLL REQUIRING TREATMENT: Enlarging symptomatic lymph nodes (> 10 cm) Enlarging symptomatic spleen (> 6 cm) Progressive lymphocytosis (ALC 50% over a 2- month period or a LDT < 6 months) CLL associated cytopenia Hemoglobin < 11 g/dl Platelets < 100, 000 cells/μl Disease- associated constitutional symptoms Autoimmune hemolytic anemia or immune thrombocytopenia refractory to steroids 1.The IWCLL- Working Group guidelines do not include any single threshold value of lymphocytes, as lymphocytosis in and of itself is rarely detrimental to patient health. 2.However, there is a theoretical risk of hyperviscosity at extremely high levels. 3.We recommend the consideration of treatment for total white blood cell counts of more than approximately 250 x 10 9 /L. 4.This number is entirely empirical and without evidence (C). Adapted from: Clinical Care Options, In Practice CLL, 2015.

WATCH AND WAIT IN CLL 1. Early treatment may not provide survival benefit in patients with asymptomatic, early- stage disease; may cause unnecessary treatment toxicity 1. Observation recommended for newly diagnosed patients: patients should be monitored every 3-4 months (sooner if indications of aggressive disease) with a history, physical exam, and CBC 1. Two large French studies and a meta- analysis of several trials demonstrated no survival benefit for early treatment with chlorambucil compared with deferring treatment until clinically indicated (A). [CTCG 1999; Dighiero 1998] 2. These results were not surprising, given that a significant percentage of patients with CLL never ultimately require chemotherapy, and early therapy would expose them to unnecessary treatment toxicity. Perhaps related, one study found more secondary malignancies in the treated group. [Dighiero 1998] 3. Major contemporary developments have necessitated a re- evaluation of the question of early treatment benefit. First, treatments have improved to the extent that many patients achieve complete remission. Second, new molecular markers can be used to help identify which patients are likely to have tumors that behave more aggressively. 4. Clinical trials are under way randomizing high- risk patients to early treatment vs deferred treatment. Adapted from: Clinical Care Options, In Practice CLL, 2015.

MANAGEMENT OF EARLY STAGE CLL PCV: Pneucoccus vaccine; Tdap: tetanus diphteria, acellular pertussis. Adapted from: Strati P. et alii. Monoclonal B- cell lympocytosis and early- stage chronic lymphocytic leukemia: diagnosis, natural history and risk stratification. Blood 2015, 126: 454-462.

Treatment Options for Chronic Lymphocytic Leukemia: First line Adapted from: Stilgenbauer S. et alii. Management of chronic lymphocytic leukemia. ASCO Educational Book 2015.

Treatment Options for Chronic Lymphocytic Leukemia: relapsed and refractory disease Adapted from: Stilgenbauer S. et alii. Management of chronic lymphocytic leukemia. ASCO Educational Book 2015.

FITNESS STATUS- DEPENDENT TREATMENT AIMS BEST OVERALL RESPONSE AND PROLONGED TREATMENT- FREE SURVIVAL Possibly curative? immuno- chemotherapy + new treatment options BEST PROGRESSION- FREE SURVIVAL (PALLIATIVE CARE) Possibly curative? Quality of life QUALITY OF LIFE Best supportive care AGE 50 yrs.65 yrs..75 yrs..> 75 yrs

DETERMINING THE GOALS OF TREATMENT FOR OLDER PATIENTS WITH CLL Adapted from: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.

Evolution of Healthcare Decision Making Informative Physician provides information but patient preferences not considered Patient Provider Communication Family- Centered Model 1970 1990 2000 2015 Paternalistic Doctor as Agent Shared Decision Making Doctor knows best Physician assumes he or she knows patient preference Adapted from: Shared decision making in oncology. Clinical Care Options - Oncology.

What is Shared Decision Making? Shared decision making is a model of treatment decision making in the patient encounter 4 essential elements: 1.2 participants: physician and patient 2.Both parties share information 3.Both parties take steps to build consensus about preferred treatment 4.Mutual agreement is reached between patient and healthcare member on treatment approach Adapted from: Shared decision making in oncology. Clinical Care Options - Oncology.

Evolution of Healthcare Decision Making Adapted from: Tariman J, et al. Clin J Oncol Nurs. 2015. In press.

Clinical trials: are they significant for clinical practice and therapy decision making? Medical progress is based on research based on human subjects We have always to give priority to health patient From: Helsinki Declaration on ethical principles for medical research involving human subjects, 1964. How to protect the rights of patients? 1.Informed consent 2.Role of Ethics Committees 3.Data safety and monitoring boards (DSMBs)