MANAGEMENT OF LYMPHOMAS

Transcription

1 MANAGEMENT OF LYMPHOMAS Challenges & Recommendations F. Chite Asirwa, MD. Internal Medicine Physician Medical Oncologist & Hematologist Director-AMPATH Oncology & Physicians Association Meeting 2013 #Cancer

2 Disclosures Pfizer NNHF Celgene GSK Novartis Roche PI grant PI grant PI grant Honorarium Honorarium Honorarium

3 Traditional Categories A. Hodgkin's Lymphoma or Disease (HD) B. Non-Hodgkin s Lymphoma (NHL) The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment

4 Important Points Clinical acumen Remains the main stay of good Management Good history is critical Thorough Examination Simple and wise use of the lab services Good communication with laboratory and radiological services. Sound judgment

5 Before Treatment Understand the Prognosis of the lymphoma Set realistic target for yourself and the patient Understand the limitation of your facility More importantly understand the limitations of the patient and their support system Be cognizant of the long term consequences and overall wellbeing of the patient

6 WHO classification of lymphomas Precursor lymphoid neoplasms Mature B-cell neoplasms Mature T cell and NK-cell neoplasma Hodgkin lymphoma Histiocytic and dendritic cell neoplasm Post-transplant lymphoproliferative disorders WHO 2008

7 WHO lymphoma classification requires History Morphology and grade Immuno-histochemistry (IHC) Surface CD markers Evidence of virus infection in cells (ISH) Genetic Aberration Cyto-genetics FISH DNA Micro Array

8 Lymphoma grade The grade of a lymphoma usually gives an idea of the doubling time of the tumor or the mitotic rate. Low grade usually slow growing and clone accumulates by preventing apoptosis (ageing population) High grade is fast growing and clone accumulates by proliferation (high reproductive rate)

9 B Cell Lymphomas

10 Low grade or Indolent lymphomas 1.Follicular lymphoma (grade I and II) 2.Marginal zone B cell, MALT lymphoma 3.Chronic lymphocytic leukemia/small lymphocytic lymphoma 4.Marginal zone B-cell, nodal 5.Lymphoplasmacytic lymphoma

11 Intermediate Grade Follicular Grade 2 and 3 Mantle cell

12 Aggressive or High grade lymphomas 1. Diffuse large B-cell lymphoma 2. Mediastinal large B-cell lymphoma 3. Anaplastic large cell lymphoma

13 Very Aggressive Lymphomas Burkitt Lymphoma Lymphoblastic lymphoma

14 Clinical presentation Low grade : Can be widely disseminated at diagnosis but indolent course High grade lymphoma: Short history of localized rapidly enlarging lymphadenopathy and/or constitutional symptoms Aggressive: Very fast doubling time and growth rate

15 WHO 2008: Mature T cell lymphomas T-cell lymphocytic and prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorders of NK cells

16 WHO 2008: Mature T cell lymphomas Adult T-cell leukemia/lymphoma (HTLV-1) Hepatosplenic T-cell lymphoma Mycosis fungoides Sezary syndrome

17 WHO 2008: Aggressive Mature T and NK cell lymphomas Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (ALCL), ALK positive Anaplastic large cell lymphoma (ALCL), ALK negative Aggressive NK cell leukemia

18 Figure 4 Approach to T cell lymphomas

19 Hodgkin Lymphoma Nodular lymphocyte predominant Hodgkin lymphoma (CD30 -, CD15-, + B cell markers, background T cells are CD4 +) Classical Hodgkin lymphoma (CD30+, CD15+, CD45-) - Nodular sclerosis Hodgkin lymphoma - Lymphocyte rich classical Hodgkin lymphoma - Lymphocyte depleted Hodgkin lymphoma H+E CD15 CD30 EBV-ISH WHO 2008

20 Indolent lymphomas (Diagnosis in the lab) Morphology, predominantly small cells Pan B cell markers SLL (CD5 +, CD20 dim +, FMC-7 -,CD23 +) Follicular lymphoma (CD10 +) t(14:18) Marginal zone lymphomas (CD5 -, CD10-, CD23-) Mantle (CD20+, CD5+ (CD10neg, CD23neg) t(11:14)

21 Diffuse Large B-cell Lymphoma 0 H&E H+E CD20 Ki67 Ki67 CD10 BCL6 BCL6

22 Burkitt lymphoma Monomorphic medium sized cells with finely clumped nuclei, dispersed chromatin, multiple basophillic paracentrally located nucleoli, basophilic cytoplasm and vacuoles in the cytoplasm. Diffuse pattern of infiltration Starry sky appearance High proliferation index, Ki-67: almost 100% T(8:14) MYC CD10+, CD20+ H + E Ki-67 WHO 2008

23 Lymphoma evaluation and staging History and physical exam Laboratory FBC, LFT, LDH, U&E Tissue biopsy - Report Imaging CXR, CT of the chest, abdomen and pelvis Bone marrow biopsy Lumbar puncture

24 Lymphoma staging

25 Table 1

26 Immunotherapy era Humanized Monoclonal antibodies (Mabs) manufactured to target specific cell surface antigen. Naked: Rituximab CD20 (Mabthera), Alemtuzumab CD52 (Campath), Trasitumumab Herceptin Her2.

27 Rituximab binding to CD20 on B cells and sparing NK cells that lack CD20

28 Percent Survival The Impact of Adding Rituximab To CHOP (Gela, Ricover, Mint) Post-Ritux Pre-Ritux Log rank p = Progression-Free Survival (y)

29 EFS (%) PFS (%) Overall survival (%) Treatment Young DLBCL patients with IPI = 0 and no bulk can be cured with 6 x R-CHOP p = p = p = Time (years) Time (years) Time (years) R-chemo, IPI = 0, no bulk R-chemo, IPI = 1 and/or bulk Pfreundschuh M, et al. Lancet Oncol 2011; 12:

30 Survival probability Cont d Elderly DLBCL patients can be cured with 8 x R-CHOP Log-rank p < PFS Time (years) R-CHOP CHOP year follow-up study in elderly DLBCL patients 8 x R-CHOP vs 8 x CHOP Median PFS: R-CHOP: 4.8 years CHOP: 1.2 years Improved PFS in patients treated with R-CHOP Compared to CHOP only, R-CHOP also improved: Overall survival Disease-free survival Coiffer B, et al. Blood 2010; 116:

31 The addition of MabThera to CHOP-like chemo significantly improves clinical response p < British Columbia: Overall survival by treatment era Post-MabThera (MabThera + CHOP-like chemo) Pre-MabThera (CHOP-like chemo alone) Time (years) Adding MabThera to CHOPlike chemo: Significantly improves outcome for advanced stage DLBCL compared with CHOPlike chemo alone Achieves a 50% reduction in the risk of dying at 2 years compared with CHOP-like chemo alone Sehn LH, et al. J Clin Oncol 2005; 23:

32 The addition of MabThera to CHOP improves overall survival The addition of MabThera to CHOP confers two major benefits compared with CHOP alone: 1. A decrease in the number of patients with disease progression during treatment (refractory patients) 2. A decrease in the number of relapsing patients The addition of MabThera to CHOP results in: A decrease in the number of patients with an event A reduced risk of disease progression A longer overall survival in this patient population Coiffier B, et al. Blood 2010; 116:

33 Relapses are associated with a poor prognosis The majority of relapses occur within the first 2 years after the end of first-line treatment 1 The prognosis for survival after disease progression is poor for most patients, regardless of the type of progressive disease 2 The median OS after progression was 0.6 and 0.7 months for the CHOP and R-CHOP arms, respectively 2 In the CORAL study, early relapse and prior MabThera treatment (n = 187) defined a population with a poor response rate to the standard treatment; thus, their 3-year PFS was only 23% 1 1. Gisselbrecht C, et al. J Clin Oncol 2010; 28: Coiffier B, et al. Blood 2010; 116:

34 Survival distribution function CORAL: Patients with early relapses after first-line R-chemo have a poor prognosis Event-free survival (EFS) according to prior MabThera treatment (in patients who relapsed less than 12 months after diagnosis) Prior MabThera: No (n = 41) Prior MabThera: Yes (n = 187) p = EFS (years) Gisselbrecht C, et al. J Clin Oncol 2010; 28:

35 Serum concentration ( g/ml) Peak MabThera concentration is not reached until cycle 7 MabThera serum concentration measured before each infusion, and monthly post-treatment (N = 18) * MabThera infusion number Months post-treatment * 7 patients evaluable after 9 months of treatment with 4/7 showing detectable MabThera levels. Reiser M, et al. J Clin Oncol 2006; 24:Abstract Reiser M, et al. Blood 2006; 108:Abstract 2748.

36 Rationale for 8 cycles of MabThera in DLBCL There is compelling, accumulating evidence across a broad range of clinical settings showing that the best clinical outcomes for the vast majority of patients with DLBCL are seen with 8 x MabThera 1 5 An intensive curative approach should be used for all newly diagnosed patients with DLBCL 1. Coiffier B, et al. N Engl J Med 2002;346: Coiffer B, et al. Blood 2010; 116: Pfreundschuh M, et al. Lancet Oncol 2008; 9: Pfreundschuh M, et al. J Clin Oncol 2011; 29(Suppl):Abstract Poster presentation. 5. Récher C, et al. Lancet 2011; 378:

37 8 cycles of MabThera in DLBCL: Accumulating evidence Study Regimen Outcome GELA LNH (60 80 yrs) 8 x R-CHOP-21 mpfs: 4.8 yrs 8 x CHOP-21 mpfs: 1.2 yrs 8 x R + 6 x CHOP-14 7-yr EFS: 50% RiCOVER-60 2,3 (61 80 yrs) 6 x CHOP-14 7-yr EFS: 33% 8 x R + 8 x CHOP-14 7-yr EFS: 52% 8 x CHOP-14 7-yr EFS: 40% GELA LNH03-2B 4 (18 59 yrs) 8 x R + 4 x ACVBP-14 3-yr EFS: 81% 8 x R-CHOP-21 3-yr EFS: 67% Cunningham et al. 5 8 x R + 8 x CHOP-21 PFS hazard ratio: 1.0 (p = 0.98) OS hazard ratio: 0.96 (p = 0.75) 8 X R + 6 x CHOP Coiffier B, et al. Blood 2010; 116: Pfreundschuh M, et al. Lancet Oncol 2008; 9: Pfreundschuh M, et al. J Clin Oncol 2011; 29(Suppl):Abstract Poster presentation. 4. Récher C, et al. Lancet 2011; 378: Cunningham D, et al. J Clin Oncol 2011; 29:Abstract 8000.

38 ESMO: 8 x MabThera plus 6 8 x CHOP for the vast majority of 1L DLBCL patients Age (years) 1 > 80 aaipi 0/1 (low/low intermediate risk)* < aaipi 2 (high intermediate/ high risk) MabThera + Attenuated chemo 6 x MabThera 8 x MabThera 8 x MabThera 6 x CHOP x CHOP-21 8 x CHOP-21 8 x MabThera % of 1L DLBCL patients 2 6 x CHOP-14 15% of 1L DLBCL 56% of 1L DLBCL patients 2 patients 2 aaipi = age-adapted International Prognostic Index. * For low-risk (aaipi 0) with bulky disease or low intermediate-risk (aaipi 1) patients, an alternative regimen is 8 x MabThera plus 4 x ACVBP-14. 1,2 Percentage of each sub-population in the total DLBCL population, based on patient record market research with European haematologists (2011; N = 680) Tilly H, et al. Ann Oncol 2012; 23(Suppl 7):vii78 vii Récher C, et al. Lancet 2011; 378: Roche. Data on file.

39 Survival probability 8 x MabThera in patients aged years: GELA LNH-98.5 study PFS 10-year follow-up study in elderly DLBCL patients 8 x R-CHOP vs 8 x CHOP Median PFS: R-CHOP: 4.8 years R-CHOP CHOP: 1.2 years Improved PFS in patients treated with R-CHOP Log-rank p < CHOP Compared to CHOP only, R-CHOP also improved: Overall survival Disease-free survival Time (years) Coiffer B, et al. Blood 2010; 116:

40 PFS (%) x MabThera in patients aged years: RiCOVER-60 study Elderly DLBCL patients (IPI = 1 5) 8 x R + 6 x CHOP-14 8 x R + 8 x CHOP-14 8 x CHOP-14 6 x CHOP Time (months) 6 8 cycles of CHOP ± 8 x MabThera PFS at 3 years: 8 x R + 6 x CHOP: 73.4% 6 x CHOP: 56.9% 8 x R + 8 x CHOP: 68.8% 8 x CHOP: 56.9% Addition of MabThera to CHOP treatment also improved: Overall survival EFS IPI = International Prognostic Index. Pfreundschuh M, et al. Lancet Oncol 2008; 9:

41 EFS (%) 8 x MabThera in young patients: GELA LNH03-2B study Open-label, randomised study in DLBCL patients aged years, aaipi R-ACVBP 8 x R-CHOP vs 8 x R + 4 x ACVBP 3-year EFS: R-AVCBP: 81% HR for event 0.56 (95% CI: ) p = Time (months) R-CHOP R-CHOP: 67% R-ACVBP treatment also improved: PFS Overall survival Modifications of 8 x MabThera + chemotherapy regimens are being assessed at present Récher C, et al. Lancet 2011; 378:

42 International consensus for the use of MabThera in aggressive lymphoma ESMO guidelines recommend 8 x MabThera for the vast majority of DLBCL patients, combined with 6 8 x CHOP 1 EMA- and FDA-approved schedule for first-line DLBCL is 8 x MabThera + chemo 2,3 8 x MabThera plus chemotherapy is the standard of care 1 3 that offers the best chance of a cure for patients with DLBCL Tilly H, et al. Ann Oncol 2012; 23(Suppl 7):vii78 vii MabThera SmPC. 3. RITUXAN Prescribing Information. 4. Coiffier B, et al. N Engl J Med 2002;346: Coiffer B, et al. Blood 2010; 116: Pfreundschuh M, et al. Lancet Oncol 2008; 9: Pfreundschuh M, et al. J Clin Oncol 2011;29(Suppl):Abstract Poster presentation.

43 HIV Challenge

44 Typical HIV related Lymphomas all derived from B cell lymphocytes DLBCL Centroblastic and Plasmablastic (EBV) Burkitt s (Plasmacytoid features) (EBV) Plasmablastic typically of the G.I Tract (EBV) Hodgkin Lymphoma (EBV) Primary effusion/lymphoma (HHV8+EBV) Multicentric Castlemans DLBCL (HHV8)

45 Study using CEP in Uganda and Kenya Mwanda et al. JCO.2009

46 Treatment of AIDS-related Lymphoma Kaplan-Meier PFS and OS, dose-adjusted EPOCH, HAART deferred DA-EPOCH CR: 74% Little R F et al. Blood 2003;101:

47 Treatment of AIDS-related Lymphoma Kaplan-Meier PFS and OS, dose-adjusted EPOCH, HAART deferred DA-EPOCH CR: 74% Little R F et al. Blood 2003;101:

48 Acknowledgements AMPATH Oncology and Hematology NCI Prof. Patrick J Loehrer MD Roche Stellenbosch University/Prof Akin Abayomi KAP