MANAGEMENT OF LYMPHOMAS

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

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

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

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

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

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

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

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)

B Cell Lymphomas

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

Intermediate Grade Follicular Grade 2 and 3 Mantle cell

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

Very Aggressive Lymphomas Burkitt Lymphoma Lymphoblastic lymphoma

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

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

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

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

Figure 4 Approach to T cell lymphomas

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

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)

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

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

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

Lymphoma staging

Table 1

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

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

Percent Survival The Impact of Adding Rituximab To CHOP (Gela, Ricover, Mint) 1.0.9.8.7.6.5.4 Post-Ritux Pre-Ritux.3.2.1 0 0 Log rank p =0.0009 1 2 3 4 Progression-Free Survival (y)

EFS (%) PFS (%) Overall survival (%) Treatment Young DLBCL patients with IPI = 0 and no bulk can be cured with 6 x R-CHOP-21 100 100 100 80 80 80 60 60 60 40 40 40 20 0 20 20 p = 0.005 p = 0.003 p = 0.029 0 0 0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10 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; 12:1013 1022.

Survival probability Cont d Elderly DLBCL patients can be cured with 8 x R-CHOP-21 1.0 0.8 0.6 0.4 0.2 0.0 Log-rank p < 0.0001 PFS Time (years) R-CHOP CHOP 0 2 4 6 8 10 12 10-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; 116:2040 2045.

The addition of MabThera to CHOP-like chemo significantly improves clinical response 1.0 0.8 0.6 0.4 0.2 0.0 p < 0.0001 British Columbia: Overall survival by treatment era Post-MabThera (MabThera + CHOP-like chemo) Pre-MabThera (CHOP-like chemo alone) 0.0 1 2 3 4 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; 23:5027 5033.

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; 116:2040 2045.

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; 28:4184 4190. 2. Coiffier B, et al. Blood 2010; 116:2040 2045.

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) 1.00 0.75 Prior MabThera: No (n = 41) Prior MabThera: Yes (n = 187) 0.50 0.25 0 p = 0.0010 0 1 2 3 4 5 EFS (years) Gisselbrecht C, et al. J Clin Oncol 2010; 28:4184 4190.

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) 150 100 74 95 113 114 125 117 101 50 39 55 33 0 0 1 2 3 4 5 6 7 8 1 2 3 6 5 0.7 9* 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 7537. Reiser M, et al. Blood 2006; 108:Abstract 2748.

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;346:235 242. 2. Coiffer B, et al. Blood 2010; 116:2040 2045. 3. Pfreundschuh M, et al. Lancet Oncol 2008; 9:105 116. 4. Pfreundschuh M, et al. J Clin Oncol 2011; 29(Suppl):Abstract 8029. Poster presentation. 5. Récher C, et al. Lancet 2011; 378:1858 1867.

8 cycles of MabThera in DLBCL: Accumulating evidence Study Regimen Outcome GELA LNH-98.5 1 (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-14 1. Coiffier B, et al. Blood 2010; 116:2040 2045. 2. Pfreundschuh M, et al. Lancet Oncol 2008; 9:105 116. 3. Pfreundschuh M, et al. J Clin Oncol 2011; 29(Suppl):Abstract 8029. Poster presentation. 4. Récher C, et al. Lancet 2011; 378:1858 1867. 5. Cunningham D, et al. J Clin Oncol 2011; 29:Abstract 8000.

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)* < 60 60 80 aaipi 2 (high intermediate/ high risk) MabThera + Attenuated chemo 6 x MabThera 8 x MabThera 8 x MabThera 6 x CHOP-21 6 8 x CHOP-21 8 x CHOP-21 8 x MabThera + + + + 29% 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). 3 1. Tilly H, et al. Ann Oncol 2012; 23(Suppl 7):vii78 vii82. 2. Récher C, et al. Lancet 2011; 378:1858 1867. 3. Roche. Data on file.

Survival probability 8 x MabThera in patients aged 60 80 years: GELA LNH-98.5 study 1.0 0.8 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 0.6 0.4 R-CHOP CHOP: 1.2 years Improved PFS in patients treated with R-CHOP 0.2 0.0 Log-rank p < 0.0001 CHOP Compared to CHOP only, R-CHOP also improved: Overall survival 0 2 4 6 8 10 12 Disease-free survival Time (years) Coiffer B, et al. Blood 2010; 116:2040 2045.

PFS (%) 100 90 80 70 60 50 40 30 0 8 x MabThera in patients aged 61 80 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-14 0 10 20 30 40 50 60 70 80 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; 9:105 116.

EFS (%) 8 x MabThera in young patients: GELA LNH03-2B study Open-label, randomised study in DLBCL patients aged 18 59 years, aaipi 2 100 80 R-ACVBP 8 x R-CHOP vs 8 x R + 4 x ACVBP 3-year EFS: R-AVCBP: 81% 60 40 20 0 HR for event 0.56 (95% CI: 0.38 0.83) p = 0.0035 0 12 24 36 48 60 72 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; 378:1858 1867.

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 4 7 1. Tilly H, et al. Ann Oncol 2012; 23(Suppl 7):vii78 vii82. 2. MabThera SmPC. 3. RITUXAN Prescribing Information. 4. Coiffier B, et al. N Engl J Med 2002;346:235 242. 5. Coiffer B, et al. Blood 2010; 116:2040 2045. 6. Pfreundschuh M, et al. Lancet Oncol 2008; 9:105 116. 7. Pfreundschuh M, et al. J Clin Oncol 2011;29(Suppl):Abstract 8029. Poster presentation.

HIV Challenge

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)

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

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;101:4653-4659

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;101:4653-4659

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