DLBCL,NCI Prof Hussien

Information about DLBCL,NCI Prof Hussien

Published on July 17, 2014

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Current Status Of Management of Adult Diffuse Large B Cell Lymphoma : Current Status Of Management of Adult Diffuse Large B Cell Lymphoma By Dr. Hussein M. Khaled Professor of Medical Oncology Cairo University Most Common Subtypes of NHL: Most Common Subtypes of NHL Follicular (25%) Small lymphocytic (7%) MALT type marginal zone B cell (7.5%) Nodal type marginal zone B cell (< 2%) Lymphoplasmacytic (< 2%) Diffuse large B cell (30%) T and NK cell (12%) Other subtypes (9%) Burkitt (2.5%) Mantle cell (6%) Lichtman. Williams Hematology, 7th Ed. 2006;1408. PowerPoint Presentation: Relative frequency of subtypes of Non-Hodgkin’s lymphoma Aggressive Lymphomas: Aggressive Lymphomas B cell: 1- Mantle cell lymphoma 2-FCC , grade III 3-DLBC 4-Primary mediastinal large cell T cell: 1- Peripheral T cell lymphoma 2- Intestinal T cell lymphoma 3- Angiocentric Lymphoma 4- Angioimmunoblastic lymphoma 5- ATLL 6- Anaplastic large cell lymphoma Diffuse Large B-Cell Lymphoma: Diffuse Large B-Cell Lymphoma Peak incidence in sixth decade Clinical outcomes and molecular features highly heterogeneous Large cells with loss of follicular architecture 30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms May present as extranodal disease (stomach, CNS, testis, skin) Curable in 50% or more of cases Median survival : wks to mos if not treated Michallet AS, et al. Blood Rev. 2009;23:11-23. PowerPoint Presentation: As we learn more about the biology of lymphomas, it is clear that diffuse large B-cell lymphoma is not just 1 disease New WHO Classification of DLBCL: New WHO Classification of DLBCL Centroblastic Immunoblastic Anaplastic Plasmablastic T-cell rich ALK positive CD5 positive GCB Non-GCB Primary CNS Primary cutaneous, leg type Mediastinal Intravascular Primary effusion EBV positive in elderly With chronic inflammation Lymphomatoid granulomatosis In HHV-8–associated Castleman’s disease Campo E, et al. Blood. 2011;117:5019-5032. Jaffe ES, et al. Hematology Am Soc Hematol Educ Program. 2011;2011:506-514. Other Variants of DLBCL: Other Variants of DLBCL Interface DLBCL/Burkitt Interface mediastinal DLBCL/nodular sclerosing Hodgkin’s disease Genetic subtypes—double hit ( MYC and BCL2 ) Leukemic DLBCL Age Adjusted IPI <60Y: Age Adjusted IPI <60Y P S≥1 L DH>N S tage III/IV score CR% 5Y DFS 5Y OS low 0 92 90 80 Low Int. 1 80 70 70 High Int. 2 60 50 50 High 3 50 30 30 Outcome by IPI Risk Group With or Without Rituximab: Outcome by IPI Risk Group With or Without Rituximab Estimated from Ziepert M, et al. J Clin Oncol. 2010;28:2373-2380. Adverse IPI Risk Factors, n 4-Yr Event-Free Survival, % [1] Without Rituximab With Rituximab 1 68 80 2 48 62 3 39 50 4-5 20 47 Microarray Analysis and Diffuse Large B-Cell Lymphoma Heterogeneity: Microarray Analysis and Diffuse Large B-Cell Lymphoma Heterogeneity Alizadeh AA, et al. Nature. 2000;403:503-511. GCB-DLBCL ABC-DLBCL Probability 1.0 0.5 0 0 6 10 OS (Yrs) 4 2 8 12 All Patients GC B like P = .01 19 patients, 6 deaths Activated B like 21 patients, 16 deaths PowerPoint Presentation: Nebraska Group : Treatment of a ggressive lymphomas First and only rule To cure the patient with the first line of treatment Factors Affecting Treatment Decision: Treatment Patient Age Performance score Comorbidity Lymphoma Histology Stage Tumoral mass Site IPI score Physician Lymphoma knowledge Factors Affecting Treatment Decision Clinical Issues in the Treatment of Patients With Diffuse Large B-Cell Lymphomas: Clinical Issues in the Treatment of Patients With Diffuse Large B-Cell Lymphomas Best chemotherapy regimen Localized disease Bulky masses Patient with CHF Highly proliferative tumors Elderly CHOP vs second- and third-generation regimens in aggressive NHL: Overall survival: CHOP vs second- and third-generation regimens in aggressive NHL: Overall survival N Engl J Med 1993; 328:1002–1006 . Regimen n Deaths 3-year OS CHOP 225 88 54% M-BACOD 223 93 52% ProMACE-CytaBOM 233 97 50% MACOP-B 218 93 50% 0 2 4 6 Time (years) p = 0.90 0 20 40 60 80 100 Patients (%) Management of Diffuse Large B Cell Lymphomas: Management of Diffuse Large B Cell Lymphomas How to improve on these largely unsatisfactory results – Future Directions : The combination of monoclonal antibodies with chemotherapy New active agents Dose dense therapy High dose therapy and PBSCT Strategies to overcome drug resistance Potential effects of anti-CD20 antibodies on tumor cells: Potential effects of anti-CD20 antibodies on tumor cells Complement fixation CD20 on malignant cell surface Active signaling (apoptosis induction) ADCC Fc g R CR3 GELA LNH-98.5: Improved PFS with R-CHOP after 7 years’ follow-up: GELA LNH-98.5: Improved PFS with R-CHOP after 7 years’ follow-up J Clin Oncol 2007; 25:Abstract 8009. Time (years) R-CHOP CHOP 1 0 2 3 4 5 6 7 8 Probability 0.8 0.6 0.4 0.2 0 1.0 p < 0.0001 GELA LNH-98.5: Improved OS with R-CHOP after 7 years’ follow-up: GELA LNH-98.5: Improved OS with R-CHOP after 7 years’ follow-up J Clin Oncol 2007; 25:Abstract 8009. Time (years) Probability CHOP 1 0 2 3 4 5 6 7 8 0.8 0.6 0.4 0.2 0 1.0 p = 0.0004 R-CHOP PowerPoint Presentation: Event-free Survival R-CHEMO (03/04 ) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability 0 12 24 36 48 60 72 84 96 108 120 Months 55.7 % 74.0 % 58.8 % 77.9 % R-CHEMO (07/10 ) CHEMO (07/10 ) R-CHEMO (07/10 ) p<0.0001 p<0.0001 PowerPoint Presentation: 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability 0 12 24 36 48 60 72 84 96 108 120 M o n t h s 89.8 % 80.0 % Overall Survival R-CHEMO (n=413) CHEMO (n=410) p=0.001 p=0.001 Population-Based Effect of Rituximab in DLBCL in British Columbia: Population-Based Effect of Rituximab in DLBCL in British Columbia March 2001: CHOP + rituximab recommended for all patients with newly diagnosed advanced-stage DLBCL Analysis of survival 18 mos before and 18 mos after CHOP + rituximab recommendation was conducted No difference in age, IPI score, LDH, or bulky disease Sehn LH, et al. J Clin Oncol. 2005;23:5027-5033. Patient Population n Treatment Received, % CHOP Like CHOP Like + Rituximab Before March 2001 140 90 10 After March 2001 152 14 86 PowerPoint Presentation: Sehn, L. H. et al. J Clin Oncol; 23:5027-5033 2005 Overall survival by treatment era All Patients in British Columbia: N=294 Is There a Best Chemotherapy Regimen?: Is There a Best Chemotherapy Regimen? CHOP-R-21 CHOP-R-14 EPOCH-R ACVBP-R LNH 03-6B GELA: Study Design: LNH 03-6B GELA: Study Design Final analysis of a multicenter, prospective, randomized phase III trial Median follow-up: 56 mos Delarue R, et al. ASCO 2012. Abstract 8021. Treatment-naive patients with CD20-positive stage II-IV DLBCL aged 60-80 yrs (N = 600) CHOP-14 + Rituximab + Methotrexate* (n = 304) CHOP-21 + Rituximab + Methotrexate † (n = 296) CHOP-14 + Rituximab CHOP-21 + Rituximab Induction Consolidation *Induction phase: 8 wks; consolidation phase: 10 wks. † Induction phase: 12 wks; consolidation phase 13 wks. Response assessed at beginning of consolidation phase in both arms. LNH 03-6B GELA: Efficacy Outcomes: LNH 03-6B GELA: Efficacy Outcomes No efficacy difference between different CHOP dosing regimens when combined with rituximab in elderly DLBCL patients Delarue R, et al. ASCO 2012. Abstract 8021. Efficacy Outcome CHOP-14 + Rituximab (n = 304) CHOP-21 + Rituximab (n = 296) OR, % CR/CRu PR 87 71 16 86 74 12 3-yr EFS, % 56 60 HR (95% CI) 1.04 (0.82-1.31; P = .76) 3-yr PFS, % 60 62 HR (95% CI) 0.99 (0.78-1.26; P = .90) 3-yr DFS, % 72 67 HR (95% CI) 0.80 (0.58-1.10; P =.16) 3-yr OS, % 69 72 HR (95% CI) 0.96 (0.73-1.26; P = .75) LNH 03-6B GELA: Perspectives: LNH 03-6B GELA: Perspectives In the pre-rituximab era , superior OS seen with dose-dense CHOP- 14 regimen vs CHOP- 21 However, current study shows no survival difference between CHOP-14 and CHOP-21 when rituximab is added Thus, R + CHOP-21 remains the standard of care Delarue R, et al. ASCO 2012. Abstract 8021. PowerPoint Presentation: What is certain right now is that the regimen must include rituximab PowerPoint Presentation: Localized Disease SWOG 8736: SWOG 8736   All patients had stage I, stage IE (including bulky disease), nonbulky stage II, or nonbulky stage IIE disease. Bulky disease was defined as a mediastinal mass with a maximal diameter exceeding one third the maximal chest diameter or any other mass 10 cm or more in maximal diameter. intermediate- or high-grade non-Hodgkin's lymphoma (working-formulation groups D through J), excluding patients with lymphoblastic lymphoma Patients were randomly assigned to receive eight cycles of CHOP alone or three cycles of CHOP followed by radiotherapy Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma. SWOG 8736: Overall Survival: SWOG 8736: Overall Survival CHOP + radiotherapy (n = 200) Yrs After Randomization OS (%) P = .02 CHOP alone (n = 201) Miller TP, et al. N Engl J Med. 1998;339:21-26. 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Impact of XRT on Treatment Outcome After CR to CHOP: ECOG Study 1484: Impact of XRT on Treatment Outcome After CR to CHOP: ECOG Study 1484 stage I (with risk factors) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomly assigned to 30 Gy involved-field RT or OBS. PR patients received 40 Gy RT. For patients in CR after CHOP, low-dose RT prolonged DFS and provided local control, but no survival benefit was observed. Future efforts should be directed toward improved imaging and more effective systemic therapies. Impact of XRT on Treatment Outcome After CR to CHOP: ECOG Study 1484: Impact of XRT on Treatment Outcome After CR to CHOP: ECOG Study 1484 Horning SJ, et al. J Clin Oncol. 2004;22:3032-3038. 6-Yr Outcome, % CHOP x 8 CHOP x 8 + XRT P Value FFS 53 70 .05 OS 67 79 .23 Are late relapses a reflection of inadequate systemic therapy?: Are late relapses a reflection of inadequate systemic therapy? LNH93-1 Study: Event-Free Survival: Median follow-up: 7.7 yrs Reyes F, et al. N Engl J Med. 2005;352:1197-1205. LNH93-1 Study: Event-Free Survival Probabilty of Event-Free Survival (%) 80 60 40 20 0 0 4 7 10 11 Yrs After Randomization 90 70 50 30 10 3 1 5 6 8 9 ACVBP (n = 318) CHOP(3cycles) + radiotherapy (n = 329) P < .001 100 2 MInT Study in Young Good Prognosis Patients With DLBCL: EFS and OS: MInT Study in Young Good Prognosis Patients With DLBCL: EFS and OS Mos Pfreundschuh M, et al. Lancet Oncol. 2011;12:1013-1022. OS EFS EFS (%) 100 80 60 40 20 0 0 120 Mos 90 70 50 30 10 48 24 72 96 Log-rank P = .212 R-CHOP-21, IPI = 0, no bulk R-CHOEP-21, IPI = 0, no bulk OS (%) 100 80 60 40 20 0 0 120 Mos 90 70 50 30 10 48 24 72 96 Log-rank P = .106 R-CHOP-21, IPI = 0, no bulk R-CHOEP-21, IPI = 0, no bulk Are late relapses a reflection of inadequate systemic therapy?: Are late relapses a reflection of inadequate systemic therapy? So , if you give adequate and effective systemic therapy , you may not need local radiotherapy. PowerPoint Presentation: Can PET scans help? Limited-Stage DLBCL Therapy and PET Scans: British Columbia Experience: Limited-Stage DLBCL Therapy and PET Scans: British Columbia Experience 134 patients Stage I/II No B symptoms Mass ≤ 10 cm CHOP-R x 3 → PET scan PET positive → IFRT PET negative → CHOP-R x 1 Sehn LH, et al. 2011 ICML . Abstract 028. Limited-Stage DLBCL Therapy and PET Scans (British Columbia): Outcomes: Limited-Stage DLBCL Therapy and PET Scans (British Columbia) : Outcomes Sehn LH, et al. International Conference on Malignant Lymphoma 2011. Abstract 028. PET Positive PET Negative Patients, n 30 103 Relapse/death, n 9/4 7/0 3-yr TTP, % 60 92 Probably : yes Large Masses: Any Need for Radiotherapy if the PET Scan Turns Negative?: Large Masses : Any Need for Radiotherapy if the PET Scan Turns Negative? MInT trial (retrospective analysis) suggested that radiotherapy might reduce relapse There is no prospective trial Pfreundschuh M, et al. Lancet Oncol. 2011;12:1013-1022. Regimens for Patients With Congestive Heart Failure: Regimens for Patients With Congestive Heart Failure Delete doxorubicin and add: Mitoxantrone Liposomal doxorubicin Etoposide Procarbazine Aapro M, et al. Ann Oncol. 2011;22;257-267. Corazzelli G, et al. Br J Haematol. 2011;154:579-589 . CHOP-R vs CEOP-R in Patients With DLBCL (British Columbia): CHOP-R vs CEOP-R in Patients With DLBCL (British Columbia) Patients with a contraindication to anthracycline (88% cardiac, 9% previous anthracycline) received etoposide 50 mg/m 2 on Day 1 and 100 mg/m 2 on Days 2 and 3 Moccia AA, et al. ASH 2009. Abstract 408. CHOP-R CEOP-R Patients, n 162 (matched controls) 81 5-yr TTP, % 62 57 ( P = NS) 5-yr OS, % 64 49 ( P = .02) Highly Proliferative Variants of DLBCL: Highly Proliferative Variants of DLBCL Lymphomas with characteristics intermediate between DLBCL and Burkitt Double hit DLBCL ( MYC and BCL-2 ) MYC-positive DLBCL DLBCL with Ki-67 > 90% but does not fit into the other groups Campo E, et al. Blood. 2011;117:5019-5032. Jaffe ES, et al. Hematology Am Soc Hematol Educ Program. 2011;2011:506-514. Highly Proliferative Variants of DLBCL: Highly Proliferative Variants of DLBCL There is some evidence that patients with these subtypes do better when treated with intensive regimes, such as EPOCH-R CODOX-M/IVAC-R Salaverria I, et al. J Clin Oncol. 2011;29:1835-1843. Crockett DG, et al. ASH 2011. Abstract 2710. Elderly Patient Management: Elderly Patient Management Decision regarding which older patients should receive “standard” regimens and which should receive less intensive/palliative approaches is part of the “ art ” of medicine Treatment should not be changed solely because of age —some patients in their 80s will easily tolerate CHOP-R and be cured Therapy-related morbidity/mortality can sometimes be reduced with “ prephase ” treatment Morrison VA. Expert Rev Anticancer Ther. 2008;8:1651-1658. Prephase Therapy in the Elderly: Prephase Therapy in the Elderly Done to allow workup and reduce first-cycle deaths Vincristine 1 mg x 1 and prednisone 100 mg/day x 5-7 50% reduction in first-cycle deaths Personal communication, Michael Pfreundschuh, MD. Following Patients in CR: Following Patients in CR Surveillance images are not of proven value, are expensive, and have risk Do not initiate salvage therapy without biopsy proof of relapse Recurrent Lymphomas: Recurrent Lymphomas If still chemotherapy sensitive , autotransplantation is the treatment of choice Common salvage regimens include RICE or R-DHAP Don’t forget that radiotherapy can be used to relieve symptoms NCCN. Clinical practice guidelines in oncology: non-Hodgkin’s lymphoma. v.2.2012. Novel Approaches and Ongoing Clinical Trials: Novel Approaches and Ongoing Clinical Trials Investigational Therapies for DLBCL: Investigational Therapies for DLBCL Bortezomib—proteasome inhibitor Enzastaurin—PKC β -selective inhibitor PCI-32765—Btk Inhibitor Epratuzumab—recombinant, humanized, monoclonal CD22 antibody Everolimus—mTOR inhibitor Bendamustine Lenalidomide—immunomodulator, antiangiogenic Radioimmunotherapy Tamatinib—specific inhibitor of Syk in B-cell signaling pathway MAIN: Phase III Trial of R-CHOP ± Bevacizumab in DLBCL: MAIN: Phase III Trial of R-CHOP ± Bevacizumab in DLBCL Seymour JF, et al. ASH 2012. Abstract 58. Treatment-naive patients with CD20-positive DLBCL and normal cardiac function (N = 787) Bevacizumab + R-CHOP (n = 390) Placebo + R-CHOP (n = 397) Maintenance therapy † for patients with CR Primary endpoint: PFS MAIN Trial of R-CHOP ± Bevacizumab in DLBCL: Survival: MAIN Trial of R-CHOP ± Bevacizumab in DLBCL: Survival Outcome Bevacizumab + R-CHOP (n = 390) R-CHOP (n = 397) HR (95 % CI) P Value PFS 1.09 ( 0.85-1.40) .49 Patients with events, n (%) 123 ( 32) 123 ( 31) Median PFS, mos (95% CI) 40.2 ( 36.6-48.6) 42.9 (39.5 to not reached) OS 1.03 (0.76-1.40) .84 Patients with events, n (%) 82 (21) 83 (21) Median OS Not reached Not reached Seymour JF, et al. ASH 2012. Abstract 58. Elderly Subpopulations of RICOVER-60: Study Rationale: Elderly Subpopulations of RICOVER-60: Study Rationale Little pharmacokinetic data available for rituximab in DLBCL Dosing of rituximab with CHOP based on empiric data only Carries risk of suboptimal dosing and not achieving full efficacy potential of rituximab Study investigated serum levels and pharmacokinetic parameters of rituximab when combined with CHOP among elderly patients treated in RICOVER-60 study Pfreundschuh M, et al. ASCO 2012. Abstract 8024. Elderly Subpopulations of RICOVER-60: Rituximab Clearance and Elimination: Elderly Subpopulations of RICOVER-60: Rituximab Clearance and Elimination More rapid clearance of rituximab in male vs female patients T1/2 in serum: 24.7 vs 33.4 days ( P = .003) Correlated with poorer PFS in males (RR: 1.59; P < .01) Significantly improved PFS was observed with addition of rituximab among females < 60 kg ( P = .002) but not among females >77 kg Pfreundschuh M, et al. ASCO 2012. Abstract 8024. Elderly Subpopulations of RICOVER-60:: Elderly Subpopulations of RICOVER-60: Data emphasizes the fact that patients may not necessarily require new drugs to achieve better outcomes Simply ensuring the existing agents (eg, rituximab) are given with an optimal dose and schedule may help to improve patient outcomes Pfreundschuh M, et al. ASCO 2012. Abstract 8024. DLBCL Treatment: DLBCL Treatment R CHOP the standard of care for the upfront therapy of DLBCL according to current NCCN guidelines For patients with higher risk IPI score, a clinical trial may be appropriate At the time of relapse, patients can be considered for stem cell transplantation If they are transplant candidates, they should receive salvage therapy and then transplantation or, potentially, a clinical trial For patients who are not candidates for transplantation, enrollment in a clinical trial would be appropriate. Thank you: Thank you

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