The Evolving Treatment Paradigm for Follicular Lymphoma

The Evolving Treatment Paradigm for Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM The Evolving Treatment Paradigm for Follicular Lymphoma Philip Bierman, MD Professor, Internal Medicine Section of Hematology & Oncology UNMC Oncology/Hematology Section Peggy D. Cowdery Patient Care Center Lied Transplant Center Nebraska Medical Center Omaha, Nebraska My name is Philip Bierman, MD, from the University of Nebraska Medical Center in Omaha, Nebraska. The title of this presentation is “The Evolving Treatment Paradigm for Follicular Lymphoma.” This program is supported by an educational grant from Image: 3D4Medical.com/Copyright©2010 Getty Images, Inc. All Rights Reserved. 1

Evolving Standards of Care in Non-Hodgkins Lymphoma
VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Most Common Lymphomas T lymphoblastic: 2% Other: 9% Marginal zone, nodal: 2% Burkitt: 2% Anaplastic large cell: 2% Diffuse large B cell: 31% Mediastinal large B cell: 2% Mantle cell: 6% CLL, chronic lymphocytic leukemia. This slide shows the distribution of the most common types of non-Hodgkin’s lymphoma. In the West, the most common type of lymphoma is diffuse large B-cell lymphoma, and follicular lymphoma is the second most common type. Follicular lymphomas comprise approximately 20% to 25% of all newly diagnosed lymphomas. There is wide geographic variation in the distribution of non-Hodgkin’s lymphomas. For example, in Asia, follicular lymphoma is much less common than in the West.[1] Reference 1. Biagi JJ, Seymour JF. Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood. 2002;99: Small lymphocytic/CLL: 7% Peripheral T cell: 7% Follicular: 22% Marginal zone, extranodal: 8% Armitage JO, et al. J Clin Oncol. 1998;16: Philip J. Bierman, M.D. 2

Follicular Lymphoma Classification
Evolving Standards of Care in Non-Hodgkins Lymphoma Follicular Lymphoma Classification Grade Characteristic Grade 1 0-5 centroblasts/hpf Grade 2 6-15 centroblasts/hpf Grade 3 > 15 centroblasts/hpf 3a Centrocytes present 3b Solid sheets of centroblasts Hpf, high-powered field. It is important to recognize that follicular lymphoma is not a single disease. Follicular lymphomas are divided into 3 grades depending on the number of centroblasts or large transformed cells observed per high-powered field. For example, follicular lymphoma grade 3 has more than 15 centroblasts per high-powered field. Follicular lymphoma grade 3 is further divided into grade 3a and grade 3b depending on whether centrocytes are visible or whether solid sheets of centroblasts are observed. This grade distinction is critical because follicular lymphoma grade 1 and follicular lymphoma grade 2 are generally considered to have similar behavior. However, some studies suggest that follicular lymphoma grade 3 may exhibit behavior that more closely resembles diffuse large B-cell lymphoma. These patients are most often treated with anthracycline-based regimens. It is also useful to determine the inclusion criteria outlined in the methods sections of published studies because some studies exclude patients with follicular lymphoma grade 3, whereas others include all grades of follicular lymphoma. Blood. 1997;89:

Expert Pathologist Agreement With Consensus Diagnosis (ILSG, N = 304)
Evolving Standards of Care in Non-Hodgkins Lymphoma Expert Pathologist Agreement With Consensus Diagnosis (ILSG, N = 304) Follicular Grade, % Dx 1 Dx 2 Dx 3 Any grade 93 94 Grade 1 72 73 Grade 2 61 Grade 3 60 Dx, diagnosis. The grading of follicular lymphomas is not necessarily reproducible. This slide shows results from an International Lymphoma Study Group project in which cases of follicular lymphoma were reviewed by a panel of expert hematopathologists. An initial diagnosis (diagnosis 1) was made after examination of the hematoxylin-eosin stains alone. A second diagnosis was made with the addition of immunostains and molecular data, and a third diagnosis was made when clinical information was also known. The results show that the expert pathologists were very good at making an overall diagnosis of follicular lymphoma, with > 90% concordance. However, there was only 60% to 70% agreement with a consensus diagnosis for any particular grade; this finding should be kept in mind when considering treating, for example, follicular lymphoma grade 3 differently than follicular lymphoma grade 1 and 2 based on pathologist grading. Blood. 1997;89:

FLIPI Characteristic RR (Death) Older than 60 yrs of age 2.38 Stage III-IV 2.00 Hemoglobin < 12.0 g/dL 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39 FLIPI and OS FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; OS, overall survival; RR, relative risk. A number of prognostic indices have been used for follicular lymphoma, but the Follicular Lymphoma International Prognostic Index (FLIPI) is the most widely used. This index uses 5 variables consisting of the following: age older than 60 years; stage III-IV disease; hemoglobin < 12 g/dL; elevated LDH; and > 4 nodal sites. Using these characteristics, patients are divided into low-, intermediate-, and high-risk groups with 10-year survival ranging from 71% to 36%. Risk Group Risk Factors, n 5-Yr OS, % 10-Yr OS, % Low 0-1 91 71 Intermediate 2 78 51 High ≥ 3 53 36 Solal-Céligny, et al. Blood. 2004;104:

Criticisms of the FLIPI
Evolving Standards of Care in Non-Hodgkins Lymphoma Criticisms of the FLIPI It is a compromise Many important factors not used May not agree with other indices Not all 5 prognostic factors have same relative risk Assumes that FL-3 behaves like FL-1 and FL-2 Data come from the pre-rituximab era FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index. However, there are several criticisms of the FLIPI index, including criticism that this index is a compromise. Many important prognostic variables are not included in the index, and it does not necessarily agree with other indices that have been developed. It is also important to note that not all 5 of the prognostic factors have the same relative risk, and yet they are weighted the same when developing the risk score. It also assumes that a patient with follicular lymphoma grade 3 would respond in the same way as patients with follicular lymphoma grades 1 and 2. Finally, the data that were used to develop the FLIPI were obtained during the pre-rituximab era.

The Follicular Lymphoma International Prognostic Index 2
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM The Follicular Lymphoma International Prognostic Index 2 FLIPI 2 score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point) Longest diameter of largest involved node > 6 cm Bone marrow involvement Hb < 12 g/dL Older than 60 yrs of age β2-microglobulin > ULN FLIPI2 Risk Group Risk Factors, n Patients, % 3-Yr PFS, % 5-Yr PFS, % HR Low 0-1 20 90.9 79.5 1.00 Intermediate 2 53 69.3 51.2 3.19 High 3-5 27 51.3 18.8 5.76 High vs int 1.81 FLIPI, Follicular Lymphoma International Prognostic Index; Hb, hemoglobin; HR, hazard ratio; int, intermediate; PFS, progression-free survival; ULN, upper limit of normal. The FLIPI2 was developed to determine if a better index could be established based on prospective data collection. In addition, the FLIPI2 may be more relevant than the original FLIPI because approximately two thirds of the patients assessed when developing the index were treated with more modern rituximab-containing regimens. This index uses the longest diameter of the largest involved lymph node measuring more than 6 cm, bone marrow involvement, hemoglobin < 12 g/dL, age older than 60 years, and elevated β2-microglobulin. Using this index, 3 risk groups are defined by the number of risk factors, with 5-year progression-free survival rates ranging between 80% and 20%. Federico M, et al. J Clin Oncol. 2009;27: Philip J. Bierman, M.D. 7 7

Other Emerging Prognostic Factors in FL
Evolving Standards of Care in Non-Hodgkins Lymphoma Other Emerging Prognostic Factors in FL Biomarkers in blood and bone marrow Histologic grade Immunophenotype: neoplastic cells Cytogenetics and molecular genetics Host constitutional genetics Nonneoplastic cells of the microenvironment Histologic transformation FL, follicular lymphoma. There are a number of other prognostic factors that may be useful for predicting outcome in follicular lymphoma. For example, biomarkers in the blood may be important, such as the presence of cells with (14;18) translocations or β2-microglobulin level, which is used in the FLIPI2 index. Histologic grade may also be relevant, as noted previously. The immunophenotype of neoplastic cells may have prognostic value, such as in the presence of Mcl-1–positive centroblasts as well as expression of Bcl-2 family proteins. Cytogenetics, molecular genetics, and host constitutional genetics may also play a role in predicting outcomes; for example, it is known that FcγRIII polymorphisms may correlate with response to rituximab. Nonneoplastic cells in the microenvironment may also be important. For example, there is good evidence that host T cells may impact outcomes in patients with follicular lymphoma. Finally, histologic transformation is known to be an important prognostic factor. A large percentage of patients will undergo histologic transformation during the course of disease, and this generally is associated with a poor outcome. Relander T, et al. J Clin Oncol. 2010;28:

Gene Expression: Follicular NHL
Evolving Standards of Care in Non-Hodgkins Lymphoma Gene Expression: Follicular NHL NHL, non-Hodgkin’s lymphoma. In the future, newer technologies such as gene-expression profiles may be used to evaluate prognosis and perhaps to guide therapy. This approach has been found to be useful for a wide variety of lymphomas in addition to follicular lymphoma. This slide shows an example of an expression profile in a study evaluating biopsy specimens from patients with untreated follicular lymphoma. Two gene expression signatures were identified: an immune response 1 signature was associated with favorable prognosis, whereas an immune response 2 signature was associated with poor survival. Dave SS, et al. N Engl J Med. 2004;351: Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Predictive Power of Gene Expression Signature in Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Predictive Power of Gene Expression Signature in Follicular Lymphoma Expression Signature (Prognosis) RR of Death P Value Immune response 1 (favorable) 0.15 < .0001 Immune response 2 (unfavorable) 9.35 RR, relative risk. An immune response 1 signature was associated with a relative risk of death of 0.15, whereas an immune response 2, the unfavorable expression signature, was associated with a risk of death nearly 10-fold higher than the reference group. Dave SS, et al. N Engl J Med. 2004;351:

Survival Predictor Score From Gene-Expression Signature
Evolving Standards of Care in Non-Hodgkins Lymphoma Survival Predictor Score From Gene-Expression Signature Quartile 5-Yr OS, % Median Survival, Yrs 1 86 13.6 2 11.1 3 69 10.8 4 38 3.9 OS, overall survival. Using these signatures, one could divide patients into 4 quartiles with median survivals ranging from 13.6 years to 3.9 years. It is important to note that the genes associated with these immune response signatures were not tumor-associated genes. Instead, they were genes expressed in the nonmalignant host T cells, macrophages, and dendritic cells infiltrating the tumors, suggesting that the host immune response plays an important role in the outcome of patients with follicular lymphoma. Dave SS, et al. N Engl J Med. 2004;351: Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Application of Gene Expression Profiling for Follicular NHL
Evolving Standards of Care in Non-Hodgkins Lymphoma Application of Gene Expression Profiling for Follicular NHL Clinical aggressiveness Risk of transformation Response to rituximab NHL, non-Hodgkin’s lymphoma. The use of gene expression profiling for follicular lymphoma also has a number of other applications. This technique may predict clinical aggressiveness, risk of transformation, and response to rituximab. Glas AM, et al. Blood. 2005;105: Lossos IS, et al. Proc Natl Am Sci U S A. 2002;99: Bohen SP, et al. Proc Natl Am Sci U S A. 2003;100:

Treatment Options for Advanced Low-Grade Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Treatment Options for Advanced Low-Grade Lymphoma Observation (watch and wait) Radiation Single-agent therapy Combination chemotherapy Interferon Monoclonal antibodies Hematopoietic transplantation Antisense molecules Vaccines Targeted agents There are several treatment options for advanced, low-grade lymphoma and, as shown by the National LymphoCare Study, there is no consensus on initial management of patients with follicular lymphoma in the United States. Some patients are managed with observation or a watch and wait approach. Radiation therapy may be a useful approach. Single-agent and combination chemotherapy are also options. Agents such as interferon also are useful in some cases. Monoclonal antibodies may be used by themselves or in combination with chemotherapy. Some patients are candidates for hematopoietic stem cell transplantation. In addition, newer approaches include antisense molecules, vaccines, and targeted agents. Despite all of the new methods available for treating follicular lymphomas, an initial period of observation (or watch and wait) is still a reasonable option for some patients.

Randomized Trials: Low-Grade NHL
Evolving Standards of Care in Non-Hodgkins Lymphoma Randomized Trials: Low-Grade NHL Trial Regimens  FFS  OS Young 1988[1] ProMACE-MOPP + TNI vs watch and wait Yes No Brice 1997[2] Prednimustine vs IF vs watch and wait Ardeshna 2003[3] Chl vs watch and wait Chl, chlorambucil; FFS, failure-free survival; IF, interferon; NHL, non-Hodgkin’s lymphoma; OS, overall survival; ProMACE-MOPP, prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone; TNI, total nodal irradiation. At least 3 prospective, randomized trials have been performed comparing chemotherapy with an initial watch-and-wait approach for follicular lymphoma: a study from the National Cancer Institute evaluated prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, and prednisone plus total nodal irradiation vs a watch and wait approach; a study from France evaluated prednimustine vs interferon vs a watch and wait approach; and a more recent study from the British National Lymphoma Investigation compared chlorambucil with a watch and wait approach. Although 2 of these studies showed improvement in failure-free survival associated with the use of upfront chemotherapy, none of the trials showed that overall survival was impaired by an initial watch and wait approach. In addition, an initial watch and wait approach or period of observation does not appear to increase the risk of histologic transformation. The overall survival from the British National Lymphoma Investigation trial comparing chlorambucil vs observation showed no difference in the overall survival between the 2 groups. 1. Young RC, et al. Semin Hematol. 1988;25(2 suppl 2): Brice P, et al. J Clin Oncol. 1997;15: Ardeshna KM, et al. Lancet. 2003;362:

Follicular Lymphoma: Indications for Therapy in Advanced Disease
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Follicular Lymphoma: Indications for Therapy in Advanced Disease Cytopenias secondary to bone marrow infiltration Threatened end-organ function Symptoms attributable to disease Bulk at presentation Steady progression during > 6 mos of observation Presentation with concurrent histologic transformation Massive splenomegaly Patient preference Candidate for clinical trial During the course of disease, most patients will eventually require treatment. This slide shows some of the indications for initiating treatment for patients with follicular lymphoma. These indications include: cytopenias secondary to bone marrow infiltration; threatened end-organ dysfunction; symptoms attributable to disease; bulky disease at presentation; steady progression during more than 6 months of observation; presentation with concurrent histologic transformation; massive splenomegaly; and patient preference to be treated. In addition, candidates for a clinical trial are also acceptable candidates to begin initial therapy. Philip J. Bierman, M.D. 15 15 15

CVP vs CVP + Rituximab for Stage III-IV Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM CVP vs CVP + Rituximab for Stage III-IV Follicular Lymphoma RANDOMI Z AT ION CVP arm Wks 1 4 7 10 13 16 19 22 Observation R-CVP arm CVP, cyclophosphamide, vincristine. prednisone; R, rituximab. The introduction of rituximab has changed the way follicular lymphomas as well as most other B-cell lymphomas are treated. The addition of rituximab to primary chemotherapy improves survival for patients with follicular lymphoma. One study demonstrating this improvement was an international multicenter trial comparing CVP with R-CVP for follicular lymphoma. This trial included patients with follicular lymphoma grade 3 as well as those with follicular lymphomas grade 1 and 2. Patients received 8 cycles of standard CVP or 8 cycles of CVP combined with rituximab. Marcus R, et al. J Clin Oncol. 2008;26: Philip J. Bierman, M.D. 16

CVP vs CVP + Rituximab for Advanced Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma CVP vs CVP + Rituximab for Advanced Follicular Lymphoma Outcome CVP CVP + Rituximab CR, % 10 41 Duration of response, mos 14 38 4-yr survival, % 77 83 CR, complete remission; CVP, cyclophosphamide, vincristine, prednisone. The results from that trial showed that the addition of rituximab improved the complete remission rate from 10% to 41% and improved the duration of response from a median of 14 months to a median of 38 months. In addition, the 4-year actuarial survival rate was improved from 77% to 83%. Survival data showed a significant improvement in overall survival when R-CVP was compared with CVP alone. Marcus R, et al. J Clin Oncol. 2008;26:

Prolonged Survival With Chemo + Rituximab for FL
Evolving Standards of Care in Non-Hodgkins Lymphoma Prolonged Survival With Chemo + Rituximab for FL CVP vs R-CVP[1] CHOP vs R-CHOP[2] MCP vs R-MCP[3] CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; FL, follicular lymphoma; MCP, mitoxantrone, chlorambucil, prednisolone; R, rituximab. In addition to the CVP trial, there have been randomized trials comparing CHOP vs R-CHOP, showing an improvement in survival associated with the addition of rituximab, as well as a trial comparing mitoxantrone, chlorambucil, and prednisolone vs rituximab plus mitoxantrone, chlorambucil, and prednisolone, also showing improved survival with rituximab addition. 1. Marcus R, et al. J Clin Oncol. 2008;26: Hiddemann W, et al. Blood. 2005;106: Herold M, et al. J Clin Oncol. 2007;25:

StiL: Bendamustine + Rituximab vs CHOP-R in Frontline NHL
Evolving Standards of Care in Non-Hodgkins Lymphoma StiL: Bendamustine + Rituximab vs CHOP-R in Frontline NHL CHOP-R q3w x 6 (n = 253) Patients with frontline iNHL or MCL (N = 549) (n = 513 evaluable patients) Bendamustine-Rituximab q4w x 6 (n = 260) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; iNHL, indolent non-Hodgkin’s lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; R, rituximab. Recent evidence suggests that there may be better regimens than the standard CHOP, CVP, or fludarabine-based regimens. The German Study Group for Indolent Lymphomas presented the final analysis of a trial comparing R-CHOP with R-bendamustine at the 2009 American Society of Hematology meeting. This trial included patients with mantle cell lymphoma, follicular lymphoma, and other indolent lymphomas. Bendamustine was administered at 90 mg/m2 on Days 1 and 2 of a 28-day cycle. For more information, go online to: Rituximab 375 mg/m2 on Day 1; (bendamustine 90 mg/m2 on Days 1-2 q28 days) or (standard CHOP q21 days) x 6 Rummel MJ, et al. Blood. 2009;114. Abstract 405.

StiL: Results Median observation time: 32 mos Outcome CHOP-R R-Bendamustine P Value ORR, % 92.7 91.3 -- CR, % 30.8 40.1 .0323 PFS, mos 34.8 54.9 .00012 EFS, mos 31 54 .0002 Significant PFS benefit for MCL, WM, follicular lymphoma subtypes PFS for follicular lymphoma: CHOP-R 46.7 mos vs R-bendamustine not reached (P = .0281) Significant TTNT benefit overall (P = .0002) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; EFS, event-free survival; MCL, mantle cell lymphoma; ORR, overall response rate; PFS, progression-free survival; R, rituximab; TTNT, time to next treatment; WM, Waldenström macroglobulinemia. The results for all patients are shown on this slide. There was no difference in the overall response rates when R-CHOP and R-bendamustine were compared. However, the complete response rate was higher in patients receiving R-bendamustine, as were the progression-free survival and the event-free survival. For more information, go online to: Rummel MJ, et al. Blood. 2009;114. Abstract 405.

StiL: PFS for FL Patients
Evolving Standards of Care in Non-Hodgkins Lymphoma StiL: PFS for FL Patients R-bendamustine: not reached vs CHOP-R: 46.7 mos (median) HR: 0.63 (95% CI: ; P = .0281) 1.0 0.9 0.8 0.7 R-bendamustine 0.6 Probability of PFS 0.5 0.4 CHOP-R CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CI, confidence interval; FL, follicular lymphoma; HR, hazard ratio; PFS, progression-free survival; R, rituximab. This slide depicts progression-free survival for the subset of patients with follicular lymphoma. The median progression-free survival was not reached for patients receiving R-bendamustine, and it was 46.7 months for patients receiving R-CHOP. For more information, go online to: 0.3 0.2 0.1 12 24 36 48 60 72 Mos Reprinted with permission. Rummel MJ, et al. Blood. 2009;114. Abstract 405.

StiL: Adverse Events for R-Bendamustine vs R-CHOP
Evolving Standards of Care in Non-Hodgkins Lymphoma StiL: Adverse Events for R-Bendamustine vs R-CHOP Adverse Event R-Bendamustine R-CHOP P Value Grade 3/4, % of cycles (n = 1450) (n = 1408) -- Neutropenia 10.7 46.5 < .0001 Leukocytopenia 12.1 38.2 All grades, n of patients (n = 260) (n = 253) Alopecia Infectious complications 96 127 .0025 Paresthesias 18 73 Stomatitis 16 47 CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; R, rituximab. In addition to improved progression-free survival, there were fewer adverse effects associated with the R-bendamustine regimen. There were fewer hematologic toxicities, less alopecia, fewer infections, less peripheral neuropathy, and fewer episodes of stomatitis in the R-bendamustine arm relative to the R-CHOP arm. This regimen would be a good option for the case patient, and it is likely that R-bendamustine will be used with increasing frequency in the United States, particularly for those patients who are older or who have other comorbidities. For more information, go online to: Rummel MJ, et al. ASH Abstract 405.

PRIMA: Rituximab Maintenance vs Observation in Patients With FL
Evolving Standards of Care in Non-Hodgkins Lymphoma PRIMA: Rituximab Maintenance vs Observation in Patients With FL Stratified by response to induction, chemotherapy regimen, and geographic location prior to 1:1 randomization Rituximab maintenance 375 mg/m2 q8w for 2 yrs (n = 505) Induction Immunochemotherapy 8 cycles R-CHOP or R-CVP or R-FCM Untreated patients with high tumor burden follicular lymphoma Response* (N = 1019) 5-yr follow-up Observation (n = 513) CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, unconfirmed complete response; CVP, cyclophosphamide, vincristine, prednisone; FCM, fludarabine, cyclophosphamide, mitoxantrone; FL, follicular lymphoma; PR, partial response; R, rituximab. This question was addressed in the PRIMA trial with data presented at the 2010 American Society of Clinical Oncology annual meeting. Patients with follicular lymphoma, including those with follicular lymphoma grade 3, were treated with either R-CHOP, R-CVP, or rituximab with a fludarabine-containing regimen based on the physician’s choice. Patients who responded were randomized to either observation or to rituximab maintenance with 1 dose every 8 weeks for 2 years. For more information, go online to: *Only patients with CR/CRu/PR randomized to maintenance therapy; 1 patient died during randomization. Salles GA, et al. ASCO Abstract 8004.

PRIMA: Primary Endpoint (PFS) Met at Planned Interim Analysis
Evolving Standards of Care in Non-Hodgkins Lymphoma PRIMA: Primary Endpoint (PFS) Met at Planned Interim Analysis At 24 months, the PFS was significantly better in those patients receiving rituximab maintenance: 82% vs 66% for the control arm (P <.0001) Rituximab maintenance was beneficial for patients regardless of their age group, their FLIPI index or their choice of induction chemotherapy, although the difference was only significant for those patients receiving R‑CHOP Patients who had a complete remission or a partial remission with initial therapy also benefited from rituximab maintenance More adverse events observed in rituximab maintenance arm including neutropenia and infections CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. As shown on this slide, the primary endpoint of progression-free survival was significantly better in patients receiving rituximab maintenance relative to patients managed with observation. At 24 months, the progression-free survival was 82% with rituximab maintenance as compared with 66% for the control observation arm. For more information, go online to: Salles GA, et al. ASCO Abstract 8004.

PRIMA: Conclusions 2 yrs of rituximab maintenance associated with significantly longer PFS vs observation in patients with follicular lymphoma who responded to induction with rituximab plus chemotherapy Rituximab maintenance following R-CHOP may benefit previously untreated patients more than relapsed patients HR following R-CHOP in PRIMA: 0.43[1] HR following R-CHOP in EORTC study of relapsed patients: 0.69[2] More adverse events associated with rituximab maintenance therapy vs observation, but quality of life not affected Longer follow-up needed to evaluate OS CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; R, rituximab. These results show that rituximab maintenance is a reasonable option and, in my opinion, this approach will be used with increasing frequency. However, it is also important to note that there was no overall survival benefit with maintenance rituximab vs observation, and it is not known whether equivalent results would be observed or whether it would be less expensive to re-treat with rituximab at the time of progression. Nevertheless, it is likely that the use of rituximab maintenance will become the standard of care in the United States. For more information, go online to: 1. Salles GA, et al. ASCO Abstract van Oers MH, et al. J Clin Oncol. 2010;[Epub ahead of print].

Rituximab Maintenance for FL: OS
Evolving Standards of Care in Non-Hodgkins Lymphoma Rituximab Maintenance for FL: OS Study or Subgroup Maintenance after first induction Ghielmini 2004 Hochster 2005 Hochster 2007 Subtotal (95% CI) Heterogeneity: CHi2 = 3.57; df = 2 (P = .17); I2 = 44% Test for overall effect: Z = 1.25 (P = .21) Maintenance after 2 or more inductions Forstpointner 2006 Ghielmini 2004 Hainsworth 2005 van Oers 2006 Subtotal (95% CI) Heterogeneity: Chi2 = 3.09, df = 3 (P = .38); I2 = 3% Test for overall effect: Z = 3.43 (P = .0006) Log (HR) SE Weight, % HR (95% CI) 0.98 ( ) ( ) ( ) ( ) 0.49 ( ) ( ) ( ) ( ) ( ) HR (95% CI) CI, confidence interval; FL, follicular lymphoma; HR, hazard ratio; MR, maintenance rituximab; OS, overall survival; SE, standard error. In addition to the PRIMA study, the results of a meta-analysis examining rituximab maintenance for follicular lymphoma showed that maintenance rituximab therapy after first induction improved overall survival, as did rituximab maintenance after 2 or more induction regimens. 0.01 0.1 1 10 100 Vidal L, et al. J Natl Cancer Inst. 2009;101: by permission of Oxford University Press. Favors MR Favors Control

Other Consolidation Strategies
Evolving Standards of Care in Non-Hodgkins Lymphoma Other Consolidation Strategies Interferon Radiolabeled antibodies Hematopoietic stem cell transplantation Vaccines Other consolidation strategies are potentially available, and these include interferon, radiolabeled antibodies, hematopoietic stem cell transplantation, and vaccines. Interferon has been shown to improve survival when used as consolidation therapy for follicular lymphoma. This benefit was also shown in a meta-analysis, but this regimen is deemed to have considerable toxicity and is rarely used in the United States.

Radiolabeled Antibodies (Radioimmunotherapy)
Evolving Standards of Care in Non-Hodgkins Lymphoma Radiolabeled Antibodies (Radioimmunotherapy) 131I-tositumomab 90Y-ibritumomab tiuxetan I, iodine; Y, yttrium. Another option for consolidation therapy is radiolabeled antibodies. Two radiolabeled antibodies are approved for treatment: iodine-131 tositumomab and yttrium-90 ibritumomab tiuxetan. These drugs are both US Food and Drug Administration (FDA) approved for relapsed and refractory, low-grade follicular and transformed lymphomas and recently yttrium-90 ibritumomab tiuxetan was also FDA approved for consolidation treatment of previously untreated follicular lymphoma patients who respond to upfront treatment.

First-line Indolent Lymphoma Trial
Evolving Standards of Care in Non-Hodgkins Lymphoma First-line Indolent Lymphoma Trial Induction Start of Study Consolidation CR Rituximab 250 mg/m2 IV on Days -7 and Y-ibritumomab tiuxetan 14.8 MBq/kg (max MBq/kg) on Day 0 First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combinations, or rituximab combination Unconfirmed CR Random assignment Control PR No additional treatment CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CVP, cyclophosphamide, vincristine, prednisone; PD, progressive disease; PR, partial response; Y, yttrium. The approval for yttrium-90 ibritumomab tiuxetan was based on the results of the FIT trial. In this trial, patients received upfront therapy with a variety of regimens, including chlorambucil, CVP, CHOP, CHOP-like regimens, fludarabine-based regimens, or rituximab combinations. Patients who achieved a complete remission or partial remission were randomized to observation or to consolidation with yttrium-90 ibritumomab tiuxetan. The use of consolidation radioimmunotherapy significantly prolonged progression-free survival. The median survival was 36.5 months in patients receiving consolidation therapy as compared with 13.3 months in the control patients (P < .0001). Consolidative radioimmunotherapy was one of the treatment options for the case patient, and based on these data, this would be an acceptable option. However, it is important to note that there was no difference in overall survival between the treatment arms in this study. In addition, only a small proportion of the patients received what would be considered modern therapy with rituximab-based regimens. Although this is an acceptable treatment choice in my opinion, it is not clear how frequently radiolabeled antibodies will be used for this indication, especially now that most patients will receive rituximab maintenance. Not reached PD No inclusion Morschhauser F, et al. J Clin Oncol. 2008;26:

SWOG 0016: R-CHOP vs CHOP + 131I-Tositumomab in Untreated FL
Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM SWOG 0016: R-CHOP vs CHOP + 131I-Tositumomab in Untreated FL R A N D O M I Z E R-CHOP x 6 Untreated FL, grades 1-3, stages III-IV CHOP x 6 + Tositumomab I-tositumomab CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; FL, follicular lymphoma; I, iodine; PFS, progression-free survival; R, rituximab. It is also important to note that there is a similar intergroup trial, the SWOG 0016 trial, that is ongoing. This study is comparing 6 cycles of R-CHOP with 6 cycles of CHOP followed by iodine-131 tositumomab. This trial has completed accrual, but results have not yet been reported. Endpoints: PFS, response rates, toxicity, and molecular response rates Results expected in 2010 ClinicalTrials.gov. NCT

Randomized Trials of Upfront Autologous Transplantation for FL
Evolving Standards of Care in Non-Hodgkins Lymphoma Randomized Trials of Upfront Autologous Transplantation for FL Trial Measure Transplant, % Control, % P Value GOELAMS[1] 9-yr PFS 64 39 .004 GLSG[2] 5-yr PFS 62 36 < .0001 GELA[3] 7-yr EFS 38 28 .11 GITMO/IIL[4] 4-yr EFS 61 < .001 EFS, event-free survival; FL, follicular lymphoma; PFS, progression-free survival. Another option would be to consolidate patients with upfront hematopoietic stem cell transplantation. At least 4 prospective, randomized trials including studies from the French, German, and Italian Cooperative Groups have examined this approach. As shown on this slide, all of the trials showed improvements in progression-free survival or event-free survival with hematopoietic stem cell transplantation relative to controls. For example, the Italian trial showed an improvement in the 4-year event-free survival from 28% for controls to 61% with upfront transplantation as consolidation therapy. 1. Gyan E, et al. Blood. 2009;113: Lenz G, et al. Blood. 2004;104: Sebban C, et al. Blood. 2006;108: Ladetto M, et al. Blood. 2008;111:

Randomized Trials of Upfront Autologous Transplantation for FL
Evolving Standards of Care in Non-Hodgkins Lymphoma Randomized Trials of Upfront Autologous Transplantation for FL Trial OS Transplant, % Control, % P Value GOELAMS[1] 9 yrs 76 80 .55 GLSG[2] -- GELA[3] 7 yrs 71 .53 GITMO/IIL[4] 4 yrs 81 .96 FL, follicular lymphoma; OS, overall survival. However, overall survival was not prolonged with hematopoietic stem cell transplantation in any of the trials. Therefore, these findings do not support this approach as an option for the case patient, and I do not think that upfront hematopoietic stem cell transplantation should be used for patients with follicular lymphoma outside the context of a clinical trial. 1. Gyan E, et al. Blood. 2009;113: Lenz G, et al. Blood. 2004;104: Sebban C, et al. Blood. 2006;108: Ladetto M, et al. Blood. 2008;111:

Follicular Lymphoma Vaccine Trials
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Follicular Lymphoma Vaccine Trials Mitumprotimut-T (FavId [Id-KLH]) GTOP-99 (KLH [Id-KLH]) BiovaxID (KLH [Id-KLH]) Id, idiotype; KLH, keyhole limpet hemocyanin. Another approach to consolidation that is under investigation is vaccine therapy. There have been 3 prospective randomized trials using idiotype vaccines following upfront therapy either with chemotherapy or rituximab alone for patients with follicular lymphoma. The first 2 vaccines, mitumprotimut-T[1] and GTOP-99,[2] have been evaluated in phase III trials and did not show a survival benefit. Data from a phase III trial of the third vaccine, BiovaxID, were presented at the plenary session of the 2009 American Society of Clinical Oncology annual meeting.[3] For more information, go online to: References 1. Freedman A, Neelapu SS, Nichols C, et al. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol. 2009;27: 2. Levy R, Robertson M, Ganjoo K, Leonard J, Vose J, Denney D. Results of a phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin's lymphoma (fNHL). Program and abstracts of the Annual Meeting of the American Association for Cancer Research; April 12-16, 2008; San Diego, California. Abstract LB-204. 3. Schuster SJ, Neelapu SS, Gause BL, et al. Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: phase III clinical trial results. Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 2. Philip J. Bierman, M.D. 33

Phase III Trial of Idiotype Vaccine Therapy for Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Phase III Trial of Idiotype Vaccine Therapy for Follicular Lymphoma PACE Chemotherapy CR 2:1 CR, complete remission; PACE, prednisone, doxorubicin, cyclophosphamide, etoposide. The study design is shown on this slide. Patients were initially treated with prednisone, doxorubicin, cyclophosphamide, and etoposide chemotherapy. Individuals who achieved a complete remission were randomized in a 2:1 fashion to the vaccine treatment arm or to the control arm. For more information, go online to: Vaccine Control

Phase III Trial of Idiotype Vaccine Therapy for Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Phase III Trial of Idiotype Vaccine Therapy for Follicular Lymphoma 234 patients enrolled 177 (76%) randomized 117 (50%) received ≥ 1 vaccine dose Median time to relapse: 44.2 vs 30.6 mos (P = .045) Among the 234 patients enrolled, 177 (or 76%) were randomized to vaccine or vaccine control treatment, 117 (or 50%) received at least 1 vaccine dose (active or control), and the median time to relapse was significantly better (44.2 months vs 30.6 months; P = .045) in patients who received the active vaccine vs the control vaccine. This represents the first positive phase III vaccine trial in follicular lymphoma. It provides definite proof of concept, and it shows that there is some biologic effect. It is unknown whether this product will ultimately be commercially available, however. For more information, go online to: Schuster SJ, et al. ASCO Abstract 2.

Bendamustine for Relapsed and Refractory Indolent Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Bendamustine for Relapsed and Refractory Indolent Lymphoma Study N CR, % PR, % ORR, % Friedberg[1] 45 37 44 81 Robinson[2] 54 39 93 CR, complete response; ORR, overall response rate; PR, partial response. There are a variety of agents that can be used in the salvage setting. There are also several newer agents that have activity against relapsed/refractory follicular lymphomas. One such agent is bendamustine, which is FDA approved for the treatment of indolent B-cell lymphomas that have progressed during or within 6 months of therapy with rituximab or a rituximab-containing regimen. Two multicenter phase II trials have investigated bendamustine for patients with relapsed and refractory follicular and other indolent lymphomas. The results demonstrated high overall response rates in the range of 80% to 90%. 1. Friedberg JW, et al. J Clin Oncol. 2008;26: Robinson KS, et al. J Clin Oncol. 2008;26:

Single-Agent Bortezomib in Relapsed/ Refractory Indolent Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma Single-Agent Bortezomib in Relapsed/ Refractory Indolent Lymphoma Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11 (up to 8 21-day cycles) given to 59 patients Results (53 evaluable patients) Response Outcome, n (%) CR 1 (1.9) CRu 3 (5.7) PR SD 34 (64.2) PD 12 (22.6) Measure Outcome Median time to response, mos (range) 2.2 ( ) Duration of response, mos (range) 7.9 ( ) 1-yr survival, % 73 2-yr survival. % 58 Median survival, mos (range) 27.7 ( ) Median PFS, mos (range) 5.1 ( ) Median TTP, mos (range) 5.1 ( ) Median EFS, mos (range) 1.8 ( ) CR, complete response; CRu, unconfirmed complete response; EFS, event-free survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTP, time to progression. Another new agent is bortezomib. This slide shows the results of a phase II study of single-agent bortezomib for patients with relapsed and refractory indolent lymphomas. The overall response rate was in the range of 10% to 15%. When the subset of patients with follicular lymphoma was examined, the overall response rate was in the range of 15% to 20%. Bortezomib is another agent that would be acceptable for patients with relapsed/refractory follicular lymphoma. Di Bella N, et al. Blood. 2010;115:

VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Bortezomib + Rituximab in Relapsed/ Refractory FL or MZL (Phase II Study) Bortezomib 1.3 mg/m2 twice wkly on Days 1, 4, 8, 11 of 21-day cycle x 5 + Rituximab 375 mg/m2 on Day 1 once wkly x 4 R A N D O M I Z E Patients with relapsed/refractory FL or MZL (N = 81) ASSESS Bortezomib 1.6 mg/m2/wk on Days 1, 8, 15, 22 of 35-day cycle x 3 + Rituximab 375 mg/m2 on Day 1 once wkly x 4 DR, duration of response; FL, follicular lymphoma; MZL, marginal zone lymphoma; ORR, overall response rate; TTP, time to progression. Bortezomib has been tested in combination with rituximab for patients with relapsed and refractory follicular lymphomas and marginal zone lymphomas. In this study, bortezomib was administered twice weekly for five 21-day cycles or weekly for three 35-day cycles. Primary endpoint: ORR Secondary endpoint: TTP, DR, and safety de Vos S, et al. J Clin Oncol. 2009;27: Philip J. Bierman, M.D. 38

VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Bortezomib + Rituximab in Relapsed/ Refractory FL or MZL: Phase II Efficacy Parameter Arm A Bortezomib 1.3 mg/m2 Twice Wkly (n = 41) Arm B Bortezomib 1.6 mg/m2 Once Wkly (n = 40)* ORR, n (%) 18 (49) 17 (43) CR/CRu, n (%) 5 (14) 4 (10) PR, n (%) 13 (35) 13 (33) Median TTP, mos 7 10 Median PFS, mos 5 CR, complete response; CRu, unconfirmed complete response; FL, follicular lymphoma; MZL, marginal zone lymphoma; ORR, overall response rate; PFS, progression-free survival; PR, partial response; TTP, time to progression. This slide shows that the overall response rates for each arm exceeded 40%. *1 patient with no postbaseline assessment. All differences are not statistically significant. de Vos S, et al. J Clin Oncol. 2009;27: Philip J. Bierman, M.D. 39

VBR in Relapsed/Refractory FL: VERTICAL Study Design
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM VBR in Relapsed/Refractory FL: VERTICAL Study Design Cycle 1 R Days B Cycles 2-5 V B, bendamustine; FL, follicular lymphoma; R, rituximab; V, bortezomib. The phase II VERTICAL trial combined bendamustine with bortezomib and rituximab. These results were presented at the 2009 American Society of Hematology annual meeting. Bendamustine was given on Days 1 and 2 of a 5-week cycle, and bortezomib was given weekly during each cycle. For more information, go online to: Days Patients received five 35-day treatment cycles When given on the same day, the order of administration was V  B  R Reprinted with permission. Fowler N, et al. ASH Abstract 933. Philip J. Bierman, M.D. 40

VBR in Relapsed/Refractory FL (VERTICAL Study): Best Response
VA Indolent Lymphoma v4 Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM 4/19/2017 8:58 PM VBR in Relapsed/Refractory FL (VERTICAL Study): Best Response Response, n (%) Best Response (Investigator Assessment) Last Previous Therapy (N = 62)* VBR (N = 59) ORR 37 (59) 51 (86) CR 20 (32) 31 (53) PR 17 (27) 20 (34) SD 18 (29) 5 (8) PD 7 (11) 3 (5) *Data missing for 1 patient. B, bendamustine; CR, complete response; FL, follicular lymphoma; ORR, overall response rate; PD, progressive disease; PR, partial response; R, rituximab; SD, stable disease; V, bortezomib. The overall response rate in this trial was 86%, which compared favorably with an overall response rate of 59% observed with the last previous therapy for these patients. For more information, go online to: VBR improved response rates and depth of response compared with last previous therapy Median follow-up is 177 days; 11 (17%) patients remain on treatment At data cutoff, duration of response was 1+ to 344+ days Fowler N, et al. ASH Abstract 933. Philip J. Bierman, M.D. 41

Lenalidomide in Relapsed/Refractory Indolent NHL (Phase II Study)
VA Indolent Lymphoma v4 Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM 4/19/2017 8:58 PM Lenalidomide in Relapsed/Refractory Indolent NHL (Phase II Study) A S E Relapsed/refractory indolent NHL (N = 43) Lenalidomide 25 mg on Days 1-21, 28-day cycle Primary endpoint: ORR Secondary endpoints: tumor control rate, duration of response, PFS, safety NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PFS, progression-free survival. Another newer agent with activity in the relapsed/refractory setting is lenalidomide. The use of lenalidomide for relapsed and refractory indolent lymphomas was tested in a multi-institutional phase II trial. Lenalidomide was administered at 25 mg daily on Days 1-21 of a 28-day cycle. Witzig TE, et al. J Clin Oncol. 2009;27: Philip J. Bierman, M.D. 42

Lenalidomide in Relapsed/Refractory Indolent NHL: Phase II Results
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Lenalidomide in Relapsed/Refractory Indolent NHL: Phase II Results Response Patients, % AE (Grade 3/4) ORR 23 Neutropenia 46 CR/CRu 7 Thrombocytopenia 19 PR 16 Febrile neutropenia 2 SD 37 Anemia 9 PD 40 Asthenia 5 (all grade 3) Median PFS: 4.4 mos Median DOR: > 16.5 mos 7/10 responses ongoing at mos AE, adverse event; CR, complete response; CRu, unconfirmed complete response; DOR, duration of response; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. This agent demonstrated activity with a 23% overall response rate. Witzig TE, et al. J Clin Oncol. 2009;27: Philip J. Bierman, M.D. 43

Lenalidomide ± Rituximab in Follicular Lymphoma: CALGB Phase II Study
VA Indolent Lymphoma v4 Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM 4/19/2017 8:58 PM Lenalidomide ± Rituximab in Follicular Lymphoma: CALGB Phase II Study Rituximab on Days 1, 8, 15, 22 Follicular lymphoma patients with previous rituximab exposure, but not rituximab refractory (Planned N = 180) Lenalidomide on Days 1-21 q28 days, max of 12 courses Lenalidomide on Days 1-21 q28 days + Rituximab on Days 8, 15, 22 of course 1 and Day 1 of course 2 Q, every; TTP, time to progression. The combination of lenalidomide and rituximab is being tested in a CALGB trial for patients with previously treated follicular lymphoma. The first arm, rituximab alone, has closed, but the other arms examining lenalidomide alone and lenalidomide plus rituximab are still accruing patients. Primary endpoints: response rate, TTP Secondary endpoint: toxicity ClinicalTrials.gov. NCT Philip J. Bierman, M.D. 44 44

Potential Antibody Targets for B-Cell Lymphomas
VA Indolent Lymphoma v4 Evolving Standards of Care in Non-Hodgkins Lymphoma 4/19/2017 8:58 PM 4/19/2017 8:58 PM Potential Antibody Targets for B-Cell Lymphomas CD40 CD52 CD37 CD74 CD80 CD23 Death receptors CD22 HLA-DR CD20 CD19 Surface immunoglobulin There are many other potential targets on malignant B cells for antibodies other than rituximab, and several newer antibodies are being tested for patients with relapsed and refractory follicular lymphomas. CD5 B cell Cheson BD, et al. N Engl J Med. 2008;359; Copyright © [year of publication] Massachusetts Medical Society. All rights reserved. Philip J. Bierman, M.D. 45

New Antibodies for Follicular Lymphoma
Evolving Standards of Care in Non-Hodgkins Lymphoma New Antibodies for Follicular Lymphoma Antibody Type Epratuzumab Anti-CD22 Ofatumumab Anti-CD20 Galiximab Anti-CD80 Dacetuzumab Anti-CD40 Inotuzumab-ozogamicin Veltuzumab GA-101 This slide lists some of the new antibodies that are being tested for follicular lymphoma treatment. Epratuzumab and the antibody drug conjugate inotuzumab-ozogamicin are directed against CD22 and are under evaluation in clinical trials. Ofatumumab is a human anti-CD20 antibody that recognizes a different epitope than rituximab. This antibody has been approved for treatment of chronic lymphocytic leukemia, and it also has activity against follicular lymphoma; it is being tested in combination with other agents. Galiximab and dacetuzumab target the CD80 and CD40 molecules, respectively. Veltuzumab and GA-101 are examples of humanized anti-CD20 antibodies that are under evaluation in clinical trials. It is unknown whether any of these agents are more effective than rituximab.

Transplantation The final section of this presentation will focus on transplantation for follicular lymphoma.

European CUP Trial Relapsed follicular NHL Salvage chemotherapy (3 cycles) CR or PR ASCT, autologous stem cell transplantation; CR, complete response; NHL, non-Hodgkin’s lymphoma; PR, partial response. Several large, single-institution studies and registry analyses have shown that long-term disease-free survival can be achieved following autologous hematopoietic stem cell transplantation for relapsed follicular lymphomas. The only randomized trial, however, was the European CUP trial. In this trial, patients with relapsed follicular lymphomas received 3 cycles of conventional salvage chemotherapy. Patients who achieved a complete or partial remission were randomized to 3 additional cycles of chemotherapy or transplantation using unpurged or purged autologous bone marrow. Survival for patients receiving autologous stem cell transplantation was significantly longer than for patients treated with conventional chemotherapy. Chemotherapy x 3 Unpurged ASCT Purged ASCT Schouten HC, et al. J Clin Oncol. 2003;21:

Allogeneic Transplantation for FL (CIBMTR)
Evolving Standards of Care in Non-Hodgkins Lymphoma Allogeneic Transplantation for FL (CIBMTR) Allogeneic transplantation is 1 salvage treatment with curative potential Results from study from the CIBMTR showed that the use of conventional chemotherapy regimens and reduced- intensity regimens are associated with a plateau in the OS curves and the potential for cure This treatment, however, carries the greatest risk of morbidity and mortality, but we recommend consideration of this approach for patients who are willing to accept this form of therapy and the potential for cure CIBMTR, Center for International Blood and Marrow Transplant Research; FL, follicular lymphoma. Another option is allogeneic transplantation. This approach is the one salvage treatment with definite curative potential. Results from the Center for International Blood and Marrow Transplant Research demonstrated that conventional chemotherapy regimens and reduced intensity regimens in the setting of allogeneic transplantation are associated with a plateau in the overall survival curves and the potential for cure. This treatment, however, carries the greatest risk of morbidity and mortality. Therefore, we recommend consideration of this approach for patients who are willing to accept this form of therapy and the potential for cure. Hari P, et al. Biol Blood Marrow Transplant. 2008;14:

Recurrent Follicular Lymphoma: Recommended Treatment
Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 4/19/2017 8:58 PM 4/19/2017 8:58 PM Recurrent Follicular Lymphoma: Recommended Treatment Conventional strategies Rituximab ± maintenance Chemoimmunotherapy ± maintenance Radioimmunotherapy External-beam radiotherapy Autologous transplantation Allogeneic transplantation Novel strategies Novel monoclonal antibodies Bortezomib Bendamustine Lenalidomide Others Clinical trial Many treatment options are now available for patients with recurrent follicular lymphoma. In fact, more options are currently available than have ever been available in the past. Conventional strategies include rituximab with or without maintenance, combinations of rituximab plus chemotherapy with or without maintenance, radioimmunotherapy, external beam radiotherapy, autologous hematopoietic stem cell transplantation, and allogeneic transplantation. Novel strategies include newer monoclonal antibodies and new drugs such as bortezomib, bendamustine, and lenalidomide as well as a number of other investigational agents. Patients should always be considered for clinical trials when available. The treatment approach for recurrent disease needs to be individualized. NCCN. Available at: Philip J. Bierman, M.D. 50

Conclusions: We Are Making Progress!
Evolving Standards of Care in Non-Hodgkins Lymphoma Conclusions: We Are Making Progress! 10-Yr Survival Trends for Low-Grade Lymphoma in the US Age Range, Yrs Survival, % 15-44 64 84 45-54 59 81 55-64 54 73 65-74 49 70 75 or older 31 Total 52 72 In conclusion, progress has been made in the field of follicular lymphoma treatment. Several institutions as well as cooperative groups have shown improvements in overall survival for patients with follicular lymphoma. This slide shows United States SEER data for patients with low-grade lymphomas between 1990 and 1992 and 2002 and Overall survival has improved between these 2 time periods for all age groups, and, overall, the 10-year survival rate improved from 52% to 72%. These results are quite remarkable, and I am hopeful that with additional advances in therapy we will continue to see improvements in the survival of patients with follicular lymphoma. Pulte D, et al. Arch Int Med. 2008;168:

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The Evolving Treatment Paradigm for Follicular Lymphoma

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The Evolving Treatment Paradigm for Follicular Lymphoma

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