ON
Oncology

DEBATE: AUTOLOGOUS STEM CELL TRANSPLANT AS STANDARD THERAPY FOR MANTLE CELL LYMPHOMA

March 21, 2012.
Koen Van Besien, MD,
John P. Leonard, MD,
Timothy S. Fenske, MD,

Educational Objectives

The goal of this program is to improve the management of mantle cell lymphoma (MCL). After hearing and assimilating this program, the clinician will be better able to:

1. Evaluate the evidence supporting autologous stem cell transplantation (ASCT) and intensive therapies vs less intensive therapies for MCL.

2. Compare the benefits and risks of nonintensive therapy to those of ASTC and intensive chemotherapy.

3. Determine which patients with MCL are more likely to benefit from ASCT.

4. Recognize the limitations of current research in ASCT for MCL.

5. Consider the patient’s goals for treatment in choosing a therapeutic approach to MCL.

Summary

Introduction: management of mantle cell lymphoma (MCL) controversial; outcomes appear to be improving

Argument against autologous stem cell transplantation (ASCT): German study — patients treated with conservative regimens had favorable outcomes; only one-sixth had ASCT in first remission; reason for improvements unclear (not likely due to more effective use of ASCT; novel agents not used; study may have been biased; outcomes in MCL known to be highly variable)

Stratification: study assessing MCL International Prognostic Index (MIPI) scores showed that patients classified as low risk had fairly good outcomes; most treated with low-intensity regimens; other techniques (eg, Ki-67, gene expression profiling) available; patients with MCL may require different treatment approaches based on risk

Argument for ASCT: Nordic Lymphoma Group study —patients received intensive up-front therapy; survival rate 75% at 5 yr; flattening of overall survival (OS) and event-free survival curves observed; debate — more intensive therapy up front (producing longer initial remissions) vs less risky, more easily tolerable therapy with shorter remission, but possibly similar OS; limited randomized trials available; presently, no consensus about front-line therapy for MCL (recommended regimens equally divided between ASCT and less aggressive therapies)

Pro

Koen Van Besien, MD, Professor of Medicine and Director, Stem Cell Transplantation and Lymphoma, University of Chicago, Pritzker School of Medicine, Chicago, IL

Background: 2002 data on MCL showed 20% survival after 5 yr; German study (1998) — patients achieving remission had better outcomes than those not achieving remission; ASCT best method to achieve remission; better remission leads to improved OS; intensive chemotherapy (CTX) resulted in better outcomes; Finnish study — patients with MCL treated with long course of anthracycline-containing CTX had 1 to 2 yr survival advantage, compared to patients treated with minimal CTX; rituximab — before its introduction, patients receiving ASCT relapsed (likely due to heavy contamination of stem cells by tumor); ASCT became good treatment for MCL only after introduction

Other treatments: rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone (R-CHOP) — in prospective randomized trial, achieved more remissions than CHOP alone, but nearly all patients relapsed; no improvement in survival seen after 2 yr; Romaguera study — 97 patients treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin) and dexamethasone (hyper-CVAD), alternating with high-dose methotrexate and cytarabine (ARA-C); achieved disease-free survival (DSF) of 50%; only 30% still in remission at 4 yr follow-up; 5 patients died during treatment due to regimen’s toxic effects; 5 of 35 long-term survivors developed myelodysplastic syndrome (MDS) during first remission; 29% patients did not complete therapy; hyper-CVAD has long-term effectiveness in »30% of patients, but difficult and toxic regimen

Bendamustine: has fewer adverse effects; complete remission (CR) rate reported as 40% in study of patients with follicular cell lymphoma or MCL (outcomes superior to those with R-CHOP; CR possibly lower in patients with MCL); Rummel study — no elevated rates of treatment-related MDS seen; rate of secondary MDS comparable to that seen with other regimens; Carney study — £20% of patients receiving combination therapy and nucleoside analogues experienced therapy-related MDS

Conclusions: caution necessary in use of new drugs; current MCL treatments have limited effectiveness and/or high toxicity

Efficacy of ASCT: previously, patients exposed to cyclophosphamide and total-body irradiation (CY-TBI) before collection of stem cells; now, more often exposed to CTX-based conditioning regimens; in-vivo purging of residual MCL cells that contaminate stem cells exceedingly important for achieving durable remission; Magni study (2000) — patients treated with intensive regimen of cyclophosphamide, ARA-C, melphalan, then mitoxantrone plus melphalan; stem cells collected and reinfused with rituximab after each round of CTX; 50% of stem cells devoid of detectable MCL after cyclophosphamide; after completion of all rounds of therapy, 100% of collections devoid of MCL; DFS 80% after 24 mo; Nordic Lymphoma Group study — patients treated with modified CHOP, ARA-C, and rituximab; responders given high-dose carmustine, etoposide, ARA-C, and melphalan or cyclophosphamide (BEAM or BEAC); additional rituximab given if MCL-positive on polymerase chain reaction (PCR) testing; long-term DFS »60% (patients in remission at 4-6 yr); Cancer and Leukemia Group B (CALGB) study —patients treated with methotrexate-based CTX, followed by ASCT, and received rituximab after transplantation; long-term survival 50%; ASCT associated with high rate of well-tolerated durable remissions; few treatment-related deaths and no known therapy-related MDS seen

Tolerability of ASCT: evidence supports tolerability of ASCT drug regimens in older patients; data from 2005 to 2006 — treatment-related mortality 5% in patients undergoing ASCT if transplanted during first remission (higher if ASCT done after relapse); age of patients treated with ASCT has increased (between 2003 and 2007, majority of transplanted patients 50-69 yr of age)

ASCT as front-line treatment: ASCT preferably done as soon as possible; avoid waiting until relapse (becomes less efficacious and more toxic); Seattle study — 80% DFS seen in patients treated with ASCT for MCL after first remission; DFS only £50% in patients treated after relapse; treatment-related mortality — 5% with early transplantation; 12% with late transplantation

Therapy-related leukemia: Gribben study — cumulative incidence of therapy-related MDS 20% in patients with follicular lymphoma who received ASCT in second remission; however, TBI used, as well as drugs such as etoposide for mobilization of stem cells; speaker states that MDS caused by treatments that precede ASCT; Wake Forest study — 9 of 12 patients who developed therapy-related MDS had karotypic abnormalities in pretransplantation stem cell collections; early transplantation avoids such late complications

Importance of induction regimen: retrospective studies — patients in first CR after R-CHOP induction had 30% long-term DSF after ASCT; DFS 80% after R-hyper-CVAD induction; German study — patients randomized to R-CHOP alternating with rituximab, dexamethasone, ARA-C, and cisplatin (R-DHAP) before ASCT had significantly higher CR rates and longer time to treatment failure, compared to patients treated with R-CHOP alone before ASCT; speaker concludes that induction regimen for ASCT should include ARA-C based regimen (eg, R-hyper-CVAD) in addition to anthracyclines; Hill study — patients in first remission after treatment with hyper-CVAD had poor mobilization of stem cells (10-fold fewer C34 cells collected on day 1; resulted in greater number of patients requiring 2 attempts at mobilization and more failures); speaker recommends collecting stem cells earlier in course of hyper-CVAD therapy

Con

John P. Leonard, MD, Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, Professor of Medicine, and Associate Director for Clinical Research, Weill Cornell Medical College; Clinical Director, New York-Presbyterian Hospital/Weill Cornell Center for Lymphoma and Myeloma, New York, NY

Key reminders: literature full of regimens from phase II studies (often single-center) with results that appear convincing (compared to historical data), but ultimately fail; data from randomized studies of intensive vs nonintensive therapy limited; intensive therapy beneficial, but more toxic in short term; treatment goals — cure, prolongation of life, and maintaining quality of life (QOL); speaker believes intense CTX and ASCT neither cure MCL nor prolong life; assessment of QOL varies from patient to patient (difficult to predict and quantify); patients eligible for intensive therapy have characteristics associated with better outcomes (likely to do well regardless of therapy); studies with 5-yr median OS no longer impressive (represents new norm); regimens for relapse improving; new therapies soon to become front-line therapy; speaker believes that current standard regimens poor, and that ASCT appropriate only in clinical trials using novel agents and approaches, with goals of improving outcomes and (ultimately) achieving cure; concessions —progression-free survival (PFS) improved by intensive treatments, particularly if goal prolonged remission (and “trade-off” of increased toxicity acceptable); intensive therapy required for patients with blastoid MCL

Overall survival: MIPI score — correlates with outcome in patients with MCL; younger patients with good performance status, normal lactate dehydrogenase (LDH) levels, and normal white blood cell counts have better outcomes (true of majority of study participants, regardless of type of therapy); benchmark should be 5-yr OS rather than historical 3-yr OS

Studies: predominantly single-center, conducted with patients in first remission, and had regimen that included rituximab; OS close to 5 yr

European study: ASCT associated with benefit in PFS, but not in OS; of 292 patients randomized, <50% eligible for completion of full regimen; remainder excluded from analysis (not intent–to-treat); only one-third of these patients received rituximab (may affect applicability of study); lack of response to induction therapy major reason for exclusion from analysis; median duration of response only 3 to 4 yr; OS 5 to 7 yr among responders (10–20 patients); unclear if actual cure achieved

National Comprehensive Cancer Network study: retrospective review of 167 patients; more hospitalizations seen in patients on intensive regimens (relatively few in those on R-CHOP); longer PFS (median 3-4 yr) seen in patients on intensive therapy; OS slightly better in patients given R-hyper-CVAD (but ability to draw conclusions limited, as trial nonrandomized)

Nebraska study: treatment with hyper-CVAD before ASCT associated with better outcomes than those with other induction regimens; however, only fittest 25% of patients completed hyper-CVAD, eligible for, and agreeable to ASCT (ie, outcomes may reflect better condition of patients rather than superior treatment)

Cornell study (2007): 7-yr median OS seen in all patients treated for MCL; less intensive therapy used in most patients

Memorial study: patients who received ASCT after high-intensity CTX had median OS of »7 yr; similar results possibly due to patient selection at single centers (better condition of patient likely accounts for better outcomes)

Data from single institutions: population of patients similar to those treated with high-intensity therapy in published studies; therapy choices appear to effect PFS, but not OS; data prone to biases that include referral bias, exclusions of patients, and inclusion of only CTX-responsive and/or younger patients

Conclusions: patient selection bias may account for apparent superiority of intensive treatment; randomized trials with OS and QOL endpoints (rather than PFS) key to determining whether ASCT superior to intensive therapy; building upon current strategies most logical approach; ASCT, hyper-CVAD, and other intensive therapies appropriate only as part of clinical trials with opportunity for outcomes superior to those currently achieved

Questions and Answers

ASCT outside of clinical trials: Dr. Leonard — possibly appropriate if clinician and patient value PFS, and willing to tolerate short-term high toxicity without increase in OS or cure; Dr. Van Besien —many patients remain in remission long after ASCT (some virtually cured); speaker cautions against allowing clinician’s bias to unduly influence patients; patients should decide after hearing both sides (withholding option of ASCT inappropriate)

Conclusions from Nordic Lymphoma Group data: can be used as argument against ASCT, given poor posttransplantation outcomes in patients who received nonintensive induction; Dr. Van Besien — patients with MCL require sequence of treatments; ASCT alone ineffective (rituximab essential); intensity of CTX and maintenance therapy also important

Role for advanced pathology evaluations (eg, gene expression profiling, cytogenetic arrays) in clinical trials: Dr. Leonard — patients currently treated for MCL based on age and performance status rather than biologic status; aggressiveness of particular MCL related to tumor biology may determine whether patient benefits from ASCT; unfortunately, due to small numbers of patients with MCL, further subdivision may limit clinical trials; inclusion of molecular subtyping in studies likely important for determining optimal therapy

Relevance of debate for community oncologists: Dr. Leonard —necessary to consider goals of therapy for any treatment, including ASCT; advise patients of benefits and limitations of ASCT and encourage them to choose therapy consistent with their personal goals

Readings

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Fenske is a consultant for Seattle Genetics and Spectrum Pharmaceuticals and receives research support from Takeda Pharmaceuticals, North America. Dr. Van Besien is a consultant for and receives research support from Genzyme (subsidiary of sanofi-aventis) and Otsuka. Dr. Leonard is a consultant for Abbott Laboratories, Biotest Pharmaceuticals, Calistoga Pharmaceuticals (a division of Gilead), Celgene, Cell Therapeutics Inc (CTI), Cephalon, Champions Oncology, GlaxoSmithKline, Hospira, Immunomedics, Johnson & Johnson, Millennium Pharmaceuticals (subsidiary of Takeda Pharmaceutical Company), sanofi-aventis US, and Seattle Genetics. The planning committee reported nothing to disclose. In their lectures, Drs. Fenske and Leonard present information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

8th Annual International Chicago Lymphoma Symposium, held April 29-30, 2011, in Chicago, IL

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

ON030601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

More Details - Certification & Accreditation