First-Line Therapy for Mantle Cell Lymphoma

Educational Objectives

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

1. Use prognostic markers for risk stratification in patients with MCL.
2. Identify patients with MCL who are likely to benefit from deferred therapy.
3. Select an induction chemotherapy regimen for MCL based on the age and fitness of the patient.

Summary

Background: comprises <10% of non-Hodgkin lymphoma cases; characterized by expression of cyclin D1 (by immunohistochemistry [IHC]), characteristic immunophenotype (identified by flow cytometry and IHC), and t(11:14) chromosomal translocation (identified by fluorescent in situ hybridization [FISH]); often presents as stage IV, usually with lymphocytosis and involvement of bone marrow, spleen, and gastrointestinal (GI) tract

Prognostic markers

Mantle Cell Lymphoma International Prognostic Index (MIPI): includes 4 characteristics; requires calculation to identify low-, intermediate-, and high-risk disease

Ki67 proliferative index: most experts agree that index >30% constitutes high risk; <10% may indicate lower risk; however, expression often differs throughout body, and scoring differs among pathologists

Cytogenetics: predictor of high-risk behavior; presence of complex karyotype, defined as ≥3 unrelated chromosomal abnormalities and deletion of 17p on routine karyotype, associated with high-risk behavior and lack of response to intensive therapies

Genomic aberrations and proliferation signature: not yet available for routine clinical use, but proliferation signature can be performed on preserved tissue

MIPI and patient outcomes: original study published in 2008 showed low-risk score associated with good outcomes, whereas median survival <3 yr in patients with high-risk scores; updated analysis published in 2014 showed good outcomes in low- and intermediate-risk, but not high-risk, patients; retrospective data from 5-center cohort — outcomes of patients with high-risk scores better than those previously reported; this may reflect bias (ie, patients who receive care at academic centers generally considered “better” cohort); complex karyotype strong predictor of adverse outcomes

General approach to management: confirm diagnosis and complete staging and prognostic work-up; provide intensive induction therapy prior to autologous transplantation if patient eligible, and less intensive therapy (depending on fitness) if patient not candidate for transplantation; subset of patients (<10%) can safely be observed

Phenotypes of Mantle Cell Lymphoma

“CLL-like” disease: case 1 — lymphocytosis identified incidentally in 60-yr-old woman; patient asymptomatic with no palpable adenopathy, white blood cell (WBC) count 19,000 cells/µL, absolute lymphocyte count 14,000 cells/µL, and normal hemoglobin and platelet levels; flow cytometry consistent with mantle cell lymphoma, and FISH positive for t(11:14) translocation; positron emission tomography-computed tomography (PET-CT) showed scattered lymph nodes 1 to 1.5 cm in size, with standardized uptake values of 2 to 3; bone marrow biopsy positive

Deferred therapy: several series show no association with decrease in overall survival; National Cancer Database (NCDB) project showed better overall survival with >90-day deferral for patients predicted to have well-behaving disease; associated factors include non-nodal presentation, lack of B symptoms, normal lactate dehydrogenase (LDH), and good Eastern Cooperative Oncology Group (ECOG) performance status

“Young, fit” patient: case 2 — 49-yr-old man presented with left cervical adenopathy for 6 to 8 wk; examination revealed palpable adenopathy in numerous stations and splenomegaly; laboratory tests showed mild anemia and thrombocytopenia; ECOG performance status 1; PET-CT showed scattered adenopathy (fairly significant disease burden); bone marrow biopsy positive

Treatment approach: many options available for intensive induction regimen (should include cytarabine)

Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with high-dose cytarabine and methotrexate): study at MD Anderson — median time to treatment failure ≈4.5 yr, with high overall response rate (ORR) and complete response rate (CRR); Southwest Oncology Group (SWOG) study — showed median progression-free survival (PFS) of 4.8 yr; retrospective study of National Comprehensive Cancer Network (NCCN) centers — showed 3-yr PFS of 58%; challenge — regimen highly toxic; ≈50% of patients in SWOG study had to discontinue therapy early; Emory study — 5-yr relapse-free survival 73% when used before autologous transplantation

Nordic regimen: alternates R-maxiCHOP (rituximab plus dose-intensified cyclophosphamide, doxorubicin, vincristine, and prednisone) with cytarabine; median PFS 8 to 10 yr, but most patients eventually progress

MCL Younger study: better outcomes seen with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone alternated with R-DHAP (rituximab-dexamethasone, high-dose cytarabine, and cisplatin) before stem cell transplantation, compared with R-CHOP without R-DHAP

Cancer and Leukemia Group B (CALGB) regimen: includes several cycles of R-CHOP with low-dose methotrexate and chemomobilization with cytarabine-containing regimen, followed by autologous transplantation; CALGB 59909 study showed 5-yr PFS of 56%; CALGB 50403 study showed 3-yr PFS of 67% (vs 59% in 59909 study) with addition of bortezomib after transplantation, although many patients discontinued bortezomib because of its high toxicity

Role of autologous transplantation: 2005 study showed better survival after transplantation than with interferon maintenance; however, need for transplantation now questionable because currently available therapies highly effective; retrospective registry series shows better outcomes with early vs delayed (ie, at time of relapse) transplantation; ongoing study aims to determine whether low-risk patients with excellent response to induction therapy can become minimal residual disease (MRD)-negative and avoid autologous transplantation in front-line setting

Elderly patient: case 3 — 73-yr-old man presented with diffuse adenopathy and fatigue; ECOG performance status 1; patient had palpable adenopathy with stable blood cell counts, diffuse adenopathy without organ involvement, and positive bone marrow biopsy

Bendamustine-rituximab (B-R): randomized study showed high ORR with B-R and R-CHOP, but median PFS ≈3 yr for B-R vs ≈22 mo for R-CHOP; B-R generally less toxic than R-CHOP and not associated with alopecia, but may cause cytopenia and infectious toxicities

MCL Elderly study: incorporated randomizations to R-CHOP vs rituximab-fludarabine and cyclophosphamide (R-FC) for induction, and rituximab vs interferon for maintenance; demonstrated significant benefit of rituximab maintenance, primarily for patients receiving R-CHOP

Rituximab-lenalidomide: single-arm phase 2 study gave 20 mg lenalidomide on days 1 to 21 of 28-day cycle, followed by maintenance component, and showed good long-term outcomes for many patients

“Typical” patient: case 4 — 66-yr-old man with newly diagnosed mantle cell lymphoma; patient had symptomatic adenopathy but appeared well; history includes atrial fibrillation, diabetes, and mild chronic obstructive pulmonary disease (COPD)

Challenges: patient may tolerate autologous transplantation with intensive inpatient therapy but unlikely to tolerate repeated cycles of aggressive therapy; necessity of transplantation questionable because several treatment options available at relapse

Induction options: include B-R and cytarabine, B-R alternating with rituximab and cytarabine, and B-R with autologous stem cell transplantation; consider integrating prognostic features to identify high-risk patients who may benefit from intensive approaches

Maintenance: LYMA study — addition of rituximab after transplantation associated with significant survival benefit in patients who underwent induction with R-DHAP; MCL Elderly study — R-CHOP followed by rituximab maintenance associated with benefit; CALGB 50403 study — bortezomib consolidation or maintenance appeared to be beneficial but may have toxicities; study of B-R — did not show significant benefit as maintenance therapy; pending studies — investigating maintenance with ibrutinib, lenalidomide, or ixazomib

Questions and Answers

Differentiating leukemic presentation from high-risk disease: elevated WBC count associated with high-risk MIPI; however, entire clinical scenario should be assessed, eg, MIPI may be used for patient with normal blood counts (other than WBC) and minimal adenopathy; no standardized approach developed to determine whether deferral is safe, although speaker less likely to defer therapy for patients with complex karyotype

SOX11 and TP53 as prognostic factors: deletion of 17p and TP53 mutation associated with poor outcomes, but effect on management unclear; testing for SOX11 not routine but may identify patients with indolent disease

Readings

Cohen JB et al: Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer. 2016 Aug 1;122(15):2356-63; Hermine O et al: Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75; Hoster E et al: Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014 May 1;32(13):1338-46; LaCasce AS et al: Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. Blood. 2012 Mar 1;119(9):2093-9; Rummel MJ et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10.

Disclosures

For this program, the following has been disclosed: Dr. Cohen is a consultant for AbbVie, BioInvent, and Genentech (A Member of the Roche Group), and has received research support from Bristol-Myers Squibb, Novartis AG, and Takeda Pharmaceutical Company. The planning committee reported nothing to disclose. In his lecture, Dr. Cohen discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Cohen was recorded at the 14th International Ultmann Chicago Lymphoma Symposium: Diagnosis and Management of Lymphoma, held May 5-6, 2017, in Chicago, IL, and presented by the University of Chicago Medicine and Biological Sciences. For information on future CME activities from this sponsor, please visit cme.uchicago.edu. The Audio Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

ON091401

Qualifies for:

Clinical Pharmacology

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.