Autologous stem cell transplantation has played a critical role in the treatment of mantle cell lymphoma, but in the age of novel treatments, is it always warranted? Two experts in the field explored the question at the 2015 Debates and Didactics in Hematology and Oncology Conference sponsored by Emory University, Atlanta, and held in Sea Island, Georgia.
Amelia Langston, MD, is Professor of Hematology and Medical Oncology and Director and Section Chief of the Bone Marrow and Stem Cell Transplant Program at Emory. Christopher Flowers, MD, MS, is Associate Professor of Hematology and Medical Oncology and Director of the Emory Lymphoma Program.
According to Dr. Langston, “Autologous stem cell transplant should be part of the initial treatment strategy for ‘fit’ patients with mantle cell lymphoma. It is unclear whether this represents curative therapy, but it is our most powerful approach for prolonging progression-free survival and time to next therapy.”
However, according to Dr. Flowers, robust new agents “may change the natural history of this disease” and eliminate the need for autologous stem cell transplant in some patients. “My position is that all young patients do not necessarily need to undergo [autologous stem cell transplant] for mantle cell lymphoma,” he maintained.
‘The Various Faces of Mantle Cell Lymphoma’
Dr. Langston gave a brief review of the disease state, noting that mantle cell lymphoma accounts for a relatively small proportion (3%–10%) of non-Hodgkin lymphoma. Mantle cell lymphoma, which occurs mostly in elderly males, has several morphologic variants, including the aggressive blastoid variant. Genomic studies are beginning to “unravel the various faces of mantle cell lymphoma,” but such information has not yet been integrated into risk-adapted management strategies, she added.
Although a small proportion of patients will have indolent disease, the majority present with advanced disease. “Aggressive behavior is the rule for most, but not all, patients,” according to Dr. Langston.
Transplant for Initial Therapy
Studies have consistently shown that response to conventional therapy for intermediate- or high-grade lymphoma, ie, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) with or without rituximab (Rituxan), is inadequate. Complete remission rates are low, and the duration of remission is short.
A study by the European Mantle Cell Lymphoma Network established autologous stem cell transplant as the standard of care. Patients receiving upfront CHOP or CHOP-like induction, followed by autologous stem cell transplant, had prolonged progression-free survival, compared with those on interferon maintenance (P = .0108).1 The study also showed that patients who achieved complete remission, vs partial remission, had the greatest benefit, although there was a suggestion of benefit even with partial remission. The study was not designed to evaluate overall survival, but a strong trend favored the transplant arm, she noted.
The weakness of this study was that it was initiated early in the rituximab era, and only one-quarter of patients received this drug. Another limitation was the use of CHOP or a CHOP-like regimen for induction, which is not optimal. Nevertheless, the study established autologous stem cell transplant as part of standard therapy for ‘fit’ patients with mantle cell lymphoma—ie, those up to 70 years of age who are otherwise healthy, said Dr. Langston.
What Is the Best Induction Regimen?
If R-CHOP is not the best induction regimen prior to autologous stem cell transplant, what is? Numerous phase II trials have suggested that complete remission rates are higher and disease-free survival is longer when high-dose cytarabine is incorporated into induction; therefore, any induction regimen should include high-dose cytarabine, Dr. Langston said.
For example, the European Mantle Cell Lymphoma Network Induction Study compared R-CHOP for 6 cycles with R-CHOP for 3 cycles followed by R-DHAP (rituximab/dexamethasone/cytarabine/cisplatin) for 3 cycles, with responders in each arm proceeding to autologous stem cell transplant.2 Objective response rates were similar, but complete remission rates were significantly higher in patients receiving the cytarabine-containing regimen (54% vs 40%; P = .0003). Time to failure was also significantly longer with cytarabine (88 months vs 46 months; P = .038), as was overall survival (not reached vs 82 months; P = .045).
Whether autologous stem cell transplant can be “curative” is still unclear. Although the plateauing of progression-free and overall survival curves is encouraging, Dr. Langston added, patients with mantle cell lymphoma often relapse very late, out to 8 to 10 years, and so need to be followed continuously.
Rituximab Maintenance
“The role of rituximab maintenance post [autologous stem cell transplant] needs a prospective study, but some data suggest it may produce improved response duration and survival,” Dr. Langston said. At the 2014 ASH Annual Meeting, a retrospective analysis of 157 patients from the Fred Hutchinson Cancer Center showed that rituximab maintenance reduced the risk of disease progression by 67% and the risk of dying by 60%.3 The results held up in the multivariate analysis.
Some May Not Need Transplant
Dr. Flowers acknowledged the benefits of autologous stem cell transplant but countered that all young patients do not need autologous stem cell transplant for mantle cell lymphoma. It appears that about 6% of patients can defer therapy and still have prolonged progression-free and overall survival.
He agreed with Dr. Langston that R-CHOP is inadequate for most patients and pointed to more powerful induction options. Studies in older patients suggest that bendamustine (Treanda)/rituximab may be superior to R-CHOP. A regimen that alternates R-hyperCVAD with R-M/A (rituximab/methotrexate/cytarabine) may also improve outcomes as an induction treatment without autologous stem cell transplant.4 Romaguera et al showed a marked complete remission rate (87%) and “profound” 3-year failure-free survival (64%) and overall survival (82%), suggesting this aggressive regimen produces durable remissions without autologous stem cell transplant, according to Dr. Flowers.
Treating Relapsed Disease
Regardless of these findings, mantle cell lymphoma remains largely a relapsing/remitting disease. Fortunately, the list of treatment options for these patients is growing, Dr. Flowers said.
One appears to be the proteasome inhibitor bortezomib (Velcade). Although most patients do not respond to bortezomib, those who do can have durable remissions, according to the PINNACLE trial, which evaluated single-agent bortezomib in 155 patients with relapsed/refractory disease.5 Patients achieving complete remission continued treatment for 4 more cycles; those with partial responses or stable disease continued treatment for up to 17 cycles. Among responders, progression-free survival was 91% at 1 year, and median overall survival was 35.4 months.6
“This treatment has been used for patients who relapsed even after an aggressive treatment like [autologous stem cell transplant],” said Dr. Flowers.
Lenalidomide (Revlimid) also produced meaningful complete remission rates and durable responses in those who relapsed after autologous stem cell transplant, according to a combined analysis of several trials.7 The complete remission rate was 10%, median progression-free survival was 5.4 months, and median overall survival was 23.9 months among 208 patients with relapsed/refractory disease. Lenalidomide was active even in patients who had received bortezomib upon relapse, and the benefits of this drug apply as well to patients who have not had a transplant, Dr. Flowers noted.
The most impressive new data, however, have been seen for the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) and the PI3K inhibitor idelalisib (Zydelig), reported Dr. Flowers.
Response rates for ibrutinib were essentially twice those observed in the lenalidomide studies (68%, with 21% complete responses), in the study published in The New England Journal of Medicine.8 Median progression-free survival was 13.9 months, and median overall survival was not reached. Durable responses were seen even in patients with prior exposure to bortezomib and lenalidomide.
Idelalisib also produced “appreciable responses” in mantle cell lymphoma, “albeit it was studied in a relatively small number of patients, and it is not approved for this indication,” Dr. Flowers added.
Two additional novel agents in early-phase trials include the BCL-2 inhibitor venetoclax, which has shown single-agent activity and in vitro synergy with proteasome inhibitors (ibrutinib and rituximab) and the novel oral proteasome inhibitor ixazomib (MLN9708).
The availability of these novel agents allows for combinations and sequencing of treatments in patients with relapsed/refractory disease. “They may not necessarily cure mantle cell lymphoma, but we may be able to keep the disease away with less intensive therapies than [autologous stem cell transplant], and with less toxicity,” Dr. Flowers said. “With modern therapy, we may see a change in the natural history of this disease.” ■
Disclosure: Dr. Flowers is an unpaid consultant for Genentech and Celgene; has received consulting fees from OptumRX and research support from AbbVie, Acerta, Celgene, Genentech, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Millennium/Takeda, Onyx Pharmaceuticals, Pharmacyclics, TG Therapeutics, and Spectrum.
References
1. Dreyling M, Lenz G, Hoster E, et al: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684, 2005.
2. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: Final analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network. 2012 ASH Annual Meeting. Abstract 151.
3. Graf SA, Stevenson PA, Holmberg LA, et al: Rituximab maintenance therapy after autologous stem cell transplantation improves survival of patients with mantle cell lymphoma. 2014 ASH Annual Meeting. Abstract 3985. Presented December 8, 2014.
4. Romaguera JE, Fayad L, Rodriguez MA, et al: High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 23:7013-7023, 2005.
5. Fisher RI, Bernstein SH, Kahl BS, et al: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874, 2006.
6. Goy A, Bernstein SH, McDonald A, et al: Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial. Leuk Lymphoma 51:1269-1277, 2010.
7. Witzig TE, Vose J, Zinzani PL, et al: Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. 2013 ASCO Annual Meeting. Abstract 8533. Presented May 31, 2013.
8. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013.
