Something Old, Something New: Options for Treating Relapsed Mantle Cell Lymphoma

Dr. Ruan and colleagues provide an excellent summary of available treatment options, as well as new drugs on the horizon, for the management of relapsed mantle cell lymphoma (MCL). As the authors emphasize, treatment of relapsed MCL is strongly influenced by the patient’s first-line therapy and needs to be individualized based on both patient and disease characteristics. While many potentially active agents are currently under investigation for relapsed MCL, the reality is that most patients in the United States will not have access to these agents until they are US Food and Drug Administration (FDA) approved. As in many other areas of oncology, the lack of availability of clinical trials and the reluctance of physicians to recommend or refer patients for investigational studies continues to impede progress in MCL.

Biology of Mantle Cell Lymphoma and Predictive Features of Response

Mantle cell lymphoma is typified by its aggressive clinical course with high recurrence rates and a median survival of 4 to 5 years.[1-4] Yet in a subset of patients, the disease follows a more indolent path. Some of the differences may be partially accounted for by erroneous classifications, given that MCL has been recognized as a distinct entity only since 1994 (although heterogeneity persists even in the modern era).

In a recent retrospective analysis, the authors of this review demonstrated that delayed initial therapy is an acceptable management approach for select asymptomatic patients.[5] The median time to treatment for 31 patients in the observation group was 12 months (range, 4–128 months). At a median follow-up of 55 months, the median overall survival was not reached. In comparison, the early-treatment group, comprising 66 patients, had a projected median overall survival of 64 months at a median follow-up of 41.5 months. Mantle Cell International Prognostic Index (MIPI)[6] scores, Ki67, and p53 levels failed to predict treatment groups, contrary to what one may have expected. While limitations of the study design preclude any treatment recommendations, the results nonetheless showcase the disparate behavior of the disease. Observing patients at relapse, as well as at initial diagnosis, may occasionally be appropriate. Expectant management of asymptomatic patients with minimal disease at relapse may maximize quality of life without compromising survival.

The variant of MCL with small-cell morphology presenting in leukemic phase with splenomegaly and absence of nodal disease often behaves indolently, with reported survivals of 5 to 12 years.[7,8] In contrast, blastoid and pleomorphic histologies behave aggressively, but whether this reflects the cytologic variants themselves or the respective proliferation profiles is debated.[9] Elevated Ki-67 staining indexes correlate with worse prognoses even with dose-intensive and immunochemotherapy regimens.[10,11] Gene-expression profiling further adds to survival prediction,[12,13] though microarray-based platforms and mRNA expression by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) are not yet feasible for routine application, and have not been tested in large enough cohorts to guide treatment decisions.

The simplified MIPI score, based on four clinical variables, has not yet been evaluated prospectively, and attempts by others to validate the tool were unsuccessful.[14] Several ongoing national and international consortium correlative studies are attempting to better characterize the clinical and biologic attributes of MCL that impact outcome. Importantly, none of the existing potential prognostic indicators have been evaluated in the relapsed setting, and there is currently no objective tool for accurately predicting prognosis at relapse.

Tailoring Treatment Approaches

Although no randomized trials have compared aggressive upfront regimens to standard-dose approaches, the results of a number of phase II studies showing median remission durations of 5-years or more with R-hyperCVAD-like regimens (rituximab [Rituxan], hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone, alternating with high-dose methotrexate and cytarabine) with or without autologous stem cell transplantation (ASCT) have led to the frequent use of this approach as initial therapy for patients under age 70 without significant comorbidities.[15,16] Recent follow-up of these studies even suggests there may be a plateau in the progression-free survival curve beyond 5-years.[15,16] These results with intensive first-line therapy are in contrast to phase II studies of R-CHOP (rituximab, cyclophosphamide, doxorubicin HCl, vincristine, prednisone) as initial therapy of MCL, where the median progression-free survival is 16 months, with no patients remaining in remission beyond 3 years.[17]

For those in whom aggressive first-line therapy fails, many achieve prolonged survivals with less intense subsequent treatments. Outside the setting of a clinical trial, several options have been comprehensively discussed and referenced by Ruan in the accompanying article. These approaches include single-agent rituximab, rituximab plus standard combination chemotherapy such as R-CVP (cyclophosphamide, vincristine, prednisone) or R-FCM (fludarabine, cyclophosphamide, mitoxantrone) with or without maintenance rituximab, single-agent chemotherapy such as bortezomib (Velcade), bendamustine, oral cyclophosphamide, oral etoposide, or metronomic therapy.

Sequencing these options is somewhat arbitrary and should be based on initial remission duration, prior regimens, and comorbidities. For example, single-agent rituximab and single-agent bortezemib produce similar response rates (30%–40%) and median remission durations (< 12 months) in patients with relapsed MCL.[18,19] The toxicity profile would favor rituximab, unless the patient had recurred on maintenance rituximab or had less than a 6-month remission following prior rituximab.

The frequent, and occasionally irreversible, painful paresthesias associated with bortezomib should be weighed carefully against the benefits of a limited remission duration in nearly all patients.[20] Attempts to improve the tolerability of bortezomib by administering it weekly instead of twice weekly, decreased the neurotoxicity, but resulted in much lower response rates (personal communication, Owen O’Connor). Despite the very encouraging single-center report by Drach et al, who studied rituximab and thalidomide (Thalomid) for relapsed MCL, this treatment is not available for most patients in the United States because thalidomide is not, and probably never will be, approved by the FDA for this indication, unless additional trials are undertaken.[21] The inability to obtain this well tolerated treatment for older patients with Medicare coverage remains frustrating.

One approach for relapsed MCL, not discussed by Ruan and colleagues, is that of low-dose palliative radiotherapy. While most of the publications describing low-dose (4 Gy, 2 × 2) involved-field radiation therapy (IFRT) include mostly patients with relapsed follicular lymphoma, a “handful” of patients with relapsed MCL are also included in these series.[22-24] Haas et al reported a 75% response rate and 5-month median time to progression in 12 patients with relapsed MCL treated with 4 Gy of IFRT.[22] This treatment is virtually devoid of side effects and is an attractive option for patients without symptomatic bone marrow relapse and with a relatively limited number of sites of involvement at relapse. Multiple courses can be given as new sites of disease appear. Based on our experience and personal communication with others in the field, this approach is used more prevalently for relapsed MCL than the current literature would indicate, and attempts to publish small retrospective series should be undertaken by larger centers using this approach.

Occasionally, a second transplant-either autologous or nonmyeloablative allogeneic-is an appropriate consideration for younger patients with prolonged remissions following first transplant. In younger patients who are not treated with aggressive upfront therapy, the role of transplant in second remission is well established, and as reviewed by Ruan and coauthors, current data favor consideration of an allogeneic transplant if a suitable donor is identified.

Conclusions

Dr. Ruan and colleagues provide us with balanced recommendations for the management of MCL, highlighting a broad spectrum of therapies ranging from the well tolerated to the very intense, and from novel agents, like immunomodulatory drugs ­(IMiDs), mammalian target of rapamycin (mTOR) inhibitiors, and histone deacetylase (HDAC) inhibitors, to well established chemotherapy agents as described with metronomic therapy. Recognizing how to risk-stratify patients is paramount. We would reiterate the recommendation to consider clinical trials for all patients with relapsed MCL.

Many important questions remain unanswered. How should we incorporate new agents into first-line therapy? How should new agents be combined to maximize efficacy and minimize toxicity? We anxiously await ongoing initiatives aimed at addressing these important issues. The many new agents for mantle cell lymphoma provide continued hope of prolonged survival for patients with this difficult disease.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Fisher RI, Dahlberg S, Nathwani BN, et al: A clinical analysis of two indolent lymphoma entities: Mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): A Southwest Oncology Group study. Blood 85:1075-1082, 1995.
2. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al: Efficacy of four different regimens in 64 mantle-cell lymphoma cases: Clinicopathologic comparison with 498 other non-Hodgkin’s lymphoma subtypes. European Organisation for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 13:2819-2826, 1995.
3. Hiddemann W, Unterhalt M, Herrmann R, et al: Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: Results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol 16:1922-1930, 1998.
4. Herrmann A, Hoster E, Zwingers T, et al: Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27:511-518, 2009.
5. Martin P, Chadburn A, Christos P, et al: Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27:1209-1213, 2009.
6. Hoster E, Dreyling M, Klapper W, et al: A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558-565, 2008.
7. Orchard J, Garand R, Davis Z, et al: A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood 101:4975-4981, 2003.
8. Nodit L, Bahler DW, Jacobs SA, et al: Indolent mantle cell lymphoma with nodal involvement and mutated immunoglobulin heavy chain genes. Hum Pathol 34:1030-1034, 2003.
9. Tiemann M, Schrader C, Klapper W, et al: Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): A clinicopathological study from the European MCL Network. Br J Haematol 131:29-38, 2005.
10. Determann O, Hoster E, Ott G, et al: Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: Results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 111:2385-2387, 2008.
11. Garcia M, Romaguera JE, Inamdar KV, et al: Proliferation predicts failure-free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabine. Cancer 115:1041-1048, 2009.
12. Rosenwald A, Wright G, Wiestner A, et al: The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185-197, 2003.
13. Hartmann E, Fernandez V, Moreno V, et al: Five-gene model to predict survival in mantle-cell lymphoma using frozen or formalin-fixed, paraffin-embedded tissue. J Clin Oncol 26:4966-4972, 2008.
14. Shah JJ, Fayad L, Romaguera J: Mantle Cell International Prognostic Index (MIPI) not prognostic after R-hyper-CVAD. Blood 112:2583; author reply 2583-2584, 2008.
15. Romaguera J, Fayad L, Rodriguez A, et al: Rituximab (R) + hyperCVAD alternating with R-methotrexate/cytarabine after 9 years: Continued high rate of failure-free survival in untreated mantle cell lymphoma (MCL) (abstract 833). Blood 112(11), 2008.
16. Geisler CH, Kolstad A, Laurell A, et al: Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112:2687-2693, 2008.
17. Howard OM, Gribben JG, Neuberg DS, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288-1294, 2002.
18. Ghielmini M, Schmitz S-FH, Cogliatti S, et al: Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: A study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 23:705-711, 2005.
19. O’Connor O, Moskowitz C, Portlock C, et al: Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: Results of a multicentre phase 2 clinical trial. Br J Haematol 145:34-39, 2009.
20. Richardson PG, Briemberg H, Jagannath S, et al: Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113-3120, 2006.
21. Kaufmann H, Raderer M, Wohrer S, et al: Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood 104:2269-2271, 2004.
22. Haas RLM, Poortmans P, de Jong D, et al: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21:2474-2480, 2003.
23. Dubray B, Breton C, Delic J, et al: In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin’s lymphomas. Radiother Oncol 46:185-191, 1998.
24. Ng M, Wirth A, Ryan G, et al: Value of low-dose 2x2 Gy palliative radiotherapy in advanced low-grade non-Hodgkin’s lymphoma. Australas Radiol 50:222-227, 2006.