Intensive Treatment and Autologous Transplant for Mantle Cell Lymphoma

Abstract & Commentary

By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.

Synopsis: Long-term disease control remains an elusive target for mantle cell lymphoma (MCL), even after aggressive therapy. The Nordic Lymphoma Group treated 160 patients younger than 65 years of age on a phase II protocol using rituximab and CHOP alternating with rituximab and high-dose cytarabine followed by autologous hematopoietic cell transplantation (HCT) for responders. The overall response rate was 96% and 54% achieved CR or CR unconfirmed. The six-year overall survival was 70%, with progression-free survival of 66% and no relapses after five years. Among stem cell products assessed, only 14% were positive for minimal residual disease by molecular methods. Compared to an earlier trial by the same group following the same protocol without rituximab or cytarabine, the recent trial resulted in better response rates, higher overall and progression-free survival, and more molecular negative stem cell products. An intensive program of CHOP, cytarabine, rituximab, and autologous HCT is highly effective, and may lead to prolonged disease control.

Source: Geisler C, 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 II multicenter study by the Nordic Lymphoma Group. Blood. 2008;112:2687-2693.

Mantle cell lymphoma (MCL) is an uncommon b-cell neoplasm. Despite various attempts using intensive therapeutic approaches, MCL has a continuous pattern of relapse. Efforts to enhance long-term disease control, if not to obtain cures, remain elusive. One major thrust has been autologous hematopoietic cell transplantation (HCT), particularly as consolidation following induction and consolidation chemotherapy. The Nordic lymphoma group's initial attempt in the late 1990s at autologous HCT consolidation for mantle cell lymphoma (known as MCL-1 trial) met a similar fate as other studies, in that almost all patients relapsed.1 Subsequently, newer strategies employing rituximab showed enhanced response rates and preventing tumor cell contamination from the autologous stem cell product.2 The Nordic group embarked on this follow-up trial (the MCL-2 trial) to optimize long-term outcomes using autologous HCT as consolidation. High-dose cytarabine and rituximab were added to the pre-HCT regimen in an effort to improve tumor control and achieve lymphoma-free stem cell products.

The trial involved 160 patients with newly diagnosed Stage II- IV MCL from 2000 to 2006. Induction included CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), with alternating cycles of high-dose cytarabine of three cycles each (six cycles total). Stem cells were collected after cycle 6, with the addition of G-CSF. Between four to six doses of rituximab were given, including two doses for the stem cell mobilization cycle 6 for stem cell purging. High-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) was given for HCT conditioning. Molecular monitoring was performed by PCR. Patients who converted from PCR-negative to PCR-positive bone marrow or blood, without signs of clinical relapse after autologous HCT, were offered preemptive therapy with rituximab 375 mg/m2 weekly for four weeks.

Induction treatment afforded a response in 96%, with 54% of all patients achieving CR or CR unconfirmed. Another 42% achieved a PR, and 4% did not respond. A total of 145 responders of the original 160 patients went on to high-dose therapy and HCT. The observation time was 3.8 years. Including HCT, non-response or relapse occurred in 30%, and 8% had major protocol-terminating toxicity, including harvest failure (4.4%), graft failure (2.5), and one case of pulmonary embolism. The four-year event-free survival (EFS) rate was 63% on intention-to-treat basis, which was significantly higher than the 18% four-year EFS on the previous MCL-1 trial by this group from 1996-2000, which did not include rituximab or cytarabine (p < .001). The four-year overall survival (OS) rate was 81%, significantly higher than the 55% four-year OS of the MCL-1 trial (p = .002). No deaths have occurred after 5.2 years among 33 patients. Only one case of myelodysplasia or AML occurred. PCR-negative molecular responses were obtained in 92% of evaluable patients after HCT, compared to only 38% in the MCL-1 trial. On multivariate analysis of survival, only the morphologic variant of MCL and the IPI score demonstrated independent prognostic importance.

Commentary

Novel therapeutic strategies for mantle cell lymphoma (MCL) have been explored over the past decade to improve upon the historically poor median survival of 3-4 years after standard chemotherapy approaches such as CHOP. This includes antibody therapy with rituximab,3 novel chemotherapy combinations, and hematopoietic cell transplantation.4

In this report from Geisler et al, combining all three strategies led to very promising long-term outcomes. This trial (MCL-2) was compared to a prior series in a similar population without the addition of rituximab and cytarabine (the MCL-1 trial). The MCL-2 study confirmed higher response rates using rituximab and cytarabine for MCL relative to standard CHOP. The higher response rate is not surprising. However, other studies documenting similarly high response rates of over 90% incorporating cytarabine and rituximab to the chemotherapy regimen suffered from continued late relapses.5

The most intriguing finding of this report is the "plateau" five years after HCT where late relapses have not yet occurred. Earlier trials such as the MCL-1, with autologous HCT without the benefit of pre-transplant rituximab and cytarabine, showed many of the stem cell products harbored detectable minimal residual disease (MRD) for lymphoma. In this trial, high-dose therapy and autologous HCT allowed both additional responses and only 14% of stem cell products with molecular evidence of MRD, further confirming the enhanced activity of the pre-transplant regimen. Another approach in this regimen that may have further led to long-term control was early rituximab at the first sign of MRD after HCT without overt relapse. The incremental benefit of pre-emptive therapy can not be determined.

The standard, but always relevant, caveats of a phase II trial hold. These patients were generally a relatively select group of patients and were younger than 65 years of age. Geisler et al correctly point out that this approach, using patients older than 65 years of age, represent over half of all patients. The low relapse-related mortality for the entire treatment program of induction and autologous HCT certainly contributed to the excellent long-term outcomes. Less select patients and/or treatment outside of a strict protocol may lead to substantially worse outcomes.

Autologous HCT may have late complications, including therapy-related leukemia. Further, historical results reveal considerable variability in prognosis, with 10-year survival of 71% for low-risk to 36% for high-risk MCL applying The Follicular Lymphoma International Prognostic Index (FLIPI).6,7 Thus, 10-year follow-up is necessary and accountable. Ultimately, randomized trials would most confidently determine the absolute benefit of this intensive approach. The target is always shifting in oncology as newer treatments are introduced such as bortezomib. New treatments pose a challenge in assessing studies requiring long-term follow-up, as highly active novel therapies may increase the number of responders and thus patients eligible for autologous HCT, as well as improving the natural history of the disease without HCT.

These data will not alter treatment guidelines for mantle cell lymphoma, although this offers additional evidence to support a role of autologous HCT for consolidation for MCL. In fact, National Cancer Center Network guidelines indicate consolidation with autologous HCT may improve progression-free survival; an overall survival benefit has not been demonstrated. The option of HCT should be discussed with relatively fit patients diagnosed with MCL. Clinical trials incorporating HCT are ongoing.

References

1. Andersen NS, et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant. Eur J Haematol. 2003;71:73-80.

2. Magni M, et al: Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood. 2000; 96:864-869.

3. Howard OM, 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. 2002;20:1288-1294.

4. Dreyling M, 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 2005;105:2677-2684.

5. Romaguera JE, 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. 2005;23:7013-7023.

6. Solal-Celigny P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258-1265.

7. Moller MB, et al. Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index. Br J Haematol. 2006;133:43-49.