Advanced Stage Mantle Cell Lymphoma Research Articles

Favorable Influence of Pretransplant Rituximab but Not of High-Dose Ara-C in Upfront Autologous Stem Cell Transplantation (SCT) for Mantle Cell Lymphoma (MCL).

Recent data suggests that the prognosis of MCL might be improved by administration of rituximab and high-dose ara-C (HA) prior to upfront SCT. In order to investigate the relative contributions of rituximab and HA, respectively, we retrospectively analyzed 98 patients who received SCT as part of 1st-line treatment of advanced-stage MCL. Patients (median age 55 (29–67)) with stage II–IV MCL were treated with a sequential therapy comprising 2–8 cycles of CHOP or CHOP-like regimens +/− rituximab for remission induction, DexaBEAM (49%) or HA-containing chemotherapy (39%) for further consolidation and mobilization of stem cells, and high-dose therapy with SCT. 22% were mobilized with CHOP alone. High-dose regimens were TBI/CY (38%), TBI/CY + rituximab (R-TBI/CY; 35%), or BEAM (27%).Results: With a median follow-up of 35 (1–135) months, estimated median progression-free survival (PFS) of all 98 patients was 95 months from diagnosis and 82 months from SCT(median overall survival not reached). Pretransplant rituximab was given to 40 patients and improved PFS (3-year PFS from SCT 93% (95%CI 83–100%) vs 67% (54–79%) although this was still not statistically significant (hazard ratio (HR) .37; p .07). In contrast, pretransplant HA had no impact on PFS even after adjusting for rituximab (HR 1.9; p .61). PFS after R-TBI/CY tended to be superior to that after TBI/CY only if the 58 patients without pretransplant rituximab were considered (HR .39; p .07). Age, sex, time from diagnosis, and remission status after cytoreduction or immediately prior to SCT did not affect PFS.Conclusions: Pretransplant rituximab but not high-dose ara-C seems to improve the outcome of early SCT for MCL. Addition of rituximab to myeloablative treatment with TBI/CY might be beneficial only in the absence of pretransplant rituximab. Pretransplant rituximab with upfront SCT provides long-term disease control in a large proportion of patients with MCL.

Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle Cell Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG)

Mantle cell lymphoma (MCL) is characterized by a poor prognosis with a low to moderate sensitivity to chemotherapy and a median survival of only 3 to 4 years. In an attempt to improve outcome, the German Low Grade Lymphoma Study Group (GLSG) initiated a randomized trial comparing the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab (R-CHOP) with CHOP alone as first-line therapy for advanced-stage MCL. One hundred twenty-two previously untreated patients with advanced-stage MCL were randomly assigned to six cycles of CHOP (n = 60) or R-CHOP (n = 62). Patients up to 65 years of age achieving a partial or complete remission underwent a second randomization to either myeloablative radiochemotherapy followed by autologous stem-cell transplantation or interferon alfa maintenance (IFNalpha). All patients older than 65 years received IFNalpha maintenance. R-CHOP was significantly superior to CHOP in terms of overall response rate (94% v 75%; P = .0054), complete remission rate (34% v 7%; P = .00024), and time to treatment failure (TTF; median, 21 v 14 months; P = .0131). No differences were observed for progression-free survival. Toxicity was acceptable, with no major differences between the two therapeutic groups. The combined immunochemotherapy with R-CHOP resulted in a significantly higher response rate and a prolongation of the TTF as compared with chemotherapy alone. Hence, R-CHOP may serve as a new baseline regimen for advanced stage MCL, but needs to be further improved by novel strategies in remission.

Dose Dense, High Intensity Induction Therapy Followed by Early High Dose Chemotherapy (HDT) and Autologous Hematopoietic Stem Cell Transplantation(AHSCT) for Mantle Cell Lymphoma (MCL).

Introduction: Though response may occur with standard therapy, early relapse is common with advanced stage MCL, suggesting the importance of drug resistance in this disease process.It appears that repeated cycles of aggressive chemotherapy to a point of maximum response, followed by HDT and AHSCT, provides improved disease free intervals, though the impact on overall survival (OS) remains uncertain. A concern with this approach is that the eventual high relapse rate seen in most trials may be due to the emergence of drug resistance prior to HDT. In an attempt to circumvent the problem of drug resistance due to multiple cycles of chemotherapy, we designed a dose dense approach using only one cycle of an aggressive induction regimen. Patients demonstrating at least PR and a BM uninvolved by morphology and flow cytometry studies proceeded with chemotherapy-primed PBPC collection, before receiving HDT and AHSCT.Patients and Methods: HIDAC 3 gm/m2 over 1 hour q12 hours for 12 doses in combination with mitoxantrone 12mg/m2 daily for 3 days were given as induction therapy. Responders were mobilised with either VP-16 2 gm/m2 or cyclophosphamide 4 gm/m2 followed by G-CSF 10 mcg/kg daily until stem cell collection. The preparative regimen consisted of BCNU 15mg/kg over 2 hours D-6, VP-16 60mg/kg over 4 hours D-4 and cyclophosphasmide 100mg/kg over 2 hours D-2.Results: Twenty one stage IV patients and 2 stage III patients were enrolled, including 7 with relapsed/refratory disease. Median age was 56 yo(40–74). Nine (39%) patients achieved CR and 11 (48%) patients achieved PR with all showing >80% reduction in tumor size. Three patients died after induction: 1 from sepsis; 2 from disease progression. Seventeen (74%) of the 20 patients with CR or > 50% PR proceeded to PBPC mobilisation whereas 3 were deemed too ill to undergo HDT (2 of these were in CR from induction). A total of 14 (10 previously untreated and 4 had failed prior therapy) eventually had adequate stem cell collected and underwent planned HDT and were fully evaluable for outcome. There was no TRM to HDT and while only 6 patients entered HDT in CR, all 14 patients attained a CR at recovery from transplant. With a median follow-up from study entry for these 14 autotransplant patients of 36 months (17–68), 8 patients are still alive and in CR. The estimated 4 year OS and event free survival (EFS) for these 14 patients were both 64% and the median survival was 57 months.(see figure)Conclusions: The study shows that a dose dense, high intensity approach for advanced MCL provides a very high CR and PR rate. Those who were able to complete this protocol have a high chance of achieving favorable disease free survival. [Display omitted]

Early Consolidation with Myeloablative Radiochemotherapy Followed by Autologous Stem Cell Transplantation in First Remission Significantly Prolongs Progression-Free Survival in Mantle Cell Lymphoma - Long Term Follow up of a Prospective Randomized Trial of the European MCL Network.

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor prognosis and a median survival of only 3–4 years. In 1996, the European MCL Network initiated a randomized trial to improve the otherwise dismal outcome of MCL, comparing early consolidation with myeloablative radiochemotherapy (TBI 12 gray, cyclophosphamide 120 mg/kg bw) followed by autologous stem cell transplantation (ASCT) to a conventional a -interferon maintenance (6x106 IE IFNa 3x weekly) in first remission after a CHOP-like induction regimen. Until March 2004, a total of 269 previously untreated patients (up to 65 years) were randomized upfront. 189 (82%) of 230 patients with advanced stage MCL completed initial induction chemotherapy and 142 (75%) achieved either a complete (45 pts., 24%) or partial response (97 pts, 51%). 122 pts proceeded to consolidation therapy, 62 pts received ASCT consolidation and 60 patients were assigned to IFN maintenance.Patients in the ASCT study arm experienced a significantly longer progression-free survival (PFS) as compared to patients in the IFNa arm. The PFS at 2 years was 73% after ASCT as compared to only 43% in the IFNa arm (p = 0.0108). Similar results were achieved in the intent to treat analysis of all initially randomised MCL patients (p=0.0001). Accordingly, this advantage resulted in a trend towards an improved overall survival (OS) in the ASCT arm. After a follow-up of up to nearly 7 years (median follow-up of patients: 2.8 years), 3 year survival after ASCT was 83% in comparison to 77% under IFNa maintenance (p = 0.18). As expected, acute toxicity was higher in the ASCT group with an early mortality of 4.8%, whereas long-term effects were more frequently encountered under IFNa maintenance.Conclusion : In first line treatment of advanced stage MCL, dose-intensified consolidation with myeloablative radiochemotherapy followed by ASCT after CHOP-like induction results in a significant prolongation of PFS. Current study concepts evaluate the benefits of combined immuno-chemotherapy to further improve the overall survival.

Aktuelle Therapiestrategien beim fortgeschrittenen Mantelzell-Lymphom

Advanced stage mantle cell lymphoma (MCL) with a median survival of only three years and virtually no long-term survivors represents the lymphoma subtype with the poorest prognosis and remains incurable with conventional chemotherapy. Recently two randomized trials of the German Low Grade Lymphoma Study Group (GLSG) demonstrated the superiority of a combined immunochemotherapy with the anti-CD20 antibody rituximab in first-line therapy (R-CHOP) as well as in relapsed disease (R-FCM). In addition, in a trial of the European MCL Network, intensified-consolidation with high-dose radiochemotherapy followed by autologous stem cell transplantation significantly improved the progression-free survival in patients up to 65 years of age. However, the vast majority of patients with MCL will eventually relapse. Thus, new strategies such as allogenic transplantation after dose-reduced conditioning or novel molecular targeting agents (e. g. proteasome inhibitors or radiolabeled antibodies) are urgently warranted to further improve the long-term outcome of MCL.

Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis

The outcome of 20 patients with newly diagnosed mantle-cell lymphoma (MCL) treated on a prospective trial of autologous stem-cell transplantation (ASCT) and rituximab immunotherapy was compared with the outcome of 40 matched historical control patients treated with standard combination chemotherapy. Control patients with MCL were identified from a lymphoma database, and pairs were matched with patients receiving ASCT-rituximab for stage of disease, gender and age (+/-5 years). Only patients treated with an anthracycline- or cyclophosphamide-fludarabine-based regimen were included. Seventeen of 20 patients who received ASCT-rituximab remain alive in remission at a median of 30 months from diagnosis; one patient relapsed 2 years post-ASCT, and two died at 7 and 11 months post-ASCT without evidence of lymphoma. Of 40 patients treated with conventional chemotherapy, with a median follow-up of 80 months, 33 have relapsed or progressed and 29 have died. Overall (OS) and progression-free (PFS) survival were superior in patients treated with ASCT-rituximab compared with those treated with conventional chemotherapy (PFS at 3 years, 89% versus 29%, P <0.00001; OS at 3 years, 88% versus 65%, P = 0.052). This matched-pair analysis suggests that patients with advanced-stage MCL treated with ASCT-rituximab had statistically significantly better PFS and a trend toward better OS than patients treated with conventional chemotherapy. Longer follow-up will determine response duration and the true impact of this treatment strategy on PFS and OS.

Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma

Advanced-stage mantle cell lymphoma (MCL) is a disease for which no curative treatment strategy exists. Results with standard combination chemotherapy, with or without an anthracycline, are disappointing, and new and better therapies are needed. High-dose therapy and autologous stem-cell transplantation (ASCT) have been performed in patients with MCL both up front and at relapse with varying degrees of success. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) has shown moderate response rates in patients with MCL. It has also been used safely and effectively as an in vivo purge during ASCT for patients with lymphoma. We are currently investigating an aggressive protocol in patients with newly diagnosed, untreated MCL using a combination of two promising therapeutic modalities, high-dose therapy-ASCT and rituximab. Since 1999, 13 patients with newly diagnosed MCL have been enrolled in this phase II clinical trial. CHOP (cyclophosphamide/prednisone/vincristine/doxorubicin) is used as debulking chemotherapy. Stem cells are mobilized with 5 days of granulocyte colony-stimulating factor 10 μg/kg/d, with a single infusion of rituximab 375 mg/m2 used as an in vivo purge before stem-cell collection by large-volume leukapheresis. The transplant conditioning regimen is cyclophosphamide/carmustine/etoposide. Post-transplant consolidative immunotherapy consists of rituximab 375 mg/m2, administered as two 4-week cycles at 2 and 6 months post-transplant. So far, 12 patients (7 men/5 women) with a median age of 55 years (range, 41 to 65 years) have been transplanted. Patients were first assessed and then transplanted a median of 40 and 201 days, respectively, from diagnosis. International Prognostic Index at diagnosis was low (n = 3), low-intermediate (n = 8), and high-intermediate (n = 1). A median of six cycles of CHOP was required to debulk tumor sufficiently for transplant. Response to CHOP was 100% with six complete responses, one complete response unconfirmed, and five partial responses. Transplantation was well tolerated. Patients engrafted quickly, with a median of 11.5 days to neutrophil engraftment and 10 days to platelet independence. Patients had modest transfusion requirements, requiring a median of four units of packed red blood cells and two and a half platelet transfusions. Six to 8 weeks post-transplant, six patients were in complete response, four in complete response unconfirmed, and two in partial response. Eight patients have received all eight maintenance rituximab treatments, and four have received only their first cycle. Following rituximab, the two patients in partial response and two in complete response unconfirmed converted to complete response. With a median follow-up of 239 days from transplant (range, 61 to 727 days), all patients remain alive and well with no documented relapses. Samples for molecular monitoring have been drawn from the stem-cell graft, and serially from the peripheral blood and bone marrow of patients at baseline, preapheresis, pretransplant, and post-transplant at 3-month intervals. This data shows that ASCT followed by rituximab immunotherapy is feasible and safe in patients with MCL. Although patient numbers are low and follow-up time is short, preliminary results are encouraging. Rituximab may convert partial responders to complete responders. The durability of responses will be determined with longer follow-up. Semin Oncol 29 (suppl 2):56-69. Copyright © 2002 by W.B. Saunders Company.

Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy

In advanced stage mantle cell lymphoma, conventional chemotherapy yields a complete remission rate below 40%, and the median survival rate is only about 3 years. Between 1991 and 1996 we treated nine such patients (six male; three female) with high-dose chemotherapy (six of these also with 12 Gy fractionated total body irradiation (TBI)) and peripheral stem cell support (n = 8) or allogeneic bone marrow transplantation (n = 1). The median age was 47 years (range, 28-61). At the time of high-dose chemotherapy, five patients were in first complete remission (CR), two in first partial remission (PR) and two in second remission (CR = 1; PR = 1). High-dose chemotherapy included TBI (12 Gy), etoposide and cyclophosphamide (patients 1-5), TBI and cyclophosphamide (patient 7), busulfan, etoposide and cyclophosphamide (patients 6 and 9), cyclophosphamide and busulfan (patient 8). The patterns of toxicity according to the Bearman score were usually mild (mucositis grade 2, n = 7; renal grade I, n = 2) with no therapy-related fatality. Only one patient developed hepatic toxicity grade III (veno-occlusive disease) but recovered completely. The median time to neutrophil engraftment was 10 days (range, 8-15). After high-dose chemotherapy all patients achieved complete remission. After a median follow-up of 22 months (range, 9.4-64) all patients remain in continuous complete remission. These encouraging results suggest that high-dose chemotherapy can be applied safely and leads to long-term disease-free survival in otherwise incurable disease.