Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant

OBJECTIVES: The aim of the first Nordic mantle cell lymphoma (MCL) protocol was to study the clinical significance of an augmented CHOP induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and to examine the prognostic significance of stem cell contamination rates in newly diagnosed patients with MCL. PATIENTS AND METHODS: Forty-one newly diagnosed patients below 66 yr were enrolled and given three series of an augmented CHOP regimen. Responders underwent stem cell mobilization with a fourth course of CHOP, stem cell harvest and ASCT. Stem cell purging was optional in the protocol and followed the routine of each participating centre. The number of tumour cells in the reinfused autografts was estimated by flow cytometry or quantitative PCR. RESULTS: Induction therapy led to complete remission (CR) in 11 of 41 patients (27%), partial remission (PR) in 20 of 41 patients (49%) and no response in nine patients (22%), whereas one patient was not evaluable. Twenty-seven of the 31 responders underwent ASCT and 24 achieved or maintained a CR. The overall and failure-free 4-yr survival on intention-to-treat basis were 51% and 15%, respectively. Among the transplanted patients, a significantly increased failure-free (P<0.03) and overall survival (P=0.03) was noted among patients transplanted in CR compared with PR, respectively. By contrast, reinfusion of highly variable numbers of tumour cells with the autografts (range 0.71-80 x 10(6) tumour cells), did not affect outcome. CONCLUSION: In MCL, an important strategy to improve the outcome will be to intensify the induction chemotherapy.     

Efficacy of high-dose therapy and hematopoietic stem cell transplantation for mantle cell lymphoma

Conventional treatment of mantle cell lymphoma (MCL) yields modest responses and short remissions. We report 30 hematopoietic stem cell transplants (HSCT) for MCL: 13 autologous, 10 allogeneic myeloablative, and 7 nonablative. After a median 1.2 years from diagnosis (range 0.5 to 4.7) and a median of 2 pre-HSCT chemotherapeutic regimens (range 1 to 5), their median age at HSCT was 52 years (range 37 to 67). Eleven patients (41%) were in first remission, 11 (41%) were in second remission, and 7 (25%) had resistant disease. Four died early. Nineteen achieved CR (83%) and 4 PR (17%). With median 2.7 years of follow-up, 5-year overall survival (OS) was 42% (95% CI 11-73%) after autologous versus allogeneic at 49% (95% CI 22-76%). Five-year progression-free survival (PFS) was 31% (95% CI 3-59%) and 50% (95% CI 24-76%) for autologous and allogeneic HSCT, respectively. Fourteen died: 3 from sepsis, 1 acute GVHD, 10 MCL. No autologous transplant-related deaths occurred. Allogeneic transplant-related mortality was 29% (95% CI 6-52%) at 1 and 5 years. HSCT for MCL can yield extended disease control and long-term survival.     

Four‐year follow‐up of a single arm,phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL)

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR‐MCL). We report the long‐term outcome and safety profile of a single‐centre, single arm, open‐label, phase 2 study of RR‐MCL treated with IR. Overall, the median follow‐up time was 47 months (range 1–52 months), median duration on treatment was 16 months (range 1–53 months) and median number of treatment cycles was 17 (range 1–56). Twenty‐nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty‐eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1–2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression‐free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL‐related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR‐MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR‐MCL is under exploration.     

Splenectomy in mantle cell lymphoma with leukaemia: a comparison with chronic lymphocytic leukaemia

We reviewed data on 63 patients with mantle cell lymphoma (MCL) with leukaemia (n = 16) and chronic lymphocytic leukaemia (CLL, n = 47), splenectomized over a 10-year period. Primary indications for surgery were cytopenia(s) or autoimmune phenomena and progressive or refractory disease with splenomegaly. The spleens removed were on average larger in MCL (median 2.6 kg) than in CLL (1.0 kg). Splenectomy improved the blood counts in 62% of patients with MCL and 47% with stage C CLL, both with cytopenias. The MCL patients showed a decrease in the leucocytosis (medians 60.3-29.1 x 10(9)/l before and after splenectomy), whereas there was an increase in the leucocytosis in CLL (medians 24.2-44 x 10(9)/l). With a median follow up post splenectomy of 10 months (range: < 1-128), 18 patients (four MCL and 14 CLL) have not required further therapy for up to 66 months. We conclude that splenectomy is a useful treatment in MCL and advanced CLL for the correction of cytopenias, reducing the leucocyte count and allowing prolonged periods of clinical remission without therapy. Differences seen between MCL and CLL in spleen size, and in response of the leucocytosis suggest a central role for the spleen in the evolution of MCL with leukaemia.     

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

The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enroled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively ( P  = 0·74), while both populations of patients exhibited essentially similar progression-free survival (PFS; 5·6 months vs. 3·9 months, P  = 0·81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7·8 months vs. 8·4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross-resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib.     

Rituximab plus hyper‐CVAD alternating with MTX/Ara‐C in patients with newly diagnosed mantle cell lymphoma: 15‐year follow‐up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA) . At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).     

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4–6 cycles of CTAP/VMAC induction, patients aged ≤65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients ≤55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P  = 0·001; OS P  = 0·0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.     

Ten‐year follow‐up after intense chemoimmunotherapy with Rituximab‐HyperCVAD alternating with Rituximab‐high dose methotrexate/cytarabine (R‐MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma

Mantle cell lymphoma (MCL) has a poor overall survival after treatment with conventional chemotherapy. Intense chemoimmunotherapy without consolidation stem cell transplantation is a potential therapeutic option. We report on a prospective Phase II study with rituximab in combination with fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐Hyper‐CVAD) alternating with rituximab in combination with high‐dose methotrexate‐cytarabine (R‐MA) in untreated patients with diffuse and nodular MCL and their blastoid variants. Ninety‐seven patients were treated, of whom 97% responded and 87% achieved a complete remission. At 10 years of follow up (median 8 years), the median overall survival (OS) for all patients had not been reached and the median time to failure (TTF) for all patients was 4.6 years, without a plateau in the curves. For the group of patients aged 65 years or younger, the median OS had not been reached and the median TTF was 5.9 years. Multivariate analysis revealed pre‐treatment serum levels of β₂ microglobulin, International Prognostic Index (IPI) score and mantle cell IPI (MIPI) score, as predictive of both OS and TTF. We conclude that intense chemoimmunotherapy without stem cell transplantation is effective for untreated aggressive MCL.     

The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan,melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33–61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16–53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.     

A multicentre phase II clinical experience with the novel aza-epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non-Hodgkin lymphoma and mantle cell lymphoma

The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received < or =4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 x 10(9)/l and a platelet count >50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma.     

VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m(2) × 4 weekly doses) and MR (375 mg/m(2) every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.     

Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries

Mantle cell lymphoma (MCL) has an aggressive clinical course with a median survival < 3 years and is incurable with conventional chemotherapy. A large multicentre study with adequate follow-up may clarify the role of significant factors affecting outcome in autologous stem cell transplantation for MCL. Patients receiving an autologous transplant for MCL between 1988 and 1998, and reported to the European Blood and bone Marrow Transplant (EBMT) registry or Autologous Blood and Marrow Transplant Registry (ABMTR), were included. Expert haematopathology review was required on all identified patients. Disease and transplant details were requested from the transplant centres, and the final cohort of patients with verified pathology, adequate clinical information and follow-up was analysed. One hundred and ninety-five patients were included in the analyses (149 EBMT, 46 ABMTR) with a median follow-up of 3.9 years. The 2 year and 5 year overall survival were 76% and 50%, and progression free survival was 55% and 33% respectively. Disease status at transplant was the most significant factor affecting survival: patients with chemosensitive disease but not in first complete remission (CR1) were 2.99 times (95% CI: 1.66-5.38, P < 0.001) more likely to die than patients transplanted in CR1. Autologous transplantation probably improves survival in patients with MCL especially if performed in first CR.     

Clinical and molecular remission after allogeneic blood cell transplantation in a patient with mantle-cell lymphoma

Mantle-cell lymphoma (MCL) is a B-cell tumour with a usually poor prognosis, characterized by the proliferation of small cleaved lymphocytes with a diffuse growth pattern. We report a polymerase chain reaction-based analysis of minimal residual disease in a patient who achieved complete remission after allogeneic blood cell transplantation (BCT). Rearrangement of the immunoglobulin heavy-chain genes was used to generate a lymphoma-specific molecular marker. Lymphoma cells were not detectable in a bone marrow sample collected 12 months after BCT. Our findings suggest that allogeneic BCT may offer a curative approach to MCL.     

IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients

This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk x 4) against MCL and SLL/CLL appeared to be limited, however.     

Monoclonal antibody therapy for B-cell lymphoma: clinical trials of an anti-CD20 monoclonal antibody for B-cell lymphoma in Japan

Twelve patients with relapsed CD20+ B-cell non-Hodgkin's lymphoma (B-NHL) were enrolled in a phase I study of rituximab; 4 received rituximab 250 mg/m2 and 8 received rituximab 375 mg/m2 once weekly for 4 weeks. Grade 1 or 2 infusion-related toxicity was observed. Of the 11 eligible patients, 2 achieved complete responses and 5 achieved partial responses. The elimination half-life (T1/2) of rituximab was 445 +/- 361 hours, and serum rituximab levels were detectable at 3 months. Thereafter, 90 relapse patients with indolent B-NHL or mantle cell lymphoma (MCL) were enrolled in a phase II study and treated with rituximab at 375 mg/m2 per infusion in 4 weekly infusions. Sixteen patients were ineligible in protocol compatible analyses. The overall response rates (ORR) in indolent B-NHL and MCL were 61% (37 of 61 patients) and 46% (6 of 13 patients), respectively. Factors affecting response and progression-free survival (PFS) were analyzed for 77 patients whose histopathology was centrally confirmed as indolent B-NHL or MCL. The ORR in patients receiving 1 prior chemotherapy regimen was higher than the ORR in those receiving > or = 2 regimens (P < .05). The median PFS was shorter in MCL patients, in those with extranodal disease, and in those receiving > or = 2 prior chemotherapy regimens (P < .01). The PFS of patients with higher serum rituximab levels (> or = 70 microg/mL) immediately before the third infusion was longer than that of other patients (P < .01). Several pretreatment factors and serum rituximab levels are useful for predicting the efficacy of rituximab monotherapy. Rituximab re-treatment was well tolerated in 13 patients with no grade 3 or 4 nonhematological toxicities. A partial response was observed in 5 patients (38%), and the median PFS after re-treatment was 5.1 months. In conclusion, rituximab is a highly effective agent in relapsed indolent and aggressive B-NHL and MCL and has acceptable toxicities.     

Mantle cell lymphoma in the Chinese: Clinicopathological features and treatment outcome

We report the clinical, molecular, and immunohistological findings of 20 Chinese patients with mantle cell lymphoma diagnosed over a 10-year period. The disease affected mainly elderly patients (median age, 65.5 years) with a male predominance (M/F, 3/1). Eighty percent presented with advanced stage III/IV disease but only 25% had B symptoms. Eighty-five percent had extranodal disease at presentation. Complete remission (CR) and partial remission (PR) were achieved in 45% and 40% of the patients, respectively. There was no difference in the CR rate for patients treated with anthracycline-containing or nonanthracycline-containing regimens (43% and 50%, P = 0.67). Disease progression or relapse was observed after a median of 26 months in patients who initially responded to treatment. Extranodal relapse occurred in the central nervous system (n = 1), bone marrow (n = 1), pleura (n = 2), orbit (n = 2), and the gastrointestinal tract (n = 3). The median overall survival (OS) was 52 months but there were no long-term survivors. This was not different from the median OS of 53 months of patients with diffuse large cell (DLC) lymphoma treated in the same center over the same period (log rank, P = 0.76). Of the 12 patients who were tested for bcl-1 rearrangement by polymerase chain reaction (PCR), five (42%) were positive for rearrangement in the major translocation cluster (MTC) region. The median OS rates were 45 months and 63 months for PCR positive and negative patients, respectively (P = 0.97). In conclusion, MCL is a disease mainly of the elderly in the Chinese with a male predominance and most had advanced-stage disease and extranodal involvement at presentation. Clinicopathologic features and treatment outcome were similar to Caucasian patients, in that the disease combined the aggressive nature of DLC lymphoma and the incurability of low-grade lymphoma. Am. J. Hematol. 59:295–301, 1998. © 1998 Wiley-Liss, Inc.     

Prognostic impact of interim positron emission tomography in mantle cell lymphoma patients treated with frontline R-CHOP

Although ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) is commonly used for initial staging and therapeutic response evaluation in aggressive lymphomas, its prognostic utility for mantle cell lymphoma (MCL) is controversial. Therefore, we retrospectively evaluated the correlations of interim PET (iPET) and end-of-treatment PET (ePET) response with survival outcomes in 89 consecutive advanced MCL patients treated with frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone). iPET positivity was strongly associated with inferior five-year overall survival (OS) [hazard ratio (HR) 7·84, P < 0·0001] and poor five-year progression-free survival (PFS) (HR 3·34, P < 0·0001). OS and PFS were more favourable in the order early metabolic responder (iPET^neg → ePET^neg), delayed responder (iPET^pos → ePET^neg), loss-metabolic responder (iPET^neg → ePET^pos), and never-metabolic responder (iPET^pos → ePET^pos). In the autologous haematopoietic stem cell transplantation (auto-HSCT)-fit subgroup, OS was more favourable in the order early metabolic responders, delayed metabolic responders, and non-metabolic responders, with a marginal trend toward statistical significance (HR 3·41, P = 0·051), and PFS was significantly superior in early metabolic responders (HR 4·43, P = 0·002). In a group that was ineligible for auto-HSCT, OS and PFS were significantly superior in early metabolic responders. Our results suggested that iPET is of prognostic value and an independent predictor of survival in MCL patients receiving frontline R-CHOP. Therefore, prospective clinical trials of iPET-guided treatment strategies for these patients are warranted.     

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis following first relapse. We present a subgroup analysis of an open-label phase II trial investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL. Oral lenalidomide 25 mg was self-administered once daily on days 1–21 every 28 d for up to 52 weeks, according to tolerability or until disease progression. The primary endpoint was overall response rate (ORR) and secondary endpoints were duration of response, progression-free survival (PFS) and safety. Among 15 patients with MCL with a median disease duration of 5·1 years and a median of four prior treatments, the ORR was 53%. Three patients (20%) had a complete response and 5 (33%) had a partial response. The median duration of response was 13·7 months and median PFS was 5·6 months. Four of five patients who relapsed after transplantation and two of five patients who previously received bortezomib responded to lenalidomide. The most common grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), leucopenia (27%) and thrombocytopenia (20%). In conclusion, oral lenalidomide monotherapy is well tolerated and active in relapsed or refractory MCL.     

Complementarity determining region-III is a useful molecular marker for the evaluation of minimal residual disease in mantle cell lymphoma

Bone marrow (BM) and peripheral blood (PB) involvement in 10 patients with mantle cell lymphoma (MCL) was analysed by a polymerase chain reaction (PCR)-mediated RNase protection assay. The complementarity determining regions (CDR)-III of all 10 MCLs examined was amplified efficiently with consensus V_H and J_H primers by PCR, and BM and/or PB involvement was evaluated by RNase protection assay in all 10 patients examined. Our assay showed BM and/or PB of the entire group to have neoplastic cells at presentation, despite the fact that eight patients were found to have BM and/or PB involvement on the basis of morphological examination and/or surface marker analysis. We also examined minimal residual disease (MRD) after conventional chemotherapy, and detected MRD in a patient in complete remission (CR). Although previous studies have shown that t(11;14) breakpoint amplification by PCR was only applicable to about 30–40% of cases, the present study indicates that CDR-III is a useful molecular marker and the PCR-mediated RNase protection assay is a good tool for the evaluation of MRD in MCL. It is suggested that BM and PB of MCL patients are quite frequently involved at presentation and even after conventional chemotherapy at the molecular level.     

High‐dose CD20‐targeted radioimmunotherapy‐based autologous transplantation improves outcomes for persistent mantle cell lymphoma

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high‐dose anti‐CD20 radioimmunotherapy (RIT)‐based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high‐dose RIT‐based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT‐based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT‐based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation‐based strategies in a risk‐adapted approach to ASCT for persistent MCL.