A phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium-90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non-Hodgkin lymphoma

BACKGROUND: A prospective, single-arm, open-label, nonrandomized Phase 2 study of combined fludarabine and mitoxantrone (FM) plus radioimmunotherapy was conducted to evaluate efficacy and safety in patients with untreated, indolent, nonfollicular non-Hodgkin lymphoma (NHL). METHODS: Between February 2005 and June 2006, at their institute, the authors treated 26 eligible patients with previously untreated, indolent, nonfollicular NHL (10 marginal zone lymphomas, 8 lymphoplasmacytic lymphomas, and 8 small lymphocytic lymphomas) using a novel regimen that consisted of 6 cycles of FM chemotherapy followed 6 to 10 weeks later by yttrium-90 (90Y) ibritumomab tiuxetan. RESULTS: After FM chemotherapy, the overall response rate was 80.5% and included a 50% complete remission (CR) rate (13 patients) and a 30.5% partial remission (PR) rate (8 patients). Of the 20 patients (13 with CR and 7 with PR) who were evaluable (at least a PR with normal platelet counts and bone marrow infiltration <25%) for subsequent 90Y ibritumomab tiuxetan, 100% obtained a CR at the end of the entire treatment regimen. At a median follow-up of 20 months, the estimated 3-year progression-free survival rate was 89.5%, and the estimated 3-year overall survival rate was 100%. The 90Y ibritumomab tiuxetan toxicity included grade >or=3 hematologic toxicity in 16 of 20 patients; the most common grade >or=3 toxicities were neutropenia (11 patients) and thrombocytopenia (16 patients) (adverse events were graded according to the World Health Organization criteria for toxicity). Transfusions of erythrocytes and/or platelets were given to 5 patients. CONCLUSIONS: The current study established the feasibility, tolerability, and efficacy of the FM plus 90Y ibritumomab tiuxetan regimen for the treatment of patients with untreated, indolent, nonfollicular NHL.     

Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease

BACKGROUND:

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM).

METHODS:

Forty‐three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m² intravenously on day 1 and fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses.

RESULTS:

The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow‐up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2‐microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long‐lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow‐up.

CONCLUSIONS:

The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good‐quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration. Cancer 2011;. © 2011 American Cancer Society.     

Proposed rituximab biosimilar BCD-020 versus reference rituximab for treatment of patients with indolent non-Hodgkin lymphomas: An international multicenter randomized trial

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m² for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab.     

High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m² days 1 + 2, mitoxantrone 10 mg/m² day 1, rituximab 375 mg/m² day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 - 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 - 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas.     

Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study.

BACKGROUND: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. RESULTS: Hematological toxicities (grade > or =3) occurred more frequently in females (P <0.05), and thrombocytopenia and leukopenia were more frequent in patients with high lactate dehydrogenase (LDH) levels (P <0.05). Non-hematological toxicities (grade > or =2) were more frequent in patients with extranodal disease or bone marrow involvement. The overall response rate (ORR) in patients receiving one prior chemotherapy regimen was higher than those receiving two or more regimens (P <0.05). The median PFS was shorter in MCL patients, in those with extranodal disease, or in those receiving two or more prior chemotherapy regimens (P <0.01). The PFS intervals of patients with higher serum rituximab levels (> or =70 microg/ml) immediately before the third infusion were longer than in other patients (P <0.01). CONCLUSIONS: Several prognostic factors and serum rituximab levels are useful for predicting the toxicity and efficacy of rituximab monotherapy.     

FND与CHOP方案治疗进展期惰性淋巴瘤的疗效比较

目的比较FND(氟达拉滨 米托蒽醌 地塞米松)与CHOP方案治疗进展期惰性淋巴瘤的疗效与安全性。方法临床观察的终点包括缓解率(总有效率OR和完全缓解率CR),无失败生存(FFS),总体生存(OS)及毒性。40例病人随机分组,FND和CHOP组各20例。两种治疗方案均为每28天1次,共3个疗程,之后,二组病人均采用CHOP方案巩固3个疗程。FND方案为氟达拉滨25mg/m2,ivd1~5;米托蒽醌10mg/m2,ivd1;地塞米松20mg/d,ivd1~5。CHOP方案为环磷酰胺600mg/m2,ivd1;阿霉素25mg/m2,ivd1;长春新碱1.4mg/m2,ivd1和强的松50mg/m2,pod1~5。结果FND方案的完全缓解率和总有效率显著优于CHOP(OR83%vs40%,CR50%vs15%;P<0.01)。FND组的中位FFS是32个月,而CHOP组仅为15个月。两种治疗方案的耐受性均较好,只有少量的感染并发症发生。结论FND方案的完全缓解率、总有效率均显著优于CHOP,并可有效改善预后。     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

Fludarabine–Mitoxantrone–Rituximab regimen in untreated indolent non‐follicular non‐Hodgkin's lymphoma: experience on 143 patients

Indolent non‐follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa‐associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow‐up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9‐year disease‐free survival (DFS) of 74.9% and an estimated 10‐year overall survival of 92.8%. The estimated 9‐year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine‐based regimen in combination with rituximab in the front‐line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long‐term DFS and favorable acute and long‐term safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

Fludarabine, adriamycin and dexamethasone (FAD) in newly diagnosed advanced follicular lymphoma: a phase II study by the British National Lymphoma Investigation (BNLI)

The optimal first-line treatment for symptomatic patients with advanced stage follicular lymphoma remains unclear. Fludarabine-based combination regimens have been extensively used in relapsed disease and merit consideration as first-line therapy. We here report the results of a phase II study of FAD (fludarabine, adriamycin, dexamethasone) regimen in 30 patients with advanced stage follicular lymphoma requiring treatment. The response rate was in excess of 90% with 39% achieving a complete remission. The major toxicity was myelosuppression, but only 3% of cycles were associated with grade IV leucopenia. The high response rate has not translated into major improvements in failure-free survival and consideration must be given to alternative treatment modalities to consolidate the high rate of initial responses.     

Phase I and pharmacokinetic study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin's lymphoma.

BACKGROUND: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). PATIENTS AND METHODS: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. RESULTS: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0-24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). CONCLUSIONS: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.     

Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma

BACKGROUND: The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.     

Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: phase 1 study with a dose-expansion cohort

BACKGROUND:

Pixantrone dimaleate (pixantrone) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models. FND‐R, a combination regimen of fludarabine, mitoxantrone, dexamethasone, and rituximab, has been shown to be an effective regimen for low‐grade lymphomas.

METHODS:

This dose‐escalation study, with an expansion cohort, was conducted to evaluate the safety and preliminary efficacy of FPD‐R, in which pixantrone was substituted for mitoxantrone in the FND‐R regimen, in patients with relapsed or refractory indolent non‐Hodgkin lymphoma (NHL). Escalated doses of pixantrone were administered to newly enrolled patients on day 2 of each 28‐day cycle of FPD‐R.

RESULTS:

Twenty‐eight of 29 enrolled patients received at least 1 cycle of FPD‐R (median, 5 cycles). Pixantrone 120 mg/m² was identified as the recommended dose in this regimen. Grade 3‐4 adverse events were primarily hematologic; grade 3‐4 lymphopenia occurred in 89% of patients and leukopenia in 79%. No patients developed congestive heart failure or grade 3‐4 cardiac adverse events. Left ventricular ejection fraction decreases occurred in 8 (29%) patients, and most were grade 1 or 2, transient, and asymptomatic. The overall response rate was 89%. Estimated survival was 96% after 1 year and 92% after 3 years.

CONCLUSIONS:

The FPD‐R regimen was well‐tolerated and highly active in patients with relapsed or refractory indolent NHL. Cancer 2011;. © 2011 American Cancer Society.     

Economic evaluation of rituximab plus cyclophosphamide, vincristine and prednisolone for advanced follicular lymphoma

The addition of rituximab to cyclophosphamide, vincristine and prednisolone (CVP) for advanced follicular lymphoma increases median time to progression by 17 months. A US societal cost-effectiveness of R-CVP versus CVP is estimated for a representative 50-year-old patient. Progression-free survival (PFS) and overall survival are based on a randomized Phase III trial. Costs are estimated using Medicare reimbursement rates and published drug price data, and include drug and administration costs, adverse events, treatment of relapses, and end-of-life care. Utility estimates are derived from the literature and a 3% discount rate is employed. Mean overall survival is projected to be 1.51 years longer for patients assigned to R-CVP versus CVP. The cost per quality-adjusted year of life gained is $28,565. The utility associated with stable or progressive disease and the unit drug cost of rituximab most influence the findings. The cost-effectiveness ratio of R-CVP compared with CVP is projected to be cost-effective in the United States under a range of sensitivity analyses.     

Infectious disease associations in advanced stage, indolent lymphoma (follicular and nonfollicular): developing a lymphoma prevention strategy.

BACKGROUND: Eradication of Helicobacter pylori in gastric mucosa-associated lymphoid tumor can result in lymphoma remission. We prospectively identified/treated infections in nonbulky, advanced stage indolent lymphoma (follicular; nonfollicular lymphoma) eligible for observation. Materials and methods: Stool H. pylori, hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, Chlamydia peripheral blood mononuclear cell PCR and hydrogen breath test for small bowel bacterial overgrowth (SBBO) were obtained. RESULTS: Fifty-six patients were enrolled. Positive infections: H. pylori (13); hepatitis C (3); SBBO (11). Negative: Borrelia (13); Chlamydophila psittaci (12, except one PCR). Lymphoma responses to antimicrobial therapy: H. pylori [one complete response (CR), 24+ months; one transient near CR]; hepatitis C [two CRs, 18+ and 30+ months; one partial response (PR) but hepatitis C virus persistent]; SBBO (one PR, 30+ months). Patients with associated infections, but without lymphoma CR, have required lymphoma treatment sooner than those without initial infections (treatment-free survival at 23.4 months median follow-up, 40.5% versus 74.7%, P = 0.01), indicating a different biology. CONCLUSION: Infections are common in advanced stage indolent lymphoma (37.5% in our series). Anecdotal lymphoma responses have been seen and three have been durable CRs (18 to 30+ months) with infection eradication alone. The identification and treatment of associated infections may be a first step towards developing a lymphoma prevention strategy.     

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma

BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FC-R) shows significant in vitro synergism and may improve patient outcome with little overlapping toxicity. METHODS: Between December 2000 and June 2005, 77 patients completed therapy after a median of 4 cycles of FC-R (fludarabine at a dose of 25 mg/m2 intravenously [i.v.] on Days 1-3, cyclophosphamide at a dose of 250 mg/m2 i.v. on Days 1-3, and rituximab at a dose of 375 mg/m2 on Day 1). The median age of the patients was 59 years, 65% were male; 31% had previously untreated disease; and 44% had chronic lymphocytic leukemia (CLL), 29% had follicular lymphoma, and 27% other indolent lymphoid malignancies. In addition to standard disease response criteria, patients underwent evaluation using flow cytometric and/or molecular studies. RESULTS: Objective responses (OR) and complete responses (CR) were observed in 83% and 42%, respectively, of evaluable patients (n=76), respectively. For patients with CLL, the respective OR and CR rates were 100% and 67% as firstline therapy, and 95% and 14% as salvage therapy. For patients with follicular lymphoma, the respective OR and CR rates were 100% and 86% as firstline therapy, and 87% and 67% as salvage therapy. Responders who had no detectable disease on flow cytometric and/or molecular studies experienced prolonged remissions with no recurrences reported at a median 25 months of follow-up. Peripheral stem cell collection using stem cell factor plus granulocyte-colony-stimulating factor was successful in 10 of 13 patients who underwent mobilization (77%). CONCLUSIONS: FC-R is highly active as initial or salvage therapy in patients with CLL or indolent non-Hodgkin lymphoma. Collection of autologous stem cells during molecular remission is feasible and may facilitate future exploration of high-dose therapy in these patients.     

Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B-cell lymphoma

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.     

Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas--results of a randomized comparison by the German Low-Grade Lymphoma Study Group.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.