Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation.

In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT.

Allogeneic stem cell transplant in patients with chronic lymphocytic leukemia with 17p deletion: consult-transplant versus consult- no-transplant analysis.

Allogeneic stem cell transplant (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred patients with 17p- CLL for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL who were referred to the transplant service from 2007 to 2010 were identified. Of these patients, 32 (62%) did not undergo alloSCT, mainly because of treatment- or disease-related complications (n = 15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in patients with 17p- CLL, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure.

Cytarabine, Ki-67, and SOX11 in patients with mantle cell lymphoma receiving rituximab-containing autologous stem cell transplantation during first remission.

BACKGROUND: In the current study, the authors report the results of 39 patients with mantle cell lymphoma (MCL) who were treated with chemotherapy and high-dose rituximab-containing autologous stem cell transplantation (ASCT) during their first disease remission. METHODS: The median age of the patients was 54 years. At the time of diagnosis, 87% of patients had Ann Arbor stage IV disease, and 77% had bone marrow involvement. A Ki-67 level of > 30% was found in 11 of 27 patients (40%), and SOX11 (SRY [sex determining region Y)-box 11] expression was found to be positive in 17 of 18 patients (94%). Twenty-seven patients (69%) underwent induction therapy with high-dose cytarabine-containing chemotherapy. Rituximab was administered during stem cell collection at a dose of 1000 mg/m2 on days +1 and +8 after ASCT. RESULTS: The estimated 4-year overall survival and progression-free survival rates were 82% and 59%, respectively. Twelve patients experienced disease recurrence. Fifteen of 16 patients who were alive and in complete remission at 36 months remained so at a median follow-up of 69 months (range, 38 months-145 months). The only determinant of recurrence risk found was a Ki-67 level of > 30%. Seven of 11 patients with a Ki-67 level > 30% experienced disease recurrence within the first 3 years versus only 3 of 16 patients with a Ki-67 level ≤ 30% (P = .02). Patients who received high-dose cytarabine did not have a significantly different risk of developing disease recurrence compared with other patients (P = .7). CONCLUSIONS: Administering ASCT with rituximab during stem cell collection and immediately after transplantation may induce a continuous long-term disease remission in patients with MCL with a Ki-67 level of ≤ 30%.

Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results.

In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemorefractory disease. We therefore subsequently performed a trial in which (90)Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the fludarabine, cyclophosphamide conditioning regimen ((90)YFC). Here, we report updated results of the FCR trial and outcomes after (90)YFC. For the FCR group (N = 47), since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range, 72-142 months), the 11-year overall survival and progression-free survival rates were 78%, and 72%, respectively. For the (90)YFC group (N = 26), more patients had chemorefractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year progression-free survival rates for patients with chemorefractory and chemosensitive disease were 80% and 87%, respectively (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of (90)Y to the conditioning regimen appears to be effective in patients with chemorefractory disease. This trial was registered at www.clinicaltrials.gov as NCT00048737.

Phase II study of yttrium-90-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma.

PURPOSE: This phase II trial evaluated the safety and efficacy of yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL). PATIENTS AND METHODS: Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells > or = 5,000/microL, or history of stem-cell transplant were ineligible. Patients with a platelet count > or = 150,000/microL received a dose of 0.4 mCi/kg of (90)Y-ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/microL received a dose of 0.3 mCi/kg. RESULTS: Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured > or = 5 cm (P = .015). CONCLUSION: The single-agent activity of (90)Y-ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.

Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma.

In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.

Disease staging with positron emission tomography or gallium scanning and use of rituximab predict outcome for patients with diffuse large B-cell lymphoma treated with autologous stem cell transplantation.

Tumor status, as determined by positron emission tomography or gallium scanning (PET/G), may be an important predictor of outcome for patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplantation (ASCT). ASCT conditioning regimens that include rituximab may reduce the rate of relapse. We evaluated the influence of rituximab on overall and progression-free survival in patients with DLBCL based on PET/G status before ASCT. A retrospective review of all patients with chemosensitive DLBCL who underwent ASCT in the context of research protocols at our institution between 1995 and 2005 was performed. Our study included 174 patients. Disease status before ASCT, according to PET/G, was negative in 136 patients (78%), positive in 29 patients (17%), and unknown in nine patients (5%). PET/G status and rituximab use were the only factors predictive of progression-free survival in multivariate analyses: the hazard ratios for relapse were 2.9 for PET/G-positive versus -negative patients (P < 0.001) and 0.4 for rituximab versus no rituximab use (P = 0.001). We conclude that evidence of disease on PET/G scanning prior to transplantation is associated with an increased risk for relapse after ASCT. Transplantation regimens containing rituximab can reduce this risk, regardless of PET/G status.

Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab.

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m(2) daily for 3 days), cyclophosphamide (750 mg/m(2) daily for 3 days), and rituximab (375 mg/m(2) for 1 day plus 1000 mg/m(2) for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia.

ZAP-70 (zeta-chain-associated protein 70 kDa) expression is associated with poor prognosis in patients with chronic lymphocytic leukaemia (CLL). This study evaluated the efficacy of non-myeloablative allogeneic stem cell transplantation in patients with advanced CLL and assessed the impact of ZAP-70 expression on the outcome. Thirty-nine sequential patients were included. All had previously been treated with fludarabine. All patients received a preparative regimen of fludarabine (30 mg/m(2)/d for 3 d), intravenous cyclophosphamide (750 mg/m(2)/d for 3 d), and high-dose rituximab. Immunohistochemical techniques on marrow biopsy samples were used to determine that ZAP-70 was expressed in 25 patients, whereas 13 other patients were ZAP-70 negative, and one was of indeterminate status. With a median follow-up time of 27 months, the estimated overall survival and current progression-free survival (CPFS) rates at 4 years were 48% and 44% respectively. Patients who were ZAP-70 positive had 56% survival, and their CPFS rate increased from 30% to 53% after a donor lymphocyte infusion. Multivariate analysis indicated that chemorefractory disease and mixed T cell chimerism at day 90, but not ZAP-70 positivity, were associated with the risk of disease progression after transplantation. These results demonstrate a potent graft-versus-leukaemia effect that can overcome the adverse prognostic effect of ZAP-70 expression.

Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma.

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.

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.

PURPOSE: To determine the response, failure-free survival (FFS), and overall survival rates and toxicity of rituximab plus an intense chemotherapy regimen in patients with previously untreated aggressive mantle-cell lymphoma (MCL). PATIENTS AND METHODS: This was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of six to eight cycles. RESULTS: Of 97 assessable patients, 97% responded, and 87% achieved a complete response (CR) or unconfirmed CR. With a median follow-up time of 40 months, the 3-year FFS and overall survival rates were 64% and 82%, respectively, without a plateau in the curves. For the subgroup of patients < or = 65 years of age, the 3-year FFS rate was 73%. The principal toxicity was hematologic. Five patients died from acute toxicity. Four patients developed treatment-related myelodysplasia/acute myelogenous leukemia, and three patients died while in remission from MCL. A total of eight treatment-related deaths (8%) occurred. CONCLUSION: Rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine is effective in untreated aggressive MCL. Toxicity is significant but expected. Because of the shorter FFS concurrent with significant toxicity in patients more than 65 years of age, this regimen is not recommended as standard therapy for this age subgroup. Larger prospective randomized studies are needed to define the role of this regimen in the treatment of MCL patients compared with existing and new treatment modalities.

Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.

Pentostatin in T-non-Hodgkin's lymphomas: efficacy and effect on CD26+ T lymphocytes.

Pentostatin is an adenosine deaminase (ADA) inhibitor with antineoplastic activity. CD26 is a surface glycoprotein with a key role in T cell function as the ADA binding protein. We conducted a phase II study to evaluate pentostatin efficacy in relapsed T-non-Hodgkin's lymphoma (T-NHL) and to correlate response with tumor CD26 expression. We also examined the lymphopenic effect of pentostatin on CD26+ T lymphocytes. Eighteen patients were registered for the study. Pentostatin was administered as intravenous bolus daily over 3 days at an initial dose of 5 mg/m(2)/day, repeated every 4 weeks. CD26 surface expression on tumor cells and T lymphocytes was determined by flow cytometry. Out of 14 patients evaluable for response, there was 1 (7%) complete response (CR) and 6 (43%) partial responses (PR). Median progression-free survival for responders was 6 months (range: 2-15 months); median number of courses was 4 (range: 1-6). Responders included 1 of 2 CD26+ and 5 of 9 CD26- cases. Pentostatin also specifically depleted CD26+ rather than CD26- T lymphocytes, potentially associated with immunosuppression. We therefore conclude that while pentostatin is a safe and active agent for T-NHL regardless of CD26 expression, it may selectively deplete CD26+ T lymphocytes, with potentially significant clinical implications.

Irinotecan in relapsed or refractory non-Hodgkin's lymphomas. Indications of activity in a phase II trial.

Because irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity, we investigated its activity in relapsed or refractory non-Hodgkin's lymphomas (NHLs). Irinotecan at 300 mg/m2 i.v. was administered every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 44 registered patients, 32 are evaluable for response. Seventeen patients had received one previous regimen, and 15 patients had received two. Disease was refractory to the regimen preceding irinotecan in 12 patients. At baseline, serum lactate dehydrogenase levels were high in 47% (14/30), and beta-2-microglobulin levels were higher than 3.0 mg/L in 29% (8/28) of patients. Responses were seen in 12 of 32 (38%) patients (95% confidence interval [CI] = 21%-56%). Response rates were 43% for seven indolent (95% CI = 10%-82%), 0% for three mantle cell (95% CI = 0%-71%), 44% for 18 relapsed aggressive (95% CI = 22%-69%), and 20% for five refractory aggressive NHLs (95% CI = 1%-72%). Grade 3/4 toxicities included myelosuppression, neutropenic fever, and diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive or indolent NHL. Accrual to this study is continuing for better determination of response rates in all histologic subtypes of NHL.