Phase 2 Open-Label Study of Bortezomib,Cladribine, and Rituximab in Advanced,Newly Diagnosed,and Relapsed/Refractory Mantle-Cell and Indolent Lymphomas

Background

Mantle-cell lymphoma (MCL) and indolent non-Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front-line and R/R settings in MCL and iNHL (NCT00980395).

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.     

Efficacy and toxicity of 2 schedules of frontline rituximab plus cyclophosphamide,doxorubicin, vincristine,and prednisone plus bortezomib in patients with B‐cell lymphoma

BACKGROUND:

Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with the addition of bortezomib in patients with B‐cell lymphoma.

METHODS:

Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R‐CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m² in Arm A and 1.3 mg/m² in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m² and 1.6 mg/m² in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.

RESULTS:

Forty‐nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.

CONCLUSIONS:

R‐CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose‐limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies. Cancer 2009. © 2009 American Cancer Society.     

Efficacy and safety of the combination of rituximab,fludarabine, and mitoxantrone for rituximab‐naive,recurrent/refractory follicular non‐Hodgkin lymphoma with high tumor burden

BACKGROUND:

This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R‐FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

METHODS:

Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP‐like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion >7cm), 56% had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3‐5), and 22% were refractory. Treatment consisted of 4 courses of R‐FM (rituximab 375 mg/m² intravenously on Day 1, fludarabine 25 mg/m² intravenously on Days 2 through 4, and mitoxantrone 10 mg/m² intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab).

RESULTS:

The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R‐FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow‐up of 4 years, the 3‐year progression‐free survival rate was 47%, the event‐free survival rate was 41%, and the 3‐year overall survival rate was 66%. Grade ≥3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively.

CONCLUSIONS:

Cytoreduction with 4 courses of R‐FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome. Cancer 2010. © 2010 American Cancer Society.     

Proliferation predicts failure‐free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide,vincristine, doxorubicin,and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine

BACKGROUND:

It has been demonstrated that the tumor proliferation index has prognostic significance in patients with mantle cell lymphoma (MCL). Patients in most of studies, however, have been treated with relatively traditional chemotherapy regimens. At the authors' institution, patients with MCL received an aggressive chemotherapy regimen: rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine (R‐hyper‐CVAD).

METHODS:

The authors assessed the proliferation rate of MCL using immunohistochemistry and an antibody specific for Ki‐67 in 71 untreated patients who subsequently received R‐hyper‐CVAD. The study group included 59 patients who had classic MCL and 12 patients who had the blastoid variant of MCL.

RESULTS:

For the entire study group and for the group of patients with classic MCL, a proliferation index of >20% Ki‐67‐positive cells was correlated significantly with shorter failure‐free survival. There was no correlation between the proliferation index and overall survival.

CONCLUSIONS:

The current results indicated that the proliferation index in patients with MCL predicted prognosis in those who uniformly received the R‐hyper‐CVAD chemotherapy regimen. Cancer 2009. © 2009 American Cancer Society.     

Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

Expression of eukaryotic initiation factor 4E predicts clinical outcome in patients with mantle cell lymphoma treated with hyper‐CVAD and rituximab,alternating with rituximab,high‐dose methotrexate,and cytarabine

BACKGROUND:

Oncogenic AKT/mammalian target of rapamycin (mTOR) signaling has recently been shown to contribute to tumor survival and proliferation in mantle cell lymphoma (MCL) through its downstream effector eukaryotic initiation factor 4E (eIF4E), which may control cyclin D1 protein levels. However, the clinical significance of eIF4E expression in MCL is unknown.

METHODS:

The authors investigated the prognostic significance of eIF4E expression in 70 MCL patients uniformly treated with hyper‐CVAD and rituximab, alternating with the rituximab, high‐dose methotrexate, and cytarabine regimen (R‐hyper‐CVAD). eIF4E expression was assessed using tissue biopsy specimens obtained before treatment, immunohistochemical methods, and a highly specific monoclonal antibody. Failure‐free (FFS) and overall (OS) survival were used as endpoints in univariate and multivariate survival analysis.

RESULTS:

High eIF4E expression was found in 28 (40%) MCL tumors. After a median follow‐up of 51 months for survivors, the 5‐year FFS was 20.6% for patients with high eIF4E expression, compared with 63.5% for patients with low or no eIF4E expression (P = .01, log‐rank). Similarly, the 5‐year OS was 40.1% for patients with high eIF4E expression, compared with 73.8% for patients with low or no eIF4E expression (P = .018, log‐rank). In multivariate analysis, eIF4E expression was associated with poorer FFS and OS, along with age >60 years and high β₂–microglobulin in the final prognostic model.

CONCLUSIONS:

In summary, eIF4E, which seems to recapitulate most of the biologic effects of mTOR signaling in MCL, is an independent predictor of clinical outcome in MCL patients uniformly treated with the R‐hyper‐CVAD regimen. Cancer 2009. © 2009 American Cancer Society.     

Combination therapy with rituximab and intravenous or oral fludarabine in the first‐line,systemic treatment of patients with extranodal marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue type

BACKGROUND:

Currently, there are no consensus guidelines regarding the best therapeutic option for patients with extranodal marginal zone lymphomas of the mucosa‐associated lymphoid tissue (MALT) type.

METHODS:

Patients with systemically untreated or de novo extranodal MALT lymphoma received rituximab 375 mg/m² intravenously on Day 1 and fludarabine 25 mg/m² intravenously on Days 1 through 5 (Days 1‐3 in patients aged >70 years) every 4 weeks, for 4 to 6 cycles. After the first cycle, oral fludarabine could be given orally at 40 mg/m² on the same schedule. After 3 cycles, a workup was done. Patients who achieved a complete remission (CR) received an additional cycle, and patients who achieved a partial remission (PR) received a total of 6 cycles.

RESULTS:

Twenty‐two patients were studied, including 12 patients with gastric lymphoma and 10 patients with extragastric MALT lymphoma. Six patients (27%) had stage IV disease. In total, 101 cycles were administered (median, 4 cycles per patients). After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a PR. Primary extragastric disease was an adverse factor to achieve CR after 3 cycles of chemotherapy (hazard ratio, 23.3; 95% confidence interval, 2.0‐273.3). At the end of treatment, the overall response rate was 100%, and 90% of patients achieved a CR. The progression‐free survival rate at 2 years in patients with gastric and extragastric MALT lymphoma was 100% and 89%, respectively. Toxicities were mild and mainly were hematologic.

CONCLUSIONS:

Combination therapy with rituximab and fludarabine is a very active treatment with favorable safety profile as first‐line systemic treatment for patients with extranodal MALT lymphoma. Cancer 2009. © 2009 American Cancer Society.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Modified VR-CAP,Alternating With Rituximab and High-dose Cytarabine: An Effective Pre-transplant Induction Regimen for Mantle Cell Lymphoma

Background

Initial treatment of mantle cell lymphoma (MCL) incorporating autologous stem cell transplantation affords long-term remissions, but relapses still occur. Optimal pretransplant therapy will afford high complete response rates and not impair stem cell collection. Incorporation of bortezomib represents a natural evolution of pretransplant therapy, given its proven first-line efficacy and minimal impact on stem cell collection.

Durable responses with the metronomic rituximab and thalidomide plus prednisone,etoposide, procarbazine,and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma

BACKGROUND:

Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT‐PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).

METHODS:

RT‐PEPC included induction (Months 1‐3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells.

RESULTS:

Twenty‐five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52‐81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high‐risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1‐7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow‐up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression‐free survival was 10 months. Four CRs were ongoing (≥6 months, ≥31 months, ≥48 months, and ≥50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment.

CONCLUSIONS:

RT‐PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low‐intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients. Cancer 2010. © 2010 American Cancer Society.     

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.     

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.     

Anthracycline‐fludarabine‐containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma

BACKGROUND:

Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients.

METHODS:

In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments.

RESULTS:

The complete remission (CR) rate for BACOP/FND was 62%. After a median follow‐up of 60 months, the failure‐free survival (FFS) and overall survival (OS) rates at 4 years were 53% and 77%, respectively. The CR rate for BACOP/FR was 79%. After a median follow‐up of 36 months, the FFS and OS rates at 4 years were 56% and 97%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty‐five of 42 bcl‐2‐positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia.

CONCLUSIONS:

The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline‐fludarabine–containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. © 2009 American Cancer Society.     

Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma

BACKGROUND:

The use of ¹⁸F‐fluorodeoxyglucose positron‐emission tomography (PET) scan has increased considerably in the clinical management of non‐Hodgkin lymphoma patients, and its role as a prognostic factor during chemotherapy has been established recently.

METHODS:

Between May 2003 and May 2009, 91 newly diagnosed patients with primary mediastinal large B‐cell lymphoma (PMLBCL) and diffuse large B‐cell lymphoma (DLBCL) were treated with 12 weekly cycles of rituximab‐MACOP‐B (n = 12 patients with PMLBCL), 6 cycles of rituximab‐CHOP21 (n = 65 patients with DLBCL, aged < 60 years and 1 patient with PMLBCL), or 8 weekly cycles of rituximab‐VNCOP‐B (n = 13 DLBCL patients, aged ≥ 60 years). All patients underwent a staging PET examination at baseline and a midtreatment (interim) PET examination after 6 weeks of rituximab‐MACOP‐B treatment, 3 cycles of rituximab‐CHOP21 treatment, or 4 weeks of rituximab‐VNCOP‐B treatment and again at the end of the chemo‐immunotherapy regimen.

RESULTS:

At midtreatment evaluation, 35 patients showed a persistently positive PET scan; only 6 (17%) of these patients achieved a continuous complete response (CCR). However, 56 patients presented with a negative interim PET, and 50 (89%) of these patients achieved and maintained a CCR. Comparison between the 2 PET groups indicated a statistically significant association between PET findings and event‐free survival (P = .0001) and overall survival (P = .0001).

CONCLUSIONS:

The results of this study indicated that midtreatment PET may represent a significant step forward in helping physicians make crucial decisions on further treatment. Cancer 2011. © 2010 American Cancer Society.     

Impressive and durable response in a case of multiple relapsed mantle cell lymphoma treated with bortezomib and rituximab

Relapsed mantle cell lymphoma (MCL) usually represents a hard challenge, especially after the failure of high-dose therapy or in elderly patients, and although new agents have been investigated, responses are often short and a significant proportion of patients finally die from progressive disease. Here, we report a case of a relapsed MCL patient that achieved durable response with bortezomib and rituximab. Treatment regimen consisted of bortezomib 1.6 mg/m² and rituximab 375 mg/m² intravenously on days 1–8–15–22 for the 1st course, followed by 2 courses of bortezomib with the same schedule. After the third course, patients in CR, PR or SD received other 3 courses. The patient achieved a CR, but because of the high risk of relapse we started a 4-week maintenance therapy with rituximab and bortezomib for 4 courses administered at six month interval. After a follow-up of 62 months, the patient maintained CR. We suggest rituximab plus bortezomib could play an important role in the treatment of patients with relapsed/refractory MCL. Maintenance therapy could be an interesting option, especially for patients with a high relapse risk rate.     

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma

BACKGROUND:

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R‐EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)‐associated, aggressive B‐cell, non‐Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.

METHODS:

The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV‐associated NHL who received either R‐CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R‐EPOCH (n = 51; AMC034). Age‐adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R‐CHOP vs R‐EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event‐free survival (EFS) and overall survival (OS).

RESULTS:

Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R‐EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment‐associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).

CONCLUSIONS:

The current analysis provided additional level 2 evidence supporting the use of concurrent R‐EPOCH in patients with HIV‐associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R‐EPOCH with R‐CHOP in immunocompetent patients with diffuse large B‐cell lymphoma (National Clinical Trial no. NCT00118209). Cancer 2012. © 2011 American Cancer Society.     

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma

Background

The proteasome inhibitor bortezomib has demonstrated marked preclinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. The present study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL).

VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study

Introduction

VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL.

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation

BACKGROUND:

Indolent nonfollicular non‐Hodgkin B‐cell lymphomas (INFLs) are clonal mature B‐cell proliferations for which treatment has not been defined to date.

METHODS:

In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first‐line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m² intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m² intravenously on days 2‐4, cyclophosphamide 250 mg/m² intravenously on Days 2‐4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m² intravenously on day 1) every 2 months for responders.

RESULTS:

Forty‐seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow‐up of 40.9 months, the failure‐free survival and progression‐free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients.

CONCLUSIONS:

FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society.