Julie E. Chang

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/m2 × 4 weekly doses) and MR (375 mg/m2 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.

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomibs contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537.

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.

Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125−3.11 mg/m2 on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1−36). MTD was determined to be 2.34 mg/m2. Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾3 events were reported. Plasma exposure increased dose proportionally from 0.5−3.11 mg/m2; terminal half-life was 4−12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.

Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study†

Arsenic trioxide (As2O3) has established clinical activity in acute promyelocytic leukaemia and has pre‐clinical data suggesting activity in lymphoid malignancies. Cell death from As2O3 may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic‐mediated apoptosis. This multi‐institution phase II study investigated a novel dosing schedule of As2O3 and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As2O3 0.25 mg/kg IV and AA 1000 mg IV for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2–6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl‐2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non‐Hodgkins lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two‐stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre‐treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As2O3 and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies. Copyright

Augmented and standard Berlin–Frankfurt–Münster chemotherapy for treatment of adult acute lymphoblastic leukemia

The augmented Berlin–Frankfurt–Münster (aBFM) regimen has demonstrated improved outcomes in children with acute lymphomblastic leukemia (ALL), but efficacy in adults is unknown. In this retrospective study, we evaluated clinical outcomes in 29 adult ALL patients (aged 19–70) treated with standard BFM (sBFM) or dose-intensive aBFM. Patients were stratified into risk groups based on age, cytogenetic abnormalities, peripheral leukocytosis and response to induction chemotherapy. Inter-mediate risk patients less than 50 years old and all high-risk patients were assigned to aBFM. Complete remission after induction therapy was achieved in 93% of patients. Fifteen patients completed a full course of BFM chemotherapy, with seven discontinuing because of relapse, three because of toxicity, two because of transplantation and two toxic deaths. Five-year event-free survival (EFS) was 45% (95% CI 30–67%), with 39% and 50% rates of EFS observed in the aBFM and sBFM subgroups at 5 years, respectively. Overall survival at 5 years was 62% (95% CI 46–82%), with 61% and 62% in the aBFM and sBFM subgroups alive at 5 years, respectively. Two toxic deaths were observed, and infections and neuropathy were the most common toxicities. sBFM and aBFM have efficacy and toxicity comparable with other adult ALL regimens.

Phase I Study of the Anti-CD22 Antibody–Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Purpose: Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy–related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167–76. ©2016 AACR.

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study

Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression‐free survival (PFS) after BR is <18 months. This study was designed to determine if maintenance lenalidomide after BR induction could improve PFS in R/R CLL/SLL. Thirty‐four patients with R/R CLL/SLL who had received 1–5 prior chemotherapy regimens were treated with 6 cycles of BR induction. Patients achieving at least a minor response received twelve 28‐d cycles of lenalidomide 5–10 mg/d. The primary endpoint was PFS. The median age was 67 years, with a median of 2 prior therapies. Eleven patients had confirmed presence of 17p and/or 11q deletions. Twenty‐five (74%) completed 6 cycles of induction BR (response rate 56%). Nineteen (56%) patients received maintenance lenalidomide; only 6 patients completed the intended 12 cycles, highlighting the limited feasibility of lenalidomide in this setting, primarily due to haematological and infectious toxicities. The observed median PFS of 18·3 months is not significantly different from that of BR induction in R/R CLL/SLL without maintenance therapy (15·2 months). It is possible that lenalidomide maintenance may be more feasible and effective in the front‐line setting, which is being tested in an ongoing trial (NCT01754857).

Current status of targeted therapies for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma (NHL) with treatment outcomes that have historically been poorer than those observed with other NHL subtypes. Patients typically present with dvanced-stage disease and frequent extranodal involvement; the median age at diagnosis is >60 years. Recent improvements in progression-free and overall survival have been observed with more dose-intensive strategies, although at least half of patients diagnosed with MCL are not eligible for such treatment approaches based on age and co-morbidities. In addition, therapy options for relapsed MCL are limited. Only bortezomib is approved for treatment of relapsed MCL in the US. Development of targeted therapy approaches to minimize toxicities while preserving anti-neoplastic properties is of particular importance in MCL. Multiple ongoing studies are attempting to build on the known efficacy of bortezomib by evaluating combination regimens with other targeted agents or cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has known activity in MCL, making this an attractive class of agents for further investigation in combination regimens. Rituximab and other monoclonal antibodies are being evaluated for novel roles in MCL treatment, including as maintenance therapy. Other classes of drugs being investigated in MCL are immunomodulatory agents, inhibitors of the phosphoinositide 3-kinase/Akt and B-cell receptor signalling pathways, and inhibitors of bcl-2 and histone deacetylase. Although many of the agents appear to have modest single-agent activity, the favourable toxicity profile of many agents will make them best suited for incorporation into combination regimens.

Thalidomide maintenance following high-dose melphalan with autologous stem cell support in myeloma.

BACKGROUND Recent experience with thalidomide maintenance after high-dose chemotherapy with autologous stem cell support has demonstrated improvement in progression-free survival (PFS) and overall survival (OS). We further explored the tolerability and efficacy of lower doses of maintenance thalidomide in this single-institution study. PATIENTS AND METHODS Thirty-eight patients with myeloma were enrolled and treated with melphalan 200 mg/m(2) followed by autologous stem cell transplantation. Thalidomide 50 mg per day was started on day > or = 60 after recovery of blood counts and was escalated to a maximum dose of 200 mg per day. Responses were assessed at 2 months, 1 year, and 2 years after transplantation. RESULTS Of the 38 enrolled patients, 7 patients never received thalidomide. Among 31 patients receiving thalidomide, complete or very good partial responses were observed in 65% and 42% of patients at 1 and 2 years, respectively. Tolerability was a major issue, with only 17 patients completing 1 year of thalidomide. The goal of dosing 200 mg per day was achieved in just 17 of 31 patients, and the median tolerated thalidomide dose was 100 mg per day. Sensory neuropathy was the primary reason for dose modification and discontinuation. No thromboembolic events were observed. The median PFS was 20.8 months, and the median OS was > 60 months. CONCLUSION Thalidomide maintenance at a goal dose of 200 mg per day was not feasible in this population, with our data suggesting that 100 mg per day is a more reasonable maintenance dose.

Rituximab and CHOP Chemotherapy Plus GM-CSF for Previously Untreated Diffuse Large B-Cell Lymphoma in the Elderly: A Wisconsin Oncology Network Study

PURPOSE Human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) may potentiate rituximab activity by upregulating CD20 expression and activating effector cells necessary for antibody-dependent cellular cytotoxicity. GM-CSF was combined with standard rituximab + CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy (R-CHOP) in the treatment of elderly patients with de novo diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS Thirty-eight patients over the age of 60 years with newly diagnosed DLBCL were treated with R-CHOP every 21 days for 6-8 cycles and GM-CSF 250 µg/m2 per day on days 3-10. Patients were evaluated for response after cycles 4, 6, and 8. The primary endpoint was the rate of complete response, and secondary endpoints were progression-free survival (PFS), event-free survival, and overall survival (OS). RESULTS Thirty-eight patients were enrolled, with a median age of 72 years, and 29% of patients having high-risk disease (International Prognostic Index [IPI] score ≥ 4). A complete or unconfirmed complete response (CR) was achieved in 53% of patients. After a median follow-up of 51.1 months, the 3-year PFS and OS were 78% and 84%. Twenty-one percent of patients discontinued protocol treatment because of chemotherapy-related toxicity and 16% because of GM-CSF toxicity. Dose intensity for planned chemotherapy cycles was 81.1%. CONCLUSION These data suggest that survival outcomes may be modestly improved when GM-CSF is combined with R-CHOP in the treatment of elderly DLBCL. GM-CSF had toxicity precluding planned administration in 16% of patients, which may limit usefulness of this agent. Further investigation of GM-CSF in combination with rituximab-containing chemotherapy is warranted.