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Prospective identification of candidates for deferred therapy is not standardized and many patients receive immediate therapy regardless of risk. We conducted a retrospective, multi-center cohort analysis of MCL patients with comprehensive clinical data to examine the use and safety of deferred therapy for newly diagnosed patients. Previously untreated patients ≥18 years-old with MCL diagnosed in 1993-2015 at five academic sites were included. Of 395 patients, 72 (18%) received deferred therapy (defined as receipt of first treatment >90 days following initial diagnosis). Patients receiving deferred therapy were more likely to have an ECOG performance status of 0 (67 versus 44% p = .001), have no B symptoms (83 versus 65% p = .003) and have normal LDH levels at diagnosis (87 versus 55% p < .001). In multivariable analysis, deferred therapy was not associated with a significant difference in OS (HR 0.64: 95% CI 0.22-1.84, p = .407).

Mantle cell lymphoma (MCL) is a heterogeneous disease with high relapse rates. Limited data guide the use of surveillance imaging following treatment. We constructed a retrospective cohort from two academic institutions of patients with MCL who completed first-line therapy and underwent follow-up for relapse, analyzing the effect of surveillance imaging on survival. Of 217 patients, 102 had documented relapse, with 38 (37%) diagnosed by surveillance imaging and 64 (63%) by other methods. Relapse diagnosis by surveillance imaging had no significant advantage in overall survival from diagnosis date (hazard ratio [HR] = 0.80, p = .39) or relapse date (HR = 0.72, p = .22). Of 801 surveillance images, PET/CT had a positive predictive value (PPV) of 24% and number needed-to-scan/treat (NNT) of 51 to detect one relapse, and CT had a PPV of 49% and NNT of 24. For MCL after first-line therapy, relapse detection by surveillance imaging was not associated with improved survival and lacks clinical benefit.

The initial dose of bendamustine, an alkylating agent used in treating indolent lymphoma (iNHL) and mantle cell lymphoma, is variable in clinical practice. 134 patients treated with bendamustine and rituximab were evaluated for starting dosage, patient characteristics, toxicities, and clinical outcome. The starting dosage ranged from 50 to 90 mg/m 2 . Lower starting dosage (<90 mg/m 2 ) was associated with relapsed disease, increased age and worse performance status (PS), histologic subtype other than follicular lymphoma, baseline renal impairment, and cytopenias. No significant difference was observed in toxicities between patients treated with 90 mg/m 2 compared with lower doses. The starting dose of 90 mg/m 2 was associated with a higher complete response rate (56% vs. 29%) and longer progression free survival (PFS) (39.5 months vs. 19.7 months). However, in a multivariable model, the higher starting dose was not associated with longer PFS in those with similar age, histology, PS, and number of prior therapies.

Cancer and Leukemia Group B designed a phase II trial of lenalidomide + bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete/partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free (PFS), event-free (EFS) and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median followup was 46 (range, 12-67) months. Best response was CR 15%, PR 25%. 5/8 CR, and 4/13 PR patients received maintenance. Six CR and one PR patient remain in remission (median, 3.2 years). Thirty-three (62%) patients have died. One-year PFS, EFS and OS are 40%, 25% and 68%, respectively. This combination will not be pursued further.

Abstract This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150 mg/m(2) and bortezomib 0.7 mg/m(2). Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p = 0.005) and increase in AUC (p = 0.032) of 17-amino-17-demethoxygeldanamycin (17-AG), not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML. Next-generation HSP90 inhibitors are appealing for further development in this area.

We evaluated the safety and efficacy of the purine nucleoside analogue, clofarabine, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Six patients with DLBCL (n = 5) or MCL (n = 1) and a median age of 68 years were treated with 40 mg/m(2) clofarabine IV over 2 h for 5 days, repeated every 28 days, for 1-2 cycles. The overall response rate was 50% (complete response = 1, complete response unconfirmed = 1, partial response = 1). Median progression-free survival was 3.5 months (range 1.5-10 months) and the median overall survival was 7.8 months (range 3-31 months). Grade 3-4 neutropenia and thrombocytopenia was universal, with a median of 34 (range 19-55) and 77 (range 0-275) days required for neutrophil and platelet recovery. Grade 3 non-hematologic toxicities included transaminitis, febrile neutropenia, non-neutropenic infections and orthostatic hypotension. Further accrual to the study was terminated due to prolonged Grade 3-4 myelosuppression and orthostatic hypotension in five of six patients. Clofarabine exhibits evidence of single agent activity in relapsed or refractory DLBCL. However, further study with novel administration schedules that maintain this efficacy and limit toxicity is warranted.

The transformation of follicular lymphoma (FL) to high-grade histology occurs in up to 70% of FL patients. Studies reporting outcomes of transformed FL patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are scant. Eight FL patients with histologically confirmed transformation to diffuse large B-cell lymphoma underwent HSCT at our institution. The median age was 56 years (range 44-63 years). Median follow-up is 60 months. Progression free survival and overall survival at 4-years for patients undergoing allogeneic HSCT is 56% and 66%, respectively. Four patients developed grade II-IV acute GVHD, whereas four patients had extensive chronic GVHD. Day 100 and overall non-relapse mortality rate was 12.5% and 25%, respectively. Allogeneic HSCT appears feasible in patients with transformed FL and is associated with acceptable treatment-related mortality and low relapse rates.

Constitutive activation of nuclear factor-kappaB (NF-kappaB) has been described in patient-derived Reed - Sternberg cells and Hodgkin lymphoma (HL) cell lines and contributes to the proliferation and survival of HL. Therapeutic inhibition of the proteasome with bortezomib may inhibit over-expression of nuclear NF-kappaB by preventing degradation of IkappaB, which sequesters NF-kappaB in the cytoplasm. To evaluate this hypothesis, the Cancer and Leukemia Group B (CALGB) conducted a multi-institutional phase II trial of single agent bortezomib in patients with relapsed or refractory classical HL. Thirty patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11 and every 21 days for a median of 2 cycles (range, 1 - 8). Patients were heavily pre-treated with a median of four prior therapies, and 83% were previously transplanted. No responses were observed, 9 patients had stable disease, and 21 progressed. The median progression-free and overall survivals were 1.4 months [95% CI, (1.28, 1.91)] and 14.8 months [95% CI (11.2, 22.3)], respectively. Grade 3 - 4 adverse events, primarily thrombocytopenia, occurred in 15 patients. Therefore, although well tolerated, 1.3 mg/m(2) bortezomib administered biweekly has no single agent activity in relapsed/refractory classical HL.