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B-cell non-Hodgkin lymphomas (NHL) display dysregulation of pathways controlling cell proliferation and apoptosis. Combined proteasome and mTOR inhibition, demonstrated with bortezomib and everolimus in a preclinical model, thus warrants evaluation in humans. We conducted a phase I study to identify the maximum tolerated dose (MTD) and safety of this combination in relapsed/refractory (r/r) NHL. Twenty-nine patients were enrolled from July 2008 to March, 2015. Toxicities were primarily hematologic, and dose-limiting thrombocytopenia defined the MTD as 5 mg everolimus daily with 1.3 mg/m 2 bortezomib d1, 4, 8, and 11 every 21 days. Of 25 response-evaluable patients there was one complete response in a patient with MCL and three partial responses (two MCL, one FL) for an overall response rate of 16%. In conclusion, the combination of everolimus and bortezomib results in dose limiting thrombocytopenia, but is tolerable. This combination has limited clinical activity in heavily pretreated NHL.

Background: Young fit patients with mantle cell lymphoma (MCL) are commonly treated with induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT). Induction regimens with modifications of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and/or incorporation of high-dose cytarabine (HDAC) appear more effective than R-CHOP alone., Patients and Methods: We adopted a modification of the Nordic protocol using standard, rather than higher dose R-CHOP, alternating with HDAC (rituximab plus HDAC), for 3 cycles each or, for patients already treated with R-CHOP alone before referral for AHCT, an additional 2 cycles of rituximab plus HDAC. We herein report our experience with 28 patients treated with this regimen who proceeded to AHCT, and compare their outcomes with patients treated with either standard-dose R-CHOP (n = 38) or R-HCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate, and cytarabine; n = 21), before AHCT., Results: With a median follow-up duration of 26 months, our data show that this modification of the Nordic regimen is a highly effective pre-AHCT first-line therapy for MCL (3-year progression-free and overall survival rates of 69% and 75%, respectively)., Conclusion: By using a less intense induction, this regimen can serve as a platform for combined use of novel agents, with less risk of additive toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate) is an intense chemotherapy regimen frequently used for hematologic malignancies including mantle cell lymphoma. To address whether treatment with hyper-CVAD impairs mobilization of peripheral blood stem cells, we retrospectively analyzed mobilization data from 77 consecutive adult patients with mantle cell lymphoma who underwent peripheral blood stem cell (PBSC) mobilization for planned autologous stem cell transplant (ASCT). Compared to patients treated with alternative regimens, patients treated with hyper-CVAD collected fewer CD34+ cells, required more total days of pheresis, and more frequently required a second mobilization attempt, despite being more likely to have undergone mobilization with a VP16-containing regimen. In multivariable linear regression analysis, treatment with hyper-CVAD was associated with a significant reduction in total CD34+ cells mobilized (p < 0.001). These findings suggest that alternative mobilizing strategies prior to ASCT are needed for patients with mantle cell lymphoma who have received hyper-CVAD.

The long-term follow-up is presented for 317 patients with acute myeloid leukaemia who underwent human leucocyte antigen-identical sibling marrow transplants between 1984 and 1995 following preparation with busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. Among the 142 (45%) who were alive and leukaemia-free 3 years following transplantation, the leukaemia-free survival at 15 years was 72.8%. The cumulative incidence of late (>3 years beyond transplant) non-relapse mortality at 15 years was 12.9% and of late relapse was 16.5%. None of the variables considered (including age, disease stage, and graft-versus-host disease) were predictive of late failure.

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens to treat diffuse large B cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, however, many patients develop refractory or recurrent DLBCL and then undergo autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes after AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n = 176; +R cohort) or was not (n = 818; -R cohort) administered with front-line or salvage therapy before AuHCT. The +R cohort had superior progression-free survival (PFS; 50% vs 38%; P = .008) and overall survival (OS; 57% vs 45%; P = .006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Nonrelapse mortality (NRM) did not differ significantly between the 2 cohorts. In multivariate analysis, the +R cohort had improved PFS (relative risk of relapse/progression or death, 0.64; P < .001) and improved OS (relative risk of death, 0.74; P = .039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival after AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for chronic myelogenous leukemia (CML). Failure, because of relapse or nonrelapse mortality (NRM), generally occurs within 3 years of transplantation, but large studies with long-term follow-up are limited. We present mature results in 335 patients with CML who underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings following busulfan and cyclophosphamide (BU/Cy2). Two hundred twenty-nine were in chronic phase (CP) and 106 in accelerated or blastic phase at transplantation. Median follow-up exceeded 14 years. The estimated probability of 18-year leukemia-free survival (LFS) for CP patients was 55.6% and for those beyond CP, 10.5%. Of 182 patients who survived leukemia-free at 3 years, the estimated probability of LFS at 18 years was 61.9%. Late relapse (P = .039) and late NRM (P = .008) occurred at higher rates in patients beyond CP at transplantation. There was no plateau in LFS.

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.