Michele L. Donato

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.

Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma

Relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first‐relapse or primary refractory DLBCL. Dose‐escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose‐limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high‐risk DLBCL patients.

Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies.

Most patients eligible for allogeneic hematopoietic stem cell transplantation will require identification of an alternate (unrelated or mismatched related) donor. We explored the transplantation outcomes for a sequential series of 54 patients undergoing haploidentical donor transplantation (HAPLO) compared to those from a control group of patients receiving cells from matched or mismatched unrelated donors (URD) selected by diagnosis and stem cell source. Patients undergoing HAPLO transplantations received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (Cy). Day 15 neutrophil recovery was lower after HAPLO than in URD recipients (43% versus 77%, P < .001), as was day 30 platelet recovery (67% versus 84%, P = .043). HAPLO patients receiving bone marrow achieved neutrophil engraftment at a median of 17 days and platelet engraftment at a median of 29 days, compared with 16 days and 24 days, respectively, for recipients of peripheral blood stem cells. The incidence of graft failure was similar for both HAPLO and URD recipients (P = .42). HAPLO recipients were more likely to reach donor CD3 chimerism >95% by day 28 after transplantation (88% versus 62%, P = .003). The cumulative incidence of grades II to IV acute GVHD (aGVHD) at 6 months after transplantation did not differ for these 2 groups (63% for HAPLO and 53% for URD recipients; P = .269), nor did the cumulative incidence of severe grade III/IV aGVHD (13% for HAPLO and 8% for URD recipients; P = .44). The cumulative incidence of moderate or severe chronic GVHD at 2 years did not differ, with probabilities of 24% for HAPLO and 18% for URD recipients (P = .43). The cumulative incidence of cytomegalovirus reactivation by day 100 after transplantation did not differ (45% for HAPLO and 46% for URD recipients; P = .96). The HAPLO recipients experienced a lower incidence of Epstein-Barr virus reactivation by day 100 (6% versus 32%, P < .001) but a higher incidence of Human Herpesvirus-6 reactivation (35% versus 10%, P = .001). Relapse risk, regimen-related mortality, progression-free survival, and overall survival probabilities did not differ between these 2 groups. These data support the use of HAPLO transplantation with post-transplantation Cy as an alternate transplantation technique for patients lacking HLA-matched sibling donors. Transplantation of peripheral blood stem cells does not appear to enhance the speed of neutrophil recovery. The different patterns of viral reactivation require additional studies to explain.

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

The association between the GOELAMS MCL-PET prognostic index and survival in patients treated with rituximab-hypercvad (R-HyCVAD) or high-dose therapy with autologous stem cell rescue (HDT/ASCT).

8050 Background: Prognostic models in MCL are still debated particularly in dose-intensive treatment approaches (R-HyCVAD or HDT/ASCT) since they include both age (med age dx, mid 60s) and performance status. Additional prognostic factors have been looked at including Ki-67 (MIB-1) and more recently PET scan. The GOELAMS group proposed a model to predict OS and PFS in MCL in the 1st-line setting based on a dichotomized SUV max (≤ 6 vs. >6 = 1 point) + IPI score (≤ 2 vs. >2 = 1 point) in 44 heterogeneously treated pts (3 groups: score 0-2). We sought to validate this approach in MCL pts treated in the 1st-line setting. METHODS Single center retrospective study to assess the clinical utility of the GOELAMS MCL-PET prognostic index in newly diagnosed MCL pts treated with R-HCVAD or HDT/ASCT using PFS and OS as 1° endpoints. PET-CT images were centrally reviewed to determine SUV max at diagnosis and response (International Harmonization Project in Lymphoma criteria) by 3 radiologists blinded to outcomes. RESULTS 83 pts (median age 58, range 35-74) with advanced stage (98% stage IV) MCL treated with 1st line R-HyCVAD (60%) or HDT/ASCT (40%) were indentified for this analysis. Overall treatment response (IWG) was 93% (76% CR + 17% PR). 60 pts had clinical and radiologic data available for the validation study. Median baseline characteristics: WBC 7.75 (range 2.5-918), Ki-67 30% (range 5-90%), IPI 3 (52% ≥3), MIPI 3.5 (40% int+high risk), SUV Max 7.8 (range 2.4-36.7). Estimated 3 year OS and PFS were 82% and 76% (med follow-up 35 months). Using Cox regression and Kaplan Meir survival analyses, the MCL-IPI-PET model did not stratify pts into 3 groups with distinct PFS (HR 1.3, p=.24 LR test) or OS (HR 3.1, p .13 LR test). Baseline SUV max was not an independent predictor of outcome in multivariate analysis (PFS: HR 1.4, p=.71, OS: HR 2.3, p=.29) when added to IPI. CONCLUSIONS The MCL-IPI-PET model was not validated in our series of newly diagnosed MCL pts treated with intensive approaches. This study highlights the need to develop and validate models to identify pts at risk for inferior survival treated with dose-intensive approaches.

Delayed daily filgrastim compared to early alternate day filgrastim following autologous peripheral blood stem cell transplantation for multiple myeloma

18015 Background: High-dose chemotherapy with autologous peripheral blood stem cell rescue has become a standard therapy in newly diagnosed multiple myeloma. To reduce the duration of neutropenia and risk of infections filgrastim is commonly administered post- transplantation. A large national trial in myeloma utilized melphalan 200 mg/m2 on day -2 followed by G-CSF daily beginning day +5. However, at Hackensack University Medical Center we have used the same chemotherapy on day -1 with G-CSF given on alternate days beginning day +3 (and daily on day +10). Methods: A retrospective review of all autologous peripheral blood stem cell transplants for myeloma performed between January 1, 2005 and March 31, 2007. All received prophylactic antibiotics consisting of ciprofloxacin, acyclovir, and fluconazole. Results: 24 patients were treated on the national trial using the delayed daily (DD) G-CSF schedule. 210 patients received the early alternate (EA) G-CSF schedule. The DD cohort (national trial) was younger ...