Rima M. Saliba

Cord-blood engraftment with ex vivo mesenchymal-cell coculture.

BACKGROUND Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells. METHODS We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood. RESULTS Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram--doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001). CONCLUSIONS Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.).

Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m(2) daily for 3 days), cyclophosphamide (750 mg/m(2) daily for 3 days), and rituximab (375 mg/m(2) for 1 day plus 1000 mg/m(2) for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

Nonablative Allogeneic Stem-Cell Transplantation for Advanced/Recurrent Mantle-Cell Lymphoma

PURPOSE Patients with relapsed mantle-cell lymphoma have poor prognosis and short survival. Our aim was to determine the efficacy of nonablative allogeneic stem-cell transplantation in patients with relapsed mantle-cell lymphoma. PATIENTS AND METHODS Eighteen patients were treated in one of two consecutive trials. Thirteen patients underwent a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and high-dose rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 daily for 4 days), fludarabine (30 mg/m2 daily for 2 days), and cytarabine (1,000 mg/m2 daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis. RESULTS The median age was 56.5 years. Patients underwent a median of three prior chemotherapy regimens. Prior autologous transplantation failed in five (28%) patients and 16 (89%) had chemosensitive disease. Donor cell engraftment occurred in all patients. Eight patients (44%) required no platelet or RBC transfusion, and acute graft-versus-host disease of greater than grade 2 did not develop in any patient. The day-100 mortality was 0%. Complete remission (CR) occurred in 17 patients. Three patients progressed, and one was reinduced into continuous CR with donor lymphocyte infusion. With a median follow-up period of 26 months, the actuarial probability of current-event-free-survival at 3 years was 82% (95% CI, 65% to 99%). CONCLUSION Our data suggest that nonablative allogeneic transplantation is a safe and potentially effective strategy for patients with relapsed and chemosensitive mantle-cell lymphoma.

Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.

Chronic graft‐versus‐host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid‐resistant cGVHD. Thirty‐five patients who developed GVHD after day 100 post‐transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count ≥100 × 109/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD‐free survival are warranted.

Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Hodgkin’s Lymphomas

PURPOSE We investigated the efficacy and safety of administering high-dose rituximab (HD-R) in combination with high-dose carmustine, cytarabine, etoposide, and melphalan chemotherapy and autologous stem-cell transplantation (SCT) in patients with recurrent B-cell aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Sixty-seven consecutive patients were treated. Rituximab was administered during stem-cell mobilization (1 day before chemotherapy at 375 mg/m(2) and 7 days after chemotherapy at 1,000 mg/m(2)), together with granulocyte colony-stimulating factor 10 mug/kg and granulocyte-macrophage colony-stimulating factor 250 microg/m(2) administered subcutaneously daily. HD-R of 1,000 mg/m(2) was administered again days 1 and 8 after transplantation. The results of this treatment were retrospectively compared with those of a historical control group receiving the same preparative regimen without rituximab. RESULTS With a median follow-up time for the study group of 20 months, the overall survival rate at 2-years was 80% (95% CI, 65% to 89%) for the study group and 53% (95% CI, 34% to 69%) for the control group (P = .002). Disease-free survival was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004). The median time to recovery of absolute neutrophil count to >/= 500 cells/microL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group (P = .001). However, infections were not significantly increased in patients treated with rituximab. CONCLUSION The results of this study suggest that using HD-R and autologous SCT is a feasible and promising treatment for patients with B-cell aggressive NHL.

Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience.

Allogeneic stem cell transplantation is employed in patients with relapsed and refractory Hodgkins lymphoma. In this setting, transplant-related mortality is particularly high. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning appears to be associated with a significant reduction in transplant-related mortality. Background The role of reduced-intensity conditioning allogeneic stem cell transplantation in relapsed/refractory Hodgkin’s lymphoma remains poorly defined. We here present an update of our single-center experience with fludarabine-melphalan as a preparative regimen. Design and Methods Fifty-eight patients with relapsed/refractory Hodgkin’s lymphoma underwent RIC and allogeneic stem cell transplantation from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). Forty-eight (83%) had undergone prior autologous stem cell transplantation. Disease status at transplant was refractory relapse (n=28) or sensitive relapse (n=30). Results Cumulative day 100 and 2-year transplant-related mortality rates were 7% and 15%, respectively (day 100 transplant-related mortality MRD vs. MUD 8% vs. 6%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) graft-versus-host disease in the first 100 days was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic graft-versus-host disease at any time was 73% (MRD vs. MUD 57% vs. 85%, p=0.006). Projected 2-year overall and progression-free survival rates are 64% (49–76%) and 32% (20–45%), with 2-year disease progression/relapse at 55% (43–70%). There was no statistically significant differences in overall survival progression-free survival, and disease progression/relapse between MRD and MUD transplants. There was a trend for the response status pretransplant to have a favorable impact on progression-free survival (p=0.07) and disease progression/relapse (p=0.049), but not on overall survival (p=0.4) Conclusions Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in progression-free survival Hodgkin’s lymphoma is associated with a significant reduction in transplant-related mortality, with comparable results in MRD and MUD allografts. Optimizing pretransplant response status may improve patients’ outcome.

Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen

Summary:A total of 40 patients with relapsed/refractory Hodgkins disease (HD) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18–58). Disease status at allo-SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens were fludarabine-cyclophosphamide±antithymocyte globulin (n=14), a less intensive regimen, and fludarabine-melphalan (FM) (n=26), a more intensive one. The two groups had similar prognostic factors. The median time to neutrophil recovery (ie absolute neutrophil count ⩾500/μl) was 12 days (range 10–24). The median time to platelet recovery (ie platelet count ⩾20 000/μl) was 17 days (range 7–132). Day 100 and cumulative (18-month) transplant-related mortalities (TRMs) were 5 and 22%. Twenty-four patients (60%) are alive (14 in complete remission or complete remission, unconfirmed/uncertain) with a median follow-up of 13 months (4–78). In all, 16 patients expired (TRM n=8, disease progression n=8). FM patients had better overall survival (73 vs 39% at 18 months; P=0.03), and a trend towards better progression-free survival (37 vs 21% at 18 months; P=0.2). RIC allo-SCT is feasible in relapsed/refractory HD patients with a low TRM. The intensity of the preparative regimen affects survival.

Nonmyeloablative Allogeneic Hematopoietic Transplantation: A Promising Salvage Therapy for Patients With Non-Hodgkin's Lymphoma Whose Disease Has Failed a Prior Autologous Transplantation

PURPOSE Allogeneic transplantation for patients with lymphoma who experience a recurrence after an autologous transplantation has been considered a hazardous therapeutic choice. We investigated the safety and efficacy of nonmyeloablative stem-cell transplantation in these patients. PATIENTS AND METHODS Patients were required to have chemosensitive or stable disease. Twenty consecutive patients were treated in two sequential trials. Fifteen patients underwent a preparative regimen of fludarabine (30 mg/m(2) daily for 3 days), intravenous cyclophosphamide (750 mg/m(2) daily for 3 days), and rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m(2) continuous infusion daily for 4 days), fludarabine (30 mg/m(2) daily for 2 days), and cytarabine (1,000 mg/m(2) daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis. RESULTS All patients experienced engraftment of donor cells. One patient (5%) experienced grade 2 acute graft-versus-host disease, and no patients experienced a higher grade. One patient experienced disease progression at 115 days post-transplantation and responded to donor lymphocyte infusion. The remaining patients remained disease-free. One patient died at 10.5 months from a fungal infection. With a median follow-up time of 25 months, the estimated 3-year current progression-free survival rate was 95%. CONCLUSION These data suggest that nonmyeloablative allogeneic stem-cell transplantation is an effective option in lymphoma patients with chemosensitive or stable disease who experience disease recurrence following autologous transplantation.

Impairment of Filgrastim-Induced Stem Cell Mobilization after Prior Lenalidomide in Patients with Multiple Myeloma

Lenalidomide is an agent that has shown great activity in patients with multiple myeloma (MM). However, studies have suggested that this drug negatively affects subsequent stem cell collection. To investigate whether lenalidomide impairs stem cell mobilization and collection, we reviewed data for patients with MM who underwent mobilization with filgrastim. Predictors of mobilization failure were evaluated using logistic regression analysis. In 26 (9%) of 302 myeloma patients, stem cell mobilization failed. Mobilization failed in 25% of patients who had previously received lenalidomide, compared with 4% of patients who had not received lenalidomide (P < .001). In a multivariate analysis, prior lenalidomide use (odds ratio: 5.9; 95% confidence interval [CI]: 2.4-14.3) and mobilization more than 1 year after diagnosis (odds ratio: 4.6; 95% CI: 1.9-11.1) were significantly associated with failed mobilization. Twenty-one of 26 patients in whom mobilization with filgrastim failed underwent remobilization with chemotherapy and filgrastim; in 18 (86%) of these 21 patients, stem cells were successfully mobilized and collected. In patients with multiple myeloma, prior lenalidomide therapy is associated with failure of stem cell mobilization with filgrastim. Remobilization with chemotherapy and filgrastim is usually successful in these patients.