[Show abstract][Hide abstract] ABSTRACT: Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (
) and a TBI-based MA preparative regimen (
), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI). In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan) had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation.
Full-text · Article · Jan 2016 · Advances in Hematology
[Show abstract][Hide abstract] ABSTRACT: Outcomes of 475 consecutive patients receiving first allogeneic transplants for hematologic malignancy performed using T-replete HLA-haploidentical donors and post-transplant cyclophosphamide (HIDT, n=116) were compared to contemporaneous patients transplanted from 10 of 10 HLA allele matched unrelated donors (MUDT, n=178) or HLA-identical sibling donors ( MRDT, n=181). Uniform supportive care measures and assessments were used. Median follow-up was 45 months. HIDT patients were more likely to be black than MUDT patients (44% vs. 2%, p< 0.001). At two years following transplant, estimates of overall survival were 57%, 59%,72% For HIDT, MUDT and MRDT respectively (p=NS HIDT vs MUDT and 0.02 HIDT vs MRDT) and disease free survival were 54%, 50%, 56% (p=NS for both comparisons) . Cumulative incidences (CI) of non-relapse mortality were 17%, 16%, 14% and relapse were 29%, 34% and 30% (p=NS for all). CI of acute GVHD grade 2-4 were 41%, 48%, 28% (p=NS HIDT vs. MUDT, p=0.005 HIDT vs. MRDT). At two years, CI of moderate/severe chronic GVHD were 31%, 47% and 44% (p=0.004 HIDT vs MUDT, p=0.032 HIDT vs MRDT,) and 19% of HIDT, 42% of MUDT and 35% of MRDT remained on systemic immunosuppressive treatment (p=0.007 HIDT vs MUDT). Moderate/severe chronic GVHD remained significantly lower for HIDT than MUDT in patients receiving PBSC grafts (two year CI 25% vs. 48% p=0.002). On a multivariate analysis incorporating disease-risk-index (DRI) and other significant covariates, survival (HR 1.31, p=0.15), disease-free survival (HR=0.96, p=0.79) were not significantly different between HIDT and MUDT but chronic GVHD was lower in HIDT (moderate-severe HR 0.59, p=0.007). ). HIDT produce similar long-term survival with lower rates of chronic GVHD than optimally matched MUDT. HIDT should be considered a standard-of-care option for patients who lack a matched sibling donor.
No preview · Article · Sep 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Inadequate T-cell chimerism following reduced-intensity conditioning transplantation may contribute to graft rejection and disease relapse. Anti-thymocyte globulin (ATG) enhances early donor T-cell chimerism, but may also deplete donor T cells, increasing risks of infection and relapse. We prospectively tested administration of rabbit ATG (rATG) ⩾14 days before the infusion of the graft, followed by in vivo decay of active rATG levels, to selectively deplete host T cells. Twenty-three patients received rATG total dose 4.5 mg/kg on days -16 and -15, fludarabine 30 mg/m(2) per day on day -7 through -3, IV busulfan 130 mg/m(2) per day on days -4 and -3 and cyclophosphamide 1500 mg/m(2) on day -2. rATG levels were therapeutic in all patients on day -14, but were sub-therapeutic (<1 μg/mL) by day 0 in 82% of patients. Median donor T-cell chimerisms on days 30 and 180 were 100% (75-100%) and 100% (90-100%), respectively. Non-relapse mortality and relapse/progression at 48 months were 17 and 30%. Cumulative incidences of acute GvHD grades II-IV and III-IV were 39 and 9%. Median follow-up is 64 months (46-79 months). Survival and disease-free survival at 48 months were 70 and 52%. These data suggest that selective depletion of host T cells using this regimen is a feasible and effective strategy.Bone Marrow Transplantation advance online publication, 23 March 2015; doi:10.1038/bmt.2015.41.
No preview · Article · Mar 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Calcineurin inhibitors (CNI) form the foundation of current GVHD prophylaxis regimens. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (PTCy) and brief-course sirolimus would reduce chronic GVHD and non-relapse mortality (NRM) following reduced intensity allogeneic peripheral blood stem cell transplant (PBSCT). Twenty-six patients, median age 61 years, received an unmanipulated PBSCT from an 8/8 locus matched donor; MRD=17, MUD=9. GVHD prophylaxis consisted of PTCy and brief-course sirolimus. Donor engraftment occurred in all patients. The cumulative incidence (CI) of grade II-IV acute GVHD, grade III-IV acute GVHD, and chronic GVHD was 46%, 15%, and 31% respectively. One year NRM was 4%. Median time to immunosuppression discontinuation was day +138. With a median follow-up of 20 months, the estimated 2-year overall survival, disease-free survival, and relapse incidence was 71%, 64%, and 32% respectively. In patients with lymphoid malignancies (CLL, NHL, HD), 2-yr DFS and relapse was 100% and 0%, respectively. Good immune reconstitution was evidenced by low CMV reactivation rates, occurring in only 4 of 19 at-risk patients (21%). GVHD prophylaxis with PTCy and sirolimus achieves consistent donor engraftment, low rates of chronic GVHD and NRM, and excellent outcomes in recipients of HLA-identical related and unrelated donor allogeneic PBSCT.
No preview · Article · Nov 2014 · Biology of Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Availability of an HLA-identical sibling (MRD) or suitably matched unrelated donor (MUD) has historically been a limiting factor in the application of allogeneic hematopoietic transplantation. Although almost all patients have an HLA-haploidentical family donor, prior attempts at transplantation from such donors using T-cell replete grafts and conventional immunosuppression were associated with unacceptable rates of GVHD, and when stringent ex vivo T-cell depletion was used to control GVHD, rates of graft rejection and post-transplant infections were prohibitive. The recent approach to HLA-haploidentical donor transplantation developed in Baltimore that uses T-cell replete grafts and post-transplant CY (Haplo-post-HCT-CY) to control post-transplant allo-reactivity appears to have overcome many of the obstacles historically associated with haploidentical donor transplantation. In particular, TRM rates of <10% are usual and rapid reconstitution of immunity leads to a low rate of post-transplant infections and no post-tranplant lymphoproliferative disorders (PTLD), consistent with the hypothesis that post-transplant CY selectively depletes proliferating alloreactive T cells responsible for GVHD and graft rejection while preserving resting memory T cells essential for post-transplant immunologic recovery. In parallel trials using similar non-myeloablative conditioning regimens, Haplo-post-HCT-CY produced similar overall survival to double umbilical cord blood transplantation(DUCBT) in adult patients (62% vs 54%), with low rates of TRM (7% vs 24%), severe acute GVHD (0% vs 21%) and chronic GVHD (13% vs 25%). Furthermore, recent non-randomized comparisons adjusted for risk factors show that Haplo-post-HCT-CY achieve at least equivalent outcomes to conventional MRD and MUD transplants. Although most experience has been obtained using BM, emerging data suggest that a G-CSF mobilized PBSC graft can also safely be used for Haplo-post-HCT-CY. Haplo-post-HCT-CY also avoids the graft acquisition costs of DUCBT and MUDs and the cost of cell selection associated with T-depleted grafts. Although randomized comparisons will be forthcoming, Haplo-post-HCT-CY can already be considered a valid standard-of-care in patients who lack conventional donors thus extending the availability of allogeneic transplants to almost all patients. This donor source may also challenge the routine preference for a MUD in patients lacking an MRD.Bone Marrow Transplantation advance online publication, 19 May 2014; doi:10.1038/bmt.2014.62.
Preview · Article · May 2014 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Although pretransplant alemtuzumab can reduce GVHD following allogeneic transplantation, it may also increase the risk of mixed donor T-cell chimerism and infections. We hypothesized that the early use of DLI without withdrawal of immunosuppressive drugs in patients with mixed T-cell chimerism would lower the risk of relapse without significantly increasing the risk of GVHD post DLI. Thirty-six patients (median age 59 years) were treated in this phase II trial using reduced-intensity conditioning including s.c. alemtuzumab (total dose 43 mg) and a PBSC graft from a matched unrelated donor (UD). DLI without withdrawal of immunosuppressive drugs was administered to all 25 patients with <50% donor T-cell chimerism on day +60. The cumulative risks of acute and chronic GVHD were 42% and 59%, respectively. Estimated probabilities of non-relapse mortality (NRM) at day 100 and 1 year were 3% and 14%, respectively. With a median follow up 2.4 years, estimated survivals at day 100, 1 and 2 years were 97%, 71% and 57%, respectively. In multivariate analysis, the occurrence of acute GVHD was associated with an increased risk of mortality, whereas the occurrence of chronic GVHD had a protective effect, associated with decreased relapse and improved disease-free survival. Low-dose alemtuzumab and preemptive DLI provides favorable transplant outcomes including low NRM in an older patient population with high-risk malignancies undergoing UD transplantation.
No preview · Article · May 2014 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: PURPOSET-cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide may represent a solution for patients who require allogeneic hematopoietic cell transplantation (alloHCT) but lack a conventional donor. We compared outcomes of alloHCT using haploidentical donors with those of transplantation using conventional HLA-matched sibling donors (MRDs) and HLA-matched unrelated donors (MUDs). PATIENTS AND METHODS
Outcomes of 271 consecutive patients undergoing T-cell-replete first alloHCT for hematologic malignancies performed contemporaneously at a single center (53 using haploidentical donors; 117, MRDs; 101, MUDs) were compared. Overall and disease-free survival (DFS) were adjusted for effects of significant patient-, disease-, and transplantation-related covariates using a stratified Cox model.ResultsPatient characteristics were similar between the three donor groups. For patients undergoing MRD, MUD, and haploidentical transplantation, 24-month cumulative incidences of nonrelapse mortality were 13%, 16%, and 7% and of relapse were 34%, 34%, and 33%, respectively (P not significant [NS]). Cumulative incidences of grades 3 to 4 acute graft-versus-host disease (GVHD) at 6 months were 8%, 11%, and 11%, respectively (P NS); extensive chronic GVHD occurred in 54%, 54%, and 38% of patients, respectively (P < .05 for those undergoing haploidentical donor v MRD or MUD transplantation). Adjusted 24-month probabilities of survival were 76%, 67%, and 64% and of DFS were 53%, 52%, and 60%, respectively; these were not significantly different among the three donor groups. CONCLUSION
Haploidentical transplantation performed using T-cell-replete grafts and post-transplantation cyclophosphamide achieves outcomes equivalent to those of contemporaneous transplantation performed using MRDs and MUDs. Such transplantation represents a valid alternative for patients who lack a conventional donor.
Preview · Article · Feb 2013 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Haploidentical hematopoietic stem cell transplant (HSCT) provides an opportunity for nearly all patients to benefit from HSCT. We conducted a trial of haploidentical T cell replete allografting using a busulfan-based myeloablative preparative regimen, peripheral blood stem cells (PBSCs) as the graft source, and posttransplantation cyclophosphamide (Cy). Eligibility was limited to patients at high risk of relapse after nonmyeloablative haploidentical bone marrow transplant (BMT). Twenty patients were enrolled in the study (11 with relapsed/refractory disease and 9 who underwent transplantation while in remission and considered standard risk). Donor engraftment occurred in all 20 patients with full donor T cell and myeloid chimerism by day +30. The cumulative incidence of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) was 30% and 10%, respectively. The cumulative incidence of chronic GVHD (cGVHD) was 35%. Nonrelapse mortality (NRM) at 100 days and 1 year was 10% for all patients and 0% for standard-risk patients. With a median follow-up of 20 months, the estimated 1-year overall survival (OS) and disease-free survival (DFS) was 69% and 50%, respectively, for all patients, and 88% and 67% for standard-risk patients. Myeloablative haploidentical HSCT is associated with excellent rates of engraftment, GVHD, NRM, and DFS, and is a valid option in patients with high-risk malignancies who lack timely access to a conventional donor.
Preview · Article · Jul 2012 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15).
The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).
Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).
No preview · Article · May 2012 · New England Journal of Medicine