Matched Related Donor Transplantation Research Articles

Comparable Outcomes in Acquired Severe Aplastic Anemia Patients With Haploidentical Donor or Matched Related Donor Transplantation: A Retrospective Single-Center Experience.

Clinical data of patients with severe aplastic anemia (SAA) were retrospectively analyzed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched related sibling hematopoietic stem cell transplantation (MSD-HSCT) in complications and survivals. Thirty consecutive patients were enrolled in the study with a median follow-up of 50 months (range 4, 141), and the median age of the patients was 21 years (range 3, 49). All the patients achieved myeloid engraftment in the two cohorts. The cumulative incidences of platelet engraftment were 95.5 and 100% in HID cohort and MSD cohort, respectively. The median time for neutrophil and platelet recovery was 11 (range 9, 19) and 15 (range 10, 25) days in HID cohort, and 12 (range 10, 19) and 14 (range 8, 25) days in MSD cohort. The cumulative incidences of grade II–IV and grade III–IV acute graft vs. host disease (aGvHD) in HID cohort and in MSD cohort were 18.9 vs. 14.3% (p = 0.77) and 10.5 vs. 0% (p = 0.42), respectively. The cumulative incidences of chronic graft vs. host disease (cGvHD) was 22.7% in HID cohort and 25.5% in MSD cohort (p = 0.868). The 5-year overall survival (OS) rates and 5-year failure-free survival (FFS) rates in HID cohort and MSD cohort were 85.1 vs. 87.5% (p = 0.858), 80.3 vs. 87.5% (p = 0.635), respectively. The median time to achieve engraftment, cumulative incidence of aGvHD and cGvHD, and the 5-year OS and FFS rates were not significantly different between the two cohorts. We suggest that HID-HSCT might be a safety and effective option for SAA patients without a matched donor.

Single-Agent Cyclosporine for Graft-versus-Host Disease Prophylaxis in Patients with Acquired Aplastic Anemia Receiving Fludarabine-Based Conditioning.

Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n=106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD.

Comparison of Conventional Cyclophosphamide versus Fludarabine-Based Conditioning in High-Risk Aplastic Anemia Patients Undergoing Matched-Related Donor Transplantation

Allogeneic stem cell transplant for high-risk aplastic anemia (AA) yields inferior results using conventional cyclophosphamide (CY)-based conditioning. The use of fludarabine (Flu)-based regimens has resulted in improved outcomes in high-risk patients. Limited data are available comparing these two conditioning regimens in such patients. We retrospectively analyzed 192 high-risk patients undergoing matched-related donor transplantation from July 2001 to December 2018. The median age was 19.5 (2–52) years. Patients were divided into 2 groups, Cy200 anti-thymocyte globulin (ATG)20 (Gp1 n = 79) or Flu120–150 Cy120–160 ATG20 (Gp2 n = 113). The risk of graft failure was significantly higher in Gp1, and the majority occurred in patients with >2 risk factors (p = 0.02). The incidence of grade II-IV acute graft versus host disease (GVHD) and chronic GVHD was not significantly different between the two groups. The overall survival (OS) of the study cohort was 81.3 %, disease-free survival (DFS) 76.6 % and GVHD-free relapse-free survival (GRFS) was 64.1%. DFS and GRFS were significantly higher in Gp2 as compared to Gp1: DFS 84.1% versus 68.4 % (p = 0.02), GRFS 77.9% versus 54.4% (p = 0.01), respectively. We conclude that Flu-based conditioning is associated with superior OS, DFS and GRFS as compared to the conventional Cy-based regimen in high-risk AA.

Incidence and Impact of Community Respiratory Viral Infection (CRV) in Haploidentical and Matched Sibling Donors Receiving Post-Transplant Cyclophosphamide (PTCy): A CIBMTR Analysis

There are reports of high rates of viral infections after haploidentical transplant, particularly in the setting of PTCy (HaploCy) but detailed data on incidence are lacking. We describe here the comparative incidence of community respiratory virus (CRV) infections occurring by day 180 post-transplant by donor source and their impact on outcomes including survival, relapse, chronic GVHD, and transplant related mortality (TRM) using CIBMTR registry data. The analysis included 2765 patients, all > 2 years of age, who underwent first allogeneic HCT for AML, ALL or MDS from 100 centers between 2012 and 2017 receiving either HaploCy (n=757), Matched related donor (MRD) transplant with PTCy (SibCy n= 403), and MRD transplant with calcineurin inhibitor and either MTX or MMF (SibCNI n= 1605).The cumulative incidences of CRV in the HaploCy, SibCy and SibCNI were: 3% (99% CI, 1.6-4.8), 3% (1.3-5.5) and 2.4 %(1.5-3.5) respectively at day 30 (P =0.649, NS), but notably higher at 15.5% (12.3-19), 16.2% (11.7-21.2) and 9.4 %(7.6-11.4) at 6 months (P<.001) post-transplant [Figure 1]. Identified CRV included primarily Rhinovirus, Parainfluenza, and RSV accounting for approximately 70% of all CRV reported [Table 1]. Figure 2 shows the multivariable models through 2 years post-transplant for survival, relapse, TRM, and chronic GVHD with a reference group of SibCNI without CRV infection for the main effect variable of donor type and infection. Patients in the HaploCy cohort who developed a CRV by day 180 had a higher risk of TRM [p=0.002] and inferior survival [p = 0.001] compared to the reference group. Older age, more advanced disease, and higher HCT-CI were all associated with increased mortality.The incidence of CRVs is higher for patients receiving PTCy, regardless of donor. This finding justifies further studies to understand long-term antiviral immune recovery in different donor sources and GVHD prophylaxis regimens. The higher overall mortality for HaploCy patients developing CRV infection warrants consideration for patient education and heightened awareness for clinicians, as well as long term follow up studies of such patients.

Real-world outcomes of stem cell transplantation for severe aplastic anemia: A single-center experience in Northern India.

Stem cell transplantation is the cornerstone of therapy for transplant-eligible patients with severe aplastic anemia. Patients with severe aplastic anemia undergoing stem cell transplantation (including matched haplo-identical related donors) with a standard conditioning regimen and graft-versus-host disease (GVHD) prophylaxis were analyzed. High-risk patients were identified as having undergone >20 pre-transplant transfusions, having febrile neutropenia at the time of transplantation, or having undergone failed immunosuppressive therapy. A total of 111 patients underwent stem cell transplantation, with a median age of 17 years. Seventy-six patients received matched related donor (MRD) transplants, and 35 received haplo-identical donor (HID) transplants. Among all patients, 65.7% were high-risk patients, with a significantly higher proportion among those receiving HID transplants (38% for MRD vs. 83% for HID). Acute GVHD grades 2-4 was observed in 9% of patients, and chronic GVHD in 16.2% of patients. Primary graft rejection was more common in 9.9% of patients (21% for HID, 5% for MRD). The 2-year overall survival and disease-free survival were 67% and 66%, respectively, with better outcomes for MRD and low-risk HID transplants than for high-risk HID transplants. The most common cause of mortality was sepsis-related death (accounting for 27% of the total deaths). Sepsis-related early deaths were significantly more common among high-risk patients who received HID transplants. We conclude that MRDs remain the preferred donor source for allogeneic stem cell transplants in patients with aplastic anemia; however, HIDs can be considered as a life-saving treatment for patients with aplastic anemia.

Who Is a Better Donor for Recipients of Allogeneic Hematopoietic Cell Transplantation: A Young HLA-Mismatched Haploidentical Relative or an Older Fully HLA-Matched Sibling or Unrelated Donor?

T cell replete HLA-mismatched haploidentical transplantation (HIDT) with post-transplant cyclophosphamide is increasingly becoming an acceptable treatment approach for patients lacking timely access to a suitably matched related donor transplant (MRDT) or matched unrelated donor transplant (MUDT). Multiple recent registry and single-center studies have shown comparable overall survival (OS) and disease-free survival (DFS) rates among HIDT, MRDT, and MUDT with a significantly lower risk of acute and chronic graft-versus-host disease (GVHD) among HIDT recipients. Candidates for allogeneic hematopoietic stem cell transplantation (HSCT) often have access to multiple donor sources, and a relevant question is whether outcomes can be improved with a younger HLA-mismatched haploidentical donor (≤35 years) rather than an older matched related donor (≥35 years) or matched unrelated donor (≥35 years). We analyzed 406 consecutive allogenic HSCT recipients, with a median age of 54 years (range, 19 to 77), after a MRDT with a donor age of ≥35 years (n = 222), MUDT with a donor age of ≥35 years (n = 91), and HIDT with a donor age of ≤35 years (n = 93). Median follow-up time for survivors was 51.5 months. Compared with MRDT and MUDT, HIDT recipients had a similar median age at time of HSCT, hematopoietic cell transplant comorbidity index, disease risk index distribution, and donor recipient sex matching. The survival estimates and relapse incidence at 3 years post-HSCT were OS (64% for MRDT, 54% for MUDT, and 62% for HIDT), DFS (55% for MRDT, 44% for MUDT, and 58% for HIDT), Transplant related mortality (TRM) (19% for MRDT, 16% for MUDT, and 18% for HIDT), and relapse (26% for MRDT, 37% for MUDT, and 24% for HIDT). HIDT recipients had better 3-year relapse rates compared with MUDT recipients (24% versus 37%, P= .048), with similar DFS and OS in a univariate analysis. MRDT recipients had a better relapse rate (26% versus 37%, P = .042) compared with MUDT recipients. Recipients of HIDT also had significantly lower rates of moderate to severe chronic GVHD compared with MRDT and MUDT recipients (P = .01). Multivariable analysis showed no effect of donor on OS, DFS, relapse, and TRM. Recipients of HIDT from a young donor ≤35 years had similar OS, lower rates of chronic GVHD, and better chronic GVHD-free, relapse-free survival compared with patients undergoing transplantation with an MRD or a MUD donor ≥35 years. This study suggests that given a situation where a choice between a young haploidentical relative and an older matched unrelated donor is to be made, one can achieve similar survival with a haploidentical donor and significantly lower rates of chronic GVHD.

Myeloablative Conditioning with Alemtuzumab in Matched Related Donor Hematopoietic Cell Transplant for Sickle Cell Disease Prevents Graft-Versus-Host Disease without Compromising Engraftment

Introduction Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD). Alemtuzumab is a lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy with alemtuzumab in MRD HCT for SCD to concurrently prevent GVHD and promote durable engraftment. Methods We retrospectively reviewed outcomes for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan intravenously every 6 hours for 4 days (target AUC: 800-1200 μM per minute) and cyclophosphamide 50 mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15 kg=3 mg, 15-30 kg=5 mg, >30 kg=10 mg daily), methotrexate and a calcineurin inhibitor. Donor chimerism was evaluated periodically via short tandem repeats or fluorescent-in-situ hybridization of nucleated cells from the peripheral blood. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up. Results Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4 yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 60.5% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 23 patients (13.0%) with persistent MDC had Conclusions Myeloablative conditioning was well tolerated, and the addition of alemtuzumab minimized occurrence of significant GVHD. Chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred. This regimen may be a promising approach for patients with SCD that can tolerate myeloablative chemotherapy.

Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation.

Introduction Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p= Conclusion HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.

Is a Matched Unrelated Donor Search Needed for All Allogeneic Transplant Candidates?

IntroductionAn HLA-matched unrelated donor (MUD) has been accepted as the next best option for patients who do not have a matched-related donor (MRD) available. However, identification of a MUD may be challenging due to donor availability for some populations. In addition, the MUD search and procurement of stem cell product usually takes much longer than that of a related donor, many patients may develop progressive disease or become medically unfit while waiting for a MUD transplant, which might have a negative impact on overall survival.Therefore, in this study we hypothesized that certain groups of patients may not benefit from performing a MUD search and sought to evaluate availability of a MUD donor, ability to proceed to transplant with a MUD, as well as transplant outcomes for all patients who had a MUD search started at our institution.MethodsAll consecutive patients with a diagnosis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who had a MUD search performed between 2013 and 2015 were included. All patients had high resolution HLA typing at HLA-A, -B, -C, -DRB1 and -DQB1 performed by DNA sequencing and had unrelated donor search by the NMDP.According to standard operating procedures, a MUD search was initiated when no MRD was available, or as soon as HLA typing was completed. If no 10/10 MUD was available, the choice between a 9/10 MUD, haploidentical or umbilical cord blood (UCB) was based on the treating physician's decision.ResultsThe analysis included 242 patients with a median age of 58 years (range 9-80 years), 123 patients (51%) were male, 182 patients (75%) were Caucasian and 190 (79%) had common haplotypes.One hundred thirteen patients (47%), 35 (14%), 43 (18%) and 49 (20%) were in complete remission, primary induction failure (PIF), relapse/refractory and newly diagnosed, respectively.One hundred sixty (66%) patients had a 10/10 MUD identified. The majority of Caucasians (85%) had common haplotypes compared with only 58% of patients with other races (P<0.0001). A 10/10 MUD was found in 141/182 (77%) Caucasian patients, while only 19/60 (32%) non-Caucasian patients had a 10/10 MUD identified (P<0.0001). A significantly higher percentage of patients with common haplotypes had 10/10 MUD identification compared with those of uncommon haplotypes (82% vs. 10%, P<0.0001).Only 85 of 160 (53%) patients proceeded to MUD transplantation, while 66 (27%) patients received transplants from other donor types [9 (4%) 9/10 MUD, 20 (8%) haploidentical, 22 (9%) UCB and 15 (6%) MRD transplant], and 91 (38%) patients did not receive a transplant. The median time from MUD search to 10/10 MUD, MRD, haploidentical, 9/10 MUD and UCB transplant was 2.9, 2.3, 3.5, 4.6 3.2 months, respectively (P=0.002). Taken together, Caucasian race and having common haplotype were independently associated with 10/10 MUD identification with odds ratio (OR) of 6.8 (95%CI 3.1-14.9) and 39 (95%CI 13.9-110.4), respectively and with proceeding to MUD transplantation (OR 7.7, 95%CI 2.7-21.7 and OR 66, 95%CI 3.9->999), respectively.A multivariable analysis (MVA) for PFS of patients who received a transplant showed significant impact on transplant outcomes for disease status, cytogenetics and time from a MUD search to transplant, while donor type did not impact transplant PFS (Table 1).A second MVA for PFS was performed for all patients who had a MUD search. Patients who had intermediate/favorable cytogenetics, de novo AML, newly diagnosed/complete remission and received a transplant experienced significantly better PFS compared with their counterparts (Table 1, Figure 1).The highest percentages of 10/10 MUD identification, MUD transplant and PFS were observed for Caucasians who were newly diagnosed/complete remission with common haplotype (60% MUD identified, 69% MUD transplant, 3-year PFS rate of 46%), whereas the patient group with the lowest percentages was non-Caucasians with primary induction failure/relapsed/refractory and had uncommon haplotype (1% MUD identified, 0% MUD transplant, 3-year PFS rate of 0%).ConclusionsRace, haplotype frequency and disease status at the time of MUD search influence probability to identify a MUD and receive a transplant. Patients with low likelihood to receive a MUD transplant may proceed to a haploidentical transplant as soon as indicated, as this approach does not appear to compromise transplant outcomes. [Display omitted] DisclosuresKonopleva:Stemline Therapeutics: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Myeloablative Conditioning with Alemtuzumab in Matched Related Donor Hematopoietic Cell Transplant for Sickle Cell Disease Prevents Graft-Versus-Host Disease without Compromising Engraftment

Introduction:Matched related donor (MRD) hematopoietic cell transplant (HCT) is an accepted treatment for sickle cell disease (SCD) despite risk of graft-versus-host disease and graft rejection. Alemtuzumab is a potent lymphocytic medication that can reduce the risk of GVHD; however, it is associated with mixed donor chimerism (MDC) and graft loss when used with submyeloablative conditioning. We explored the use of myeloablative chemotherapy in conjunction with alemtuzumab in MRD HCT for SCD as a method to concurrently prevent GVHD and promote durable engraftment.Methods:We retrospectively reviewed engraftment, GVHD and survival for patients that underwent MRD HCT for SCD at Texas Children's Hospital between 2003-2017. All patients received busulfan dose adjusted to achieve target area under the curve of 800-1200μM per minute with doses administered intravenously every 6 hours for 4 days and cyclophosphamide 50mg/kg daily for 4 days. GVHD prophylaxis included intravenous alemtuzumab daily for 3-4 doses starting on day -5 (5-15kg=3mg, 15-30kg=5mg, >30kg= 10mg daily), methotrexate and a calcineurin inhibitor.Donor chimerism was evaluated via short tandem repeats (STR) or fluorescent-in-situ hybridization (FISH) of nucleated cells from the peripheral blood. If MDC was detected, follow-up chimerism studies were obtained every 1-4 weeks until stabilization on 2 or more consecutive evaluations. Persistent MDC was defined by the presence of recipient cells on 2 consecutive evaluations without return to full donor chimerism at last follow-up.Results:Thirty-eight consecutive patients underwent MRD transplant (3 non-sibling and 35 sibling) with a median age at transplant of 8.6 yrs (range: 2.9-18.4yr). Stem cell source consisted of bone marrow grafts for all patients. Two patients concurrently received cord blood from the same donor to augment cell dose. Neutrophil engraftment was achieved in all patients at a median time of 19 days (range: 13-24 days). Incidence of persistent MDC was 62.8% with a median last chimerism of 94% donor cells (range: 24-100%). Three of 22 patients (13.6%) with persistent MDC had <50% donor cells. The single patient with severe MDC <25% stabilized at 24% at 2 yrs post-HCT with concurrent Hgb S <50% on electrophoresis reflective of sickle cell trait in the donor. Graft rejection and recurrence of SCD related symptoms (vaso-occlusive crises, acute chest syndrome, stroke) were not observed in any patient at last follow-up. No additional cell products were given to manage mixed chimerism in any patient. Overall incidence of acute GVHD and severe acute GVHD (grade II-IV) were 26.3% and 5.3%, respectively. One patient developed limited chronic GVHD. Overall survival was 94.7% with a median time to last follow-up of 2.9 yrs (range: 90-4627 days). Two deaths occurred secondary to transplant-related complications including 1 death <100 days from HCT due to disseminated Mycobacterium tuberculosis and 1 secondary to hemophagocytic syndrome of uncertain etiology on day +318 from HCT.Conclusions:Myeloablative conditioning was well tolerated in this patient population, and the addition of alemtuzumab minimized occurrence of severe GVHD. While MDC was observed, chimerism stabilized at >50% donor cells in most patients and no graft rejection or recurrence of SCD occurred with a median follow-up of 2.9 yrs. The use of this regimen may be a promising approach to achieve low rates of GVHD while maintaining low rates of transplant related complications for patients with SCD that can tolerate myeloablative chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Cost Effectiveness of Hematopoietic Stem Cell Transplantation Compared with Transfusion Chelation for Treatment of Thalassemia Major

Hematopoietic stem cell transplantation (HSCT) is the only cure for thalassemia major (TM), which inflicts a significant 1-time cost. Hence, it is important to explore the cost effectiveness of HSCT versus lifelong regular transfusion-chelation (TC) therapy. This study was undertaken to estimate incremental cost per quality-adjusted life-year (QALY) gained with the intervention group HSCT, and the comparator group TC, in TM patients. A combination of decision tree and Markov model was used for analysis. A hospital database, supplemented with a review of published literature, was used to derive input parameters for the model. A lifetime study horizon was used and future costs and consequences were discounted at 3%. Results are presented using societal perspective. Incremental cost per QALY gained with use of HSCT as compared with TC was ▪64,096 (US$986) in case of matched related donor (MRD) and ▪1,67,657 (US$2579) in case of a matched unrelated donor transplantation. The probability of MRD transplant to be cost effective at the willingness to pay threshold of Indian per capita gross domestic product is 94%. HSCT is a long-term value for money intervention that is highly cost effective and its long-term clinical and economic benefits outweigh those of TC.

Fludarabine-Based Reduced Intensity Regimen for Matched Related Donor Stem Cell Transplantation in Acquired Severe Aplastic Anemia

The outcome of severe acquired aplastic anemia (SAA) has improved dramatically over the past few decades due to advances in allogeneic stem cell transplantation (allo-STC). Different conditioning regimens have been tested in matched related donor (MRD) transplants with variant results. Before 2008, we have encountered poor engraftment in our patients using high dose cyclophosphamide (200 mg/kg) and thymoglobulin (ATG). Fludarabine, low dose cyclophosphamide, ATG and total body irradiation (TBI) was used for alternative donor transplants by Bacigalubo and colleagues (1). Since 2008, we have decided to start using this regimen in our MRD transplants to improve engraftment and ultimately overall survival. To our knowledge, this abstract describes the outcome of the largest cohort of patients who received MRD allo-STC for SAA using this regimen. It represents our single institution experience over a period of 10 years.Methods: This is a retrospective chart review of all patients diagnosed with acquired SAA who underwent allo-STC between August 2005 and December 2015 at the American University of Beirut Medical Center (AUBMC)Results: A total of 22 patients underwent transplant with grafts from related HLA-matched donors. Before 2008, three patients received cyclophosphamide 50 mg/kg/day over 4 days and ATG (Fresenius) 30 mg/kg/day over 4 days. Since 2008, nineteen patients received fludarabine 30 mg/m2/day for 4 days (-6, -5, -4 and -3), cyclophosphamide 300 mg/m2/day for 4 days (-6, -5, -4 and -3) and ATG (Genzyme) 3.75 mg/m2/day for 2 days (-4 and -3). TBI at a dose of 2 Gy was added on day -1 for patients more than 15 years of age. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A with either mycophenolate mofetil (50%) or a short course of methotrexate (50%). The median age of patients was 21 years (range: 1.7-64 years). The median duration between diagnosis and transplant was 11 months (range: 1-85 months). Seven patients (31%) had failed immunosuppressive therapy before transplant. The stem cell source was bone marrow (BM) for 14 patients (64%) and peripheral blood (PB) for 8 patients (36%). The median CD34 cell dose infused was 5.4 ×106/kg (range: 1 - 19.5 ×106/kg). The 2-year overall survival rate was 82% with trend toward better survival without statistical significance when using fludarabine-based regimen (84% vs 66%, P: 0.42), if both donor and recipient had the same gender (92% vs 66%, P: 0.11), or if PB was the source of stem cells (87% vs 78%, P: 0.58). Engraftment failure was observed in 2 cases (9%). The median time for neutrophil engraftment was 20.3 days (range: 14-38 days). Neutrophil engraftment was faster when the fludarabine-based conditioning regimen was used (18 vs 38 days, P: 0.04), if PB was used as the source of stem cells (17 vs 20 days, P: 0.03) or if TBI was added to the conditioning regimen (18 vs 20 days, P: 0.07). Chimerism studies were available for 18 out of 20 engrafted patients. Two patients had partial engraftment (89% and 76%) and 16 patients had complete engraftment (>90%). The previous use of IST or the duration between diagnosis and transplant (< or > 1 or 2 years) did not affect survival or engraftment. Acute GvHD (grade I-II) occurred in 2 patients (9%). No cases of chronic GvHD or veno-occlusive disease (VOD) were reported. CMV reactivation occurred in 2 cases while CMV disease was reported in another case. EBV reactivated in one case without LPD. Hemorrhagic cystitis occurred in one case. One patient developed donor cell precursor B-cell acute lymphoblastic leukemia 2 years after transplant.Conclusions: Fludarabine-based reduced intensity regimen for MRD transplants in SAA has led to improved engraftment with minimal toxicity. This result was not affected by the previous use of IST or the long duration between diagnosis and transplant as was reported in previous studies with different conditioning regimens or donor types. Thus, this regimen may be particulary useful in countries where patients present late to transplant.

Transplantation from haploidentical donor is not inferior to that from identical sibling donor for patients with chronic myeloid leukemia in blast crisis or chronic phase from blast crisis.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for chronic myeloid leukemia (CML) patients in blast crisis (BC), and haploidentical donors (HID) are immediately available for most patients. We compared the outcomes of HID transplantation with those of matched related donor (MRD) transplantation in a cohort study. A total of 90 consecutive patients who received allogeneic HSCT because of CML-BC were investigated retrospectively. A total of 67 patients underwent transplantation from HID and 23 from MRD. Survival outcomes were compared between the two cohorts. Of the 90 patients, 86 patients were engrafted. Three-year overall survival (OS) and relapse-free survival (RFS) were comparable between HID and MRD recipients (OS: 60.0% vs 55.3%, respectively, P=.580; RFS: 51.1% vs 47.8%, respectively, P=.512). Three-year incidences of transplant-related mortality (TRM) and relapse did not differ between HID and MRD recipients (relapse: 21.0% vs 26.1%, respectively, P=.626; TRM: 27.9% vs 26.1%, respectively, P=.937). In multivariate analyses, previous chemotherapy history and not achieving CHR before HSCT are independent adverse predictors of OS. For CML-blast crisis or chronic phase from blast crisis patients, HID transplantation achieves comparable survival to MRD transplantation. HID donors can be regarded as regular donors for these special patients at selected centers.

Mesenchymal stromal cells: potential roles in graft‐versus‐host disease prophylaxis and treatment

Mesenchymal stromal cells: potential roles in graft‐versus‐host disease prophylaxis and treatment

Post-relapse survival after haploidentical transplantation vs matched-related or matched-unrelated hematopoietic cell transplantation.

Relapse remains a major cause of mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). The impact of donor type on post-relapse survival (PRS) has not been widely examined. We compared the survival outcomes for patients relapsing after haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide with those relapsing after matched-related donor transplantation (MRDT) or matched-unrelated donor transplantation (MUDT) at our institution. Two hundred and thirty-seven consecutive HCT recipients with relapse occurring after HIDT (N=48), MUDT (N=87) and MRDT (N=102) were included in this analysis. Median age was 49 years (19-77 years) and the median time to relapse was 156 days (12-2465) after HCT. HIDT recipients had similar median time to relapse (5.8 vs 4.8 vs 5.5 months, P=0.638) compared with MUDT and MRDT, respectively. One-year PRS was worse among HIDT recipients compared with MRDT and MUDT (17% vs 46% vs 40%, P<0.05). In a multivariate analysis, time to relapse (<3 vs >3 months post transplant), no use of donor lymphocyte infusion (DLI) following relapse, higher Dana Farber disease risk index and HCT comorbidity index scores at the time of transplant and delayed platelet engraftment post transplant were all predictive of worse PRS. This analysis shows that 1-year PRS is inferior among HIDT when compared with MRDT or MUDT. Lower use of DLI after HIDT may have contributed to this inferior survival.

Haploidentical Donor Transplantation Is Not Inferior to Identical Sibling Donor for Patients with Chronic Myeloid Leukemia in Blast Crisis

Objectives: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with chronic myeloid leukemia (CML) in blast crisis (BC). Haploidentical donors (HID) are immediately available for almost all of them. We compare the outcomes of HID transplantation with those of matched related donor (MRD) transplantation in cohort study.Methods: We studied 90 T-replete HID (n=67) and MRD (n=23) HSCT for CML-BC patients in our center from Jan 1st, 2001 to September 30, 2013. After transplantation, patients received tapering immunosupressant or TKI or donor lymphocyte infusion (DLI) or combined therapy as intervention based on BCR-ABL levels.Results: Of the 86 engrafted patients, 30 received intervention after transplantation. The 1-year cumulative incidence of intervention in HID transplants was significantly lower than in MRD transplants, 24.7% vs. 56.5% (P=.002). At 3 years, overall survival (OS) was similar (60.0% vs. 53.3%), 3-year event-free survival (EFS) higher (35.8% vs. 13.0%; P=.002) in HID transplants. Three-year incidences of transplant related mortality (TRM) and relapse did not significantly differ.Conclusions: HID transplantation achieves comparable OS with less post-transplant intervention, which is not inferior to MRD in CML-BC patients, and might be regular donors for those who need urgent transplantation. DisclosuresNo relevant conflicts of interest to declare.

Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. [Display omitted] [Display omitted] [Display omitted] DisclosuresSandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes

Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution.Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method.Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%.Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. DisclosuresVij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

Thymoglobulin Does Not Impact Relapse or Survival after Matched Unrelated Transplantation for AML/MDS Compared to Matched Related Donor Transplantation without Thymoglobulin Use

▪Thymoglobulin does not impact relapse or survival after matched unrelated transplantation for AML/MDS compared to matched related donor transplantation without Thymoglobulin use.Background: Thymoglobulin has been used customarily after matched related (RD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) to decrease risk of GVHD and graft rejection. However, its use has been implicated in increasing the risk of relapse. As matched sibling related donors considered the best available donor source for patients with AML /MDS, we hypothesized that production of outcomes (Relapse/Survival) after MUD transplant with use of thymoglobulin similar to RD transplantation without the use of thymoglobulin, would justify the use of thymoglobulin after MUD HCT in AML/MDS.Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan based conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC) with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/Kg single daily dose for 4 days (AUC 4200-5000). GVHD prophylaxis for FIC was Tacrolimus/mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only regardless the conditioning intensity.Results: With median follow up 696 days (RD 746 days, MUD 676 days), the overall survival at 1 year was 75% +/- 8% and 74% +/- 5% for RD and MUD respectively, P=0.66. All patient engrafted except two patients in FIC MUD group. The cumulative incidence of relapse at 1 year was 31% +/- 8% and 23% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) was 3.5% +/- 3% and 10% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-1V was 29% in RD and 49% in MUD. Grade III-IV acute GVHD was 14% in Both RD and MUD recipients. Higher cumulative incidence of extensive chronic GVHD was observed in MUD recipients of 28% vs 20% in RD recipients.Conclusion: The addition of thymoglobulin to MUD HCT did not increase the cumulative incidence of relapse compared to RD HCT patients who did not receive thymoglobulin. RD HCT remained associated with lower TRM than MUD HCT despite the addition of thymoglobulin. MUD HCT with thymoglobulin produced similar overall survival to RD HCT without thymoglobulin. Our data suggest continued use of low dose thymoglobulin with MUD HCT while avoiding its use with matched RD HCT. Table 1PatientsRelated DonorUnrelated DonorNumber2969AML2261MDS78Graft Failure02Age (Range)53 (35-71)56 (25-73)Reduced Intensity825Full Intensity2144CR11747CR245Relapsed/Refractory817 DisclosuresNo relevant conflicts of interest to declare.