Haploidentical Related Donor Research Articles

Efficacy and Safety of Unmanipulated Haploidentical Related Donor Allogeneic Peripheral Blood Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia.

Background:Studies of haploidentical-related donor (HRD) stem cell transplantation using a combination of peripheral blood stem cells (PBSCs) and bone marrow as the graft have reported encouraging results for patients with hematological diseases. However, few studies specifically reported transplantation of only PBSCs from HRDs among patients with relapsed or refractory acute myeloid leukemia (AML). Here, the long-term outcomes and side effects of unmanipulated HRD PBSC transplantation (HRD-PBSCT) for relapsed/refractory AML were analyzed.Methods:We performed a retrospective analysis of the outcomes in relapsed/refractory AML patients who underwent PBSCT from HRDs (n = 36).Results:Thirty-one (86.1%) patients in the HRD-PBSCT group achieved platelet recovery. The cumulative incidence of acute graft-versus-host disease (aGVHD) in the HRD-PBSCT group was 40.00%, and the cumulative incidence of grades 2–4 aGVHD in this group was 13.33%. A total of 13 patients in the HRD-PBSCT group had recurrent disease at a median of 183 days after transplantation (range: 10–1700 days), reaching cumulative incidences of relapse of 50.28% at 5 years. On multivariate analysis, donor age and patient age >40 years were independent risk factors for inferior disease-free survival or overall survival (P < 0.05). The results of the present study demonstrate rapid and complete neutrophil engraftment, a low incidence of grade 2–4 aGVHD, and promising survival rates in patients after HRD-PBSCT. Thus, granulocyte colony-stimulating factor–primed PBSCs may be a reliable graft source in unmanipulated HRD-HSCT under myeloablative conditioning when no matched sibling donor is available.Conclusions:Our results support the feasibility, effectiveness, and tolerability of PBSCs as a graft source in unmanipulated HRD transplantation under myeloablative conditioning in patients with leukemia.

Clinical Analysis of Refractory Primary Central Nervouse System Lymphoma Treated with High-Dose MTX-Based Chemotherapy and Haploidentical Hematopoietic Stem Cell Infusion

To investigate the efficacy and safety of high-dose methotrexate-based chemotherapy combined with granulocyte-colony stimulating factor (G-CSF)-mobilized family related haploidentical donor peripheral blood hematopoietic stem cell (G-PBHSC) infusion for the treatment of patients with refractory primary central nervouse system lymphoma (PCNSL). Three patients with refractory PCNSL were treated in Department of Hematology of the General Hospital of the PLA's Rocket Force from March 2014 to September 2015. The sex ratio of male to female was 1:2 and the median age was 54(48-66)years old. All patients received programmed infusions of G-PBHSC after high-dose methotrexate-based chemotherapy without prophylaxis for graft-versus-host disease (GVHD). Three patients had received initial chemotherapy or radiotherapy after diagnosis, one patient achieved complete remission (CR) after 3 courses of treatment and remained in CR until the end of follow-up, 2 cases achieved partial remission (PR) and the progression-free survival (PFS) time was 10 and 7 months, respectively. The patients generally well-tolerated this therapy. The main adverse effects of patients were neutropenia, thrombocytopenia and infection related with chemotherapy after each course of treatment, the median recovery times of neutrophils and platelets were 11 and 12.5 days, respectively after of programmed infusions of G-PBHSC. No GVHD was observed in any of the patients during treatment. The combination of high-dose methotrexate-based chemotherapy with programmed haploidentical G-PBHSC infusion is a potential treatment alternative for refractory PCNSL patients.

Preoperative autologous blood collection before bone marrow harvests in haploidentical related donors: is it justified?

With the increasing safety of allogeneic blood supply and declining need for transfusion due to patient blood management, the practice of preoperative autologous donation (PAD) continues to decline. The practice gained popularity during the 1980s and 1990s with the emergence of transfusion-transmitted human immunodeficiency virus and hepatitis C. At the peak of this public concern, the National Marrow Donor Program recommended that marrow donors have 1 to 3 autologous units of blood collected before their marrow harvest to minimize the likelihood of allogeneic transfusion. After three decades, the practice remains prevalent in marrow donors. We aimed to study the efficacy of PAD in healthy marrow donors. PADs performed before marrow harvest in healthy donors at our center between January 2013 and July 2015 were reviewed. The utilization of autologous units and decrease in hemoglobin levels due to PAD and marrow harvest were studied. Similar practices were assessed in the rest of the United States through a brief survey. Of a total of 262 autologous units collected from 136 donors, 25.2% were wasted. Ninety-nine percent of the marrow donors received at least 1unit of blood irrespective of the need. PAD contributed to preoperative anemia, exposing three donors to allogeneic blood transfusion. The survey results showed a mixed response with some institutions continuing and others not practicing PAD. PADs are not justified in healthy marrow donors as they expose them to a risk of preoperative anemia and hence a greater risk of transfusion.

A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαβ+ and CD19+ Cell-Depleted Stem Cell Transplantation in Patients with Wiskott-Aldrich Syndrome

Our initial experience with hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n = 12) or a haploidentical related donor (n = 6) with T cell receptor (TCR)αβ+/CD19+ graft depletion in patients with Wiskott-Aldrich syndrome (WAS) (n = 18) showed a dramatic decrease in the incidence of graft-versus-host disease (GVHD) and transplantation-related mortality, with an increased overall survival (OS) of 88.9%. Unfortunately, the treatment was associated with mixed myeloid donor chimerism and secondary graft dysfunction (severe thrombocytopenia, n = 2; graft rejection, n = 5). To improve the outcome, we hypothesized that the addition of G-CSF and plerixafor to the conditioning chemotherapy would result in more complete donor stem cell engraftment. This trial was registered at www.clinicaltrials.gov (NCT03019809). A study group of patients with WAS (n = 16) underwent TCRαβ+/CD19+-depleted HSCT (MUD, n = 6; haploidentical, n = 10). The conditioning regimen was treosulfan-fludarabine-rabbit antithymocyte globulin-melphalan (or thiophosphamide in 1 patient) with G-CSF (10 µg/kg/day for 5 days starting on day −8) and plerixafor (240 µg/kg/day for 3 days starting on day −6). The clinical outcomes in this study were compared to those in a historical dataset (n = 18). No patients had grade III/IV acute GVHD in either the study or the historical control group. Importantly, in the patients with WAS, there was no statistical significance in OS between those who underwent HSCT from haploidentical donors and those who underwent HSCT from MUDs (93.8% versus 88.5%; P = .612). All patients in the study group had full donor chimerism in whole blood and in the CD3+ compartments. The OS was 93.8%, and there were no cases of graft dysfunction. This study demonstrates the efficacy of adding G-CSF/plerixafor to the conditioning regimen before HSCT with TCRαβ+/C D19+ graft depletion in patients with WAS.

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.

Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.

GATA2 in Bone Marrow Failure

The syndrome now known as GATA2 haploinsufficiency had been published at least since the 1970s under different clinical guises. With the identification of the gene in 2011, GATA2 deficiency became the overarching diagnosis for a complex syndrome with acoustic, cutaneous, lymphatic, pulmonary, leukemic, hematologic and infectious manifestations. Arising in both spontaneous and autosomal dominant patterns, the genetics made it recognizable and diagnosable even before symptoms arose. Over the last several years it has become clear that GATA2 is a major contributor to: pediatric and adolescent MDS, AML in younger adults, some cases of ALL, severe genital HPV infection, disseminated mycobacterial infections, pulmonary alveolar proteinosis, pulmonary hypertension and is associated with a variety of solid tumors. Mutations with more profound effects on GATA2 expression (nonsense and deletions) appear to have a more severe phenotype than do intronic mutations that alter transcript level but not transcript integrity. These latter intronic mutations may be associated with later onset of disease and more variable penetrance. Elucidating the gene targets on which GATA2 works and which partners it engages will lead to important observations in the molecular genetics of hematopoietic control.This variability of penetrance and expression is most apparent with the intronic mutations, in which whole generations may be relatively protected, presumably from genes in trans to GATA2 . An active search is on for these genes that appear to regulate GATA2 . One of the consequences of the variable penetrance of GATA2 deficiency is that it may be discordant within a family, allowing a false sense of security about use of a clinically well relative for bone marrow transplant donation. Hematopoietic stem cell transplantation is highly effective for cure of GATA2 deficiency. We have now done almost 40 transplants in GATA2 deficiency with high survival rates using related haploidentical donors, as well as with fully matched donors. The effects of transplantation are profound both in terms of hematopoietic and somatic results, including resolution of most HPV lesions, resolution of pulmonary alveolar proteinosis and resolution of pulmonary hypertension, when present. We have now encountered several cases of transplant from unexpectedly affected donors into a known GATA2, all of which have had poor outcomes. These cases reinforce the critical need for molecular confirmation of the GATA2 status of any related donor, regardless of lack of symptoms.GATA2 deficiency is recently recognized but successful treatments have emerged alongside the science. Efforts to understand and allow for manipulation of GATA2 expression are underway. DisclosuresNo relevant conflicts of interest to declare.

Consolidation therapies for acute myeloid leukemia in the first complete remission: chemotherapy or transplantation?

Acute myeloid leukemia is a heterogeneous disease, and it is categorized as favorite-, intermediate-and poor-risk groups based on the cytogenetics and molecular markers. The strategies for consolidation therapies are different among the three risk groups. In the intermediate-risk group, patients can receive chemotherapy, autologous stem cell transplantation, and allogeneic hematopoietic stem cell transplantation. Many studies had observed the value of allogeneic hematopoietic stem cell transplantation as the consolidation therapy in adults and children with intermediate-risk AML. Recently, the transplant technique is developing rapidly, particularly in the area of alternative donor transplantation, and haploidentical related donor transplantation is the most important choice for those without sibling identical donors. Key words: Leukemia, myeloid, acute; Intermediate risk; Hematopoietic stem cell transplantation; Haploidentical; Drug therapy

BK Polyomavirus Hemorrhagic Cystitis following Allogeneic Bone Marrow Transplant with Haploidentical Related Donor: Case Reports from Two Patients

BK virus is well known to be associated with allograft failure in renal transplant recipients due to polyomavirus associated nephropathy PVAN BK viruses are increasingly recognized as important cause of hemorrhagic cystitis during hematopoietic stem cell transplantation HSCT Here we describe two patients with acute lymphoblastic leukemia who received a haplo identical match related donor hematopoietic stem cell transplant after myeloablative conditioning and post transplant cyclophosphamide They developed cytology proven BK Virus cystitis Both were treated with Leflunomide Treatment was effective in alleviating the symptoms temporarily but eventually the symptoms progressed and resulted in mortality of both patients nbsp

Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic blood or marrow hematopoietic cell transplantation continues to be the most potent anti-leukemic treatment for adult patients with standard, high-risk, or chemo-refractory acute myeloid leukemia. Until recently, this procedure was generally limited to those recipients who had an available matched-sibling donor or matched-unrelated donor. Technical advances in graft cell processing and manipulation, control of bidirectional T cell alloreactivity, graft-versus-host disease prophylaxis, and other supportive measures in haploidentical transplantation now enable nearly all patients with acute myeloid leukemia to benefit from the graft-versus-leukemia effect with substantial reduction in procedure-related mortality. Over recent years, haploidentical donors have been increasingly adopted as a valid donor source in allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the absence of an HLA-matched donor. Among centers of the European Society for Blood and Marrow Transplantation, the use of haploidentical related donor transplantation has increased by 250% since 2010, and 291% since 2005. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize recent utilization trends in haploidentical transplantation for acute myeloid leukemia and describe the transformative changes in haploidentical hematopoietic cell transplantation techniques over the past decade, which have led to the current widespread use of this procedure. Furthermore, we review the efficacy of haploidentical hematopoietic cell transplantation for acute myeloid leukemia from available studies, including preliminary comparative studies, and bring attention to remaining unanswered questions and directions for future research. We conclude this report with our recommendations for the role of haploidentical hematopoietic cell transplantation in acute myeloid leukemia.

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma

Allogeneic blood or marrow transplantation (alloBMT) may lead to long-term disease control in patients with multiple myeloma (MM). However, historically, the use of alloBMT in MM has been limited by its high nonrelapse mortality (NRM) rates, primarily from graft-versus-host disease (GVHD). We previously demonstrated that post-transplantation cyclophosphamide (PTCy) decreases the toxicities of both acute and chronic GVHD after alloBMT. Here, we examine the impact of PTCy in patients with MM undergoing alloBMT at Johns Hopkins Hospital. From 2003 to 2011, 39 patients with MM underwent bone marrow or peripheral blood alloBMT from HLA-matched related/unrelated or haploidentical related donors after either myeloablative or nonmyeloablative conditioning. Post-transplantation GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4 with or without mycophenolate mofetil and tacrolimus. Engraftment was detected in 95% of patients, with neutrophil and platelet recovery at a median of 15 and 16 days, respectively. The cumulative incidences of acute grades 2 to 4 and grades 3 and 4 GVHD were .41 and .08, respectively, and no cases of grade 4 acute GVHD were observed. The cumulative incidence of chronic GVHD was .13. One patient succumbed to NRM. All cases of chronic GVHD involved extensive disease and 60% of these patients received systemic therapy with complete resolution. After alloBMT, the overall response rate was 62% with complete, very good partial, and partial response rates of 26%, 21%, and 15%, respectively. The median progression-free survival was 12 months and was associated with the depth of response but not cytogenetic risk. The estimated cumulative incidence of relapse was .46 (95% confidence interval [CI], .3 to .62) at 1 year and .56 (95% CI, .41 to .72) at 2 years. At last follow-up, 23% of patients remain without evidence of disease at a median follow-up of 10.3 years after alloBMT. The median overall survival was 4.4 years and the 5-year and 10-year overall survival probabilities were 49% (95% CI, 35% to 67%) and 43% (95% CI, 29% to 62%), respectively. The use of PTCy after alloBMT for MM is feasible and results in low NRM and GVHD rates. The safety of this approach may allow the development of novel post-transplantation maintenance strategies to improve long-term disease control.

Role of Alternative Donor Allogeneic Transplants in the Therapy of Acute Myeloid Leukemia.

Adult acute myeloid leukemia (AML) is often associated with a poor prognosis, with allogeneic transplantation representing the greatest chance of cure for eligible patients. Historically, the preferred donor source is a human leukocyte antigen-matched blood relative, although only approximately 30% of patients have access to such a donor. Alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical related donors, are available for almost every patient and are increasingly being used for patients without a matched related donor. Survival outcomes with these alternative donor sources now approximate those of matched related donor transplants. Given the safety and success of alternative donor transplants, comparative trials are needed to reassess the optimal donor source for patients with AML. This review summarizes the available data on these alternative donor transplants. Further investigation is needed to contemporize donor selection algorithms, but, in the current era, donor availability should no longer preclude a patient's eligibility for an allogeneic blood or marrow transplant.

Prognostic factors on graft-versus-host disease-free and relapse-free survival after allogeneic hematopoietic stem cell transplantation for adults with acute leukemia

The cure of acute leukemia by allogeneic hematopoietic stem cell transplantation (allo-HSCT) is closely linked to major complications leading to adverse outcomes, including graft-versus-host disease (GVHD), disease relapse and death. This study retrospectively investigated a consecutive series of 312 adult patients with acute leukemia receiving allo-HSCT by using a novel concept of GVHD-free/relapse-free survival (GRFS), and further evaluated the impact of clinical factors on GRFS. Results indicated that the 1- and 2-year GRFS were 54.8% and 51.5%, respectively. In multivariable analysis, recipient age >35years (HR 1.676; p=0.006), diagnosis of acute lymphoblastic leukemia (HR 1.653; p=0.027) and acute biphenotypic leukemia (HR 2.175; p=0.010), advanced disease (HR 2.702; p<0.001), and donor age >35 years (HR 1.622; p=0.008) were significantly associated with inferior GRFS post-HSCT. GRFS of haploidentical-related donor transplant was comparable to that of matched sibling donor or matched unrelated donor transplant. Furthermore, prophylactic donor lymphocyte infusion (DLI) had an overall beneficial effect on GRFS (HR 0.645, p=0.044). Collectively, with a better understanding of these significant prognostic factors which impacted on GRFS, we can effectively evaluate the risk and probability of real recovery after allo-HSCT, further optimizing the therapeutic avenues for acute leukemia.

Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide

Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor.

Matched Sibling Versus Haploidentical Hematopoietic Transplant for Adult Patients with Acute Lymphoblastic Leukemia

Introduction:Matched sibling donor hematopoietic stem cell transplant (MSD-HSCT) had an established role in the post-remission therapy for adult patients with acute lymphoblastic leukemia (ALL), while the role of haploidentical related donor (HRD) HSCT had not been fully defined. Moreover, the outcome of HRD-HSCT has improved gradually recent years which get very close to the outcome of MSD-HSCT. We set this study to compare the outcome between MSD and HRD HSCT for adult patients with ALL, and further to evaluate the role of HRD-HSCT in the post-remission therapy of adult ALL.Methods:Between March 2008 and June 2015, a total of 130 adult patients with ALL were assigned to receive MSD or HRD HSCT in our center. The strategy of donor selection between MSD and HRD was as follows: If a fully MSD was available, patients were assigned to undergo MSD-HSCT. If an MSD was unavailable, patients were assigned to receive HRD-HSCT. High resolution DNA typing of HLA-A, -B, -C, DRB1, and -DQB1 were performed in all patients and donors in our center. All patients received myeloablative conditioning mainly involving BuCy without total body irradiation. Anti-T-lymphocyte globulin (ATG-F; Fresenius, Bad Homburg, Germany) (2.5 mg/kg per day IV on days -5 to -2) was also administered to patients receiving HRD-HSCT. The GVHD prophylaxis consisted of cyclosporin A, methotrexate, and low-dose mycophenolate mofetil. Grafts were granulocyte-colony stimulating factor mobilized peripheral blood stem cells without ex vivo T-cell depletion.Results:According to MSD availability, 42 patients were assigned to receive MSD-HSCT and 88 patients were assigned to receive HRD-HSCT. The median age of patients in the MSD cohort (36 years, range 16-51 years) was significantly older than those in the HRD cohort (24 years, range 14-50 years, P<0.001). The sex distribution of patients was also unbalanced between these two cohorts (Male/Female ratio: MSD 0.50 vs HRD 1.59, P=0.003). No significant difference of other clinical characteristics was observed between these two cohorts (P>0.05). The median follow-up time was 20.5 months (range 0.34-99.5 months) in the whole cohort.EngraftmentThree patients in the HRD cohort died within 30 days after HSCT (day 11, day 21, and day 26). Among the 129 patients surviving beyond 15 days, all patients achieved myeloid recovery. The median time and the cumulative 15-day incidences of myeloid engraftment were 12 days (range, 8-17 days) and 95.2% in the MSD cohort, and 13 days (range, 9-29 days) and 73.6% in the HRD cohort, respectively. Myeloid recovery in the HRD cohort was significantly delayed compared with URD cohort (P=0.001).Among the 127 patients surviving beyond 30 days, 5 patients in the HRD cohort experienced primary platelet engraftment failure. The median time and the cumulative 30-day incidences of platelet engraftment were 12 days (range, 7-36 days) and 95.2% in MSDs, and 15 days (range, 8-53 days) and 89.4% in HRDs, respectively. Patients receiving HSCT from HRDs experienced significantly delayed platelet recovery compared with those receiving HSCT from URDs (P<0.001).Long-term OutcomesThere was a trend of higher 5-year relapse rate for patients receiving MSD-HSCT (49.1%) in comparison with those receiving HRD-HSCT (31.2%, P=0.053). While the non-relapse mortality (NRM) rates were significantly higher in the HRD cohort (23.9%) compared with MSD cohort (2.4%, P=0.004). The opposite effects from relapse rate and NRM rate resulted to a comparable survival rates between these two cohorts: The estimated 5-year overall survival (OS) rates were 52.3% and 52.5% for MSD and HRD HSCT (P=0.510), respectively. And the estimated 5-year relapse free survival (RFS) rates were 48.5% and 44.9% for MSD and HRD HSCT (P=0.626), respectively. After adjusting for patient age and sex, OS (P=0.180) and RFS (P=0.282) were still not significantly affected by donor type. In multivariate analysis, cGVHD had beneficial effects on RFS (HR=0.385, P=0.003) while beyond CR1 at transplant had adverse effects on RFS (HR=2.145, P=0.009).Conclusion:These data suggested that HRD-HSCT could achieve similar survival rates to MSD-HSCT for adult patients with ALL. HRD-HSCT could be a frontline alternative as post-remission therapy for adult ALL patients who lack a matched sibling donor. DisclosuresNo relevant conflicts of interest to declare.

Haploidentical Stem Cell Transplantation for Rare Pediatric Diseases at Peking University People's Hospital

Background:Rare diseases requiring hematopoietic stem cell transplantation (SCT) present a challenge for BMT centers. The patients present at a low frequency, and there are often no established conditioning regimens for these disorders, especially for children without HLA matched sibling donors. We report the conditioning regimen using haploidentical related donors, and outcomes for the following rare disorders transplanted at our center from January 2013 through December 2015. During the past three years we had patients presented with the following: Fanconi anemia (FA), dyskeratosis congenital (DC), adrenal leukodystrophy (ALD) and Wiskott-Aldrich syndrome (WAS).Methods:We treated these children with rare disorders that required SCT at our center, and are reporting the transplant outcomes for these rare diseases.Results: All children were transplanted with haploidentical related donors using G-CSF mobilized bone marrow and peripheral blood stem cell. Conditioning regimens and treatment plans were mainly following Beijing protocol and varied with type of disease. Patient characteristics and outcomes are presented in Table 1. No graft failure occurred and three of 5 patients (60%) are alive and well with no evidence of disease.Conclusions: Our program has treated a variety of rare disorders with an event-free-survival rate of 60%. Our data suggests haploidentical SCT for rare pediatric diseases seems to be challenging and promising. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency

Background:Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) represents the only definitive therapy for GATA2 deficiency.Methods: We carried out myeloablative allogeneic hematopoietic stem cell transplant (HSCT) on 24 patients (mean age 24.9 years; range 16 to 46 years) with mutations in GATA2, or the MonoMAC syndrome, during the preceding three years. Three matched related donor (MRD) recipients and 13 matched unrelated donor (URD) recipients received busulfan 3.2 mg/kg/day and fludarabine 40 mg/m2/day on day's -6, -5, -4, and -3. Eight haploidentical related donor recipients received cyclophosphamide 14.5 mg/kg on day's -6 and -5, fludarabine 30 mg/m2/day on day's -6 to -2, busulfan 3.2 mg/kg/day on day's -4 and -3, and 200 cGy TBI on day -1. The majority of the MRD and URD recipients (n=13) received tacrolimus and short course methotrexate post-transplant as graft-versus host disease (GVHD) prophylaxis; three URD, while three received post-transplant cyclophosphamide (PT/CY) on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil as post-transplant immunosuppression for GVHD. All 8 haploidentical related donor recipients received PT/CY as described followed by tacrolimus/methotrexate.Results:Twenty-two of the 24 patients are alive and disease-free at a mean follow-up of 13 months (range, 2 to 36 months). One matched URD recipient died from persistent AML 110 days post-transplant, and one matched URD recipient died from GVHD 2 years post-transplant. Despite a previous history of MAC in 11 patients, including 3 patients with active MAC at the time of HSCT, there were no recurrences of MAC during or following HSCT. Similarly, 13 patients had MDS with cytogenetic abnormalities at the time of HSCT (trisomy 8, monosomy 7, 5q-, trisomy 1q), and all 13 had resolution of their cytogenetic abnormalities with no late relapses following HSCT. Three patients had lymphedema at the time of HSCT (Emberger syndrome), which was not reversed. Twenty-three of the 24 patients had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, which were severely deficient pre-transplant. One URD who received PT/CT had poor graft reconstitution and required a CD34+ donor cell boost three months post-transplant. Four of the 13 MRD and URD recipients who received tacrolimus/methotrexate developed grade III-IV acute GVHD, and 3 of the 7 who were more than one-year post-HSCT developed moderate to severe chronic GVHD. No haploidentical related donor recipient developed grade III-IV GVHD or moderate to severe chronic GVHD.Conclusions: Myeloablative HSCT in GATA2 deficiency results in uniform engraftment and reversal of the hematologic, cytogenetic, and clinical manifestations of clinical manifestations of GATA2 deficiency with low regimen-related toxicity, even in this cohort of patients with considerable co-morbidities. We are currently using PT/CY in MRD and URD recipients with normal, favorable, or intermediate cytogenetics with isolated trisomy 8 to reduce the incidence of acute and chronic GVHD. We anticipate that with HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML occurs, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Haploidentical related donor transplant appears to be particularly well suited for this disease, especially when the disease presents as a hypocellular MDS with or without trisomy 8. DisclosuresNo relevant conflicts of interest to declare.

Intensive Chemotherapy with DA-Edoch Followed By Allogeneic Hematopoietic Stem Cell Transplantation Improved the Outcome in HTLV-1 Associated Adult T Cell Leukemia (ATL)

Background:Adult T-cell leukemia (ATL) caused by human T-cell lymphotropic virus type I (HTLV-1) infection is an aggressive malignancy. There is no effective and standard treatment for it so far and most patients died within 1 year after diagnosis. Moreover, a high prevalence of HTLV-1 infection has been identified in our region by our previous work.OBJECTIVE:To improve the prognosis of ATL, we performed intensive chemotherapy including DA-EDOCH regimen, particularly followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) and evaluate the efficacy and safety profile.METHODS:A total of 12 consecutive ATL patients treated at our center from Mar. 2013 to Jul. 2015 are retrospectively analyzed. The diagnoses were confirmed by the detection of HTLV-I provirus genes by PCR, which has been established in our institute. The median age of the patients is 50.8 (range 28-66) years. 10 patients received intensive chemotherapy as the induction therapy while 2 quit at the time of diagnosis. 5 patients were administrated with DA-EDOCH regimen while 5 with other regimens than DA-EDOCH. DA-EDOCH regimen is a variation of dose-adjusted EPOCH regimen with the replacement of prednisone (60 mg/m2 per day) by dexamethasone (15 mg/m2 per day). After the intensive chemotherapy, 2 out of 5 patients with DA-EDOCH regimen were in complete remission (CR) and then transplanted from haplo-identical related donors. Before the conventional regimens Bucy followed by prophylaxis donor lymphocyte infusion, both received a course of salvage chemotherapy including fludarabine and cytarabine for 5 days registered on http:// ClinicalTrials.gov (NCT02328950). The GVHD prophylaxis consisted of ATG, CsA and MTX.RESULTS:All 5 patients who didn't receive DA-EDOCH regimen died of disease progress, while among 5 patients with DA-EDOCH regimen, 2 achieved CR, 2 PR and 1 died. With a median follow-up of 16.6 (2-20.1) months, 3 patients respond to DA-EDOCH are still alive. 2 patients in CR achieved successful engraftment with complete donor chimerism in one month post haplo-identical transplant. Both were received prophylaxis donor lymphocyte infusion and the immunosuppressive agents were abruptly discontinued for induction of a graft-verus-ATL (GVL) effect. They keep remain alive and disease free longer than 1.5 years so far without severe graft-versus-host (GVHD), and the most striking is that HTLV-1 proviral DNA became undetectable after allo-HSCT. None of these patients had severe infection or organ failure during the treatment.CONCLUSION:It revealed a significant survival benefit from DA-EDOCH regimen. When followed by allo-HSCT, it shows great promise to the long-term cure of ATL with the GVL effect. Haplo-identical transplantation can be an alternative option for the ATL patients without increasing non-relapse mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Establishment of Subspecialized Care in Hematologic Malignancies and a Hematopoietic Cell Transplantation Program

Establishment of Subspecialized Care in Hematologic Malignancies and a Hematopoietic Cell Transplantation Program