Unrelated Donor Bone Marrow Transplantation Research Articles

Prevalence and Outcome of Vexas Syndrome in Unrelated Hematopoietic Stem Cell Transplantation

Introduction Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a newly identified monogenic disorder defined by somatic UBA1 mutations in hematopoietic progenitor cells, resulting in bone marrow failure (BMF) and systemic inflammation. This syndrome is frequently associated with myelodysplastic syndrome (MDS) or plasma cell dyscrasia. Although high-dose corticosteroids alleviate symptoms and cytopenia, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potentially curative treatment. This study evaluated the safety and efficacy of unrelated HSCT for treating VEXAS syndrome and its prevalence in patients with hematologic diseases. Methods We conducted retrospective screening for UBA1 mutations in patients with BMF or plasma cell neoplasms who underwent their first HSCT from unrelated donors in Japan between 1995 and 2020. Pre-HSCT blood DNA samples and clinical data were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Multiplex real-time PCR was used to detect the most common pathogenic UBA1 mutations, including p.M41L (c.121A>C), p.M41V (c.121A>G), and p.M41T (c.122T>C), with detection limits of 0.13%, 0.5%, and 1%, respectively. The presence of these mutations was confirmed using Sanger sequencing and droplet digital PCR. In addition, we examined UBA1 mutations in 2 patients previously diagnosed with MDS but suspected of having VEXAS syndrome based on specific clinical features. Results Among 4340 patients with either BMF or plasma cell neoplasms who underwent unrelated HSCT, 1771 had available pre-HSCT blood DNA samples. The diagnoses of the 1771 patients included MDS (n = 1264), acquired aplastic anemia (n = 375), inherited BMF syndromes (n = 89), plasma cell neoplasms (n = 23), and other acquired BMF syndromes (n = 20). The median patient age at HSCT was 46 (range, 0-75; interquartile range, 20-59) years old, and the male-to-female ratio was 1.6:1. Pathogenic UBA1 mutations were detected in 2 of the 1771 patients (0.11%), both of whom were male MDS patients older than the median age (cases 1 and 2); thus, the prevalence of VEXAS syndrome within this patient subgroup was 0.36%. Both patients received chemotherapy before unrelated donor bone marrow transplantation (BMT), including induction chemotherapy and azacitidine, and achieved complete and partial responses, respectively. In addition, UBA1 mutations were detected in the 2 MDS patients at Kanazawa University Hospital (cases 3 and 4). Case 3 also underwent unrelated BMT after experiencing cytopenia relapse and inflammatory symptoms during corticosteroid reduction. The clinical characteristics and outcomes of the 4 patients with VEXAS syndrome are summarized in Table 1. Variant allele frequencies (VAFs) of UBA1 mutations ranged from 2% to 71%. The 3 patients who underwent unrelated BMT received fludarabine and busulfan-based conditioning regimens and graft-versus-graft disease (GVHD) prophylaxis with tacrolimus + methotrexate or cyclosporine + methotrexate. All 3 patients achieved neutrophil and platelet engraftment. One patient required systemic corticosteroids for acute skin GVHD. One patient died of idiopathic interstitial pneumonia 5 months after BMT. The other 2 patients were alive without relapse, chronic GVHD, or other complications at 18 and 28 months after BMT. Discussion Our results support the curative potential of allogeneic HSCT for VEXAS syndrome without excessive toxicity. The occurrence of transplant-related mortality due to idiopathic interstitial pneumonia may be related to the reported poor outcome of the p.M41V mutation following non-transplant therapy. The low prevalence of VEXAS syndrome in the current cohort may be due to the late age of onset and the rare progression to advanced MDS. The low VAFs of UBA1 mutations in the 2 patients who responded to chemotherapy before HSCT may indicate the efficacy of chemotherapy in selectively eradicating UBA1 mutant clones. Our rapid, sensitive, and cost-effective screening method for VEXAS syndrome can help optimize treatment strategies for this rare disease in future studies.

Efficacy and safety of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients aged > 65 years with unfavorable cytogenetics

Unrelated donor bone marrow transplantation (UR-BMT), unrelated donor cord blood stem cell transplantation (UR-CBT), and haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) are the main alternative stem cell sources for allogeneic hematopoietic cell transplantation (HCT) in Japan. The present study aimed to identify factors associated with the outcomes of UR-BMT, UR-CBT, and Haplo-PBSCT in older patients with acute myeloid leukemia (AML) and intermediate- or poor-risk cytogenetics to improve the clinical efficacy and safety of allogeneic HCT. We retrospectively analyzed data for 448 AML patients aged > 65 years who received UR-BMT (n = 102), UR-CBT (n = 250), or Haplo-PBSCT (n = 96) between 2014 and 2020. Overall survival (OS) in the UR-BMT group was superior (P = 0.033) to that in the other groups. However, all patients without complete remission (non-CR) who had Karnofsky performance status (KPS) < 80 at HCT and poor-risk cytogenetics died within 1 year after HCT. Multivariate Cox regression analysis identified KPS <80 at HCT and poor-risk cytogenetics as independent predictors of worse OS in non-CR patients. KPS < 80 may be an alternative indicator for non-CR AML patients with poor-risk cytogenetics during the selection of HCT, alternative treatments, or best supportive therapy, and the optimal KPS is important for the success of HCT.

A review of HLA matching to improve clinical outcome in bone marrow transplants and the role of haplotyping in unrelated donor transplants

When the first allogeneic bone marrow transplants in humans was attempted, little was known of the major histocompatibility complex (HLA) and its role in ensuring success of the graft. Therefore, many of the early attempts resulted in failure. During the 1970s just a small number of alleles were detected serologically and the mixed lymphocyte reaction (MLR) served as a surrogate for class II matching, the DR series of alleles not being formally serologically defined until 1978. Nevertheless, selection of nuclear family members who were two HLA haplotype matched became possible using serology and the MLR and transplant successes were reported. The breakthrough in technology was undoubtedly the introduction of DNA techniques, particularly DNA sequencing. This enabled fully matched unrelated individuals to be found as potential bone marrow donors. Genetic phasing or haplotyping of unrelated donors who are found on bone marrow registries has remained elusive until recently. The development of individual chromosome sequencing will permit haplotype matching in the absence of family studies and will expedite studies aimed at identifying other genes which are important matching factors. AIM: The aim of this review is to outline the technological advances that have been made in HLA genotyping over the last 50 years. The progress from serology to DNA sequence as part of the matching algorithm is one of the reasons clinical results have improved so much during this period. This review outlines the DNA techniques that have been utilised for this purpose, concluding with a discussion of the value of haplotype matching in unrelated donor transplants, where the donor has been sourced from a bone marrow registry. Haplotype matching represents one of the last remaining hurdles to be overcome in unrelated donor bone marrow transplants.

Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation.

We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.

Case Series: Bone Marrow Failure in Teen Siblings with Unique RPS19 Variant

Aplastic anemia occurs when there is a lack of hematopoiesis in the bone marrow leading to peripheral pancytopenia. It is a rare entity and is often idiopathic. However, upon presentation, inherited bone marrow failure syndromes and acquired etiologies must be considered. Investigating causality is particularly important when multiple family members are affected, especially in a short amount of time. It is also essential to identify novel causative genetic variants of bone marrow failure in order to direct treatment in these patients.In our case series, we describe two siblings who presented two weeks apart with severe pancytopenia. The first patient is a 13 year-old non-binary female (prefers pronouns they/them/theirs) who presented from clinic after getting routine labs with white blood cell (WBC) 1.83 x10(3)/mcL, absolute neutrophil count (ANC) 0.16 x10(3)/mcL, hemoglobin (Hgb) 4.8 gm/dL, platelet 13 x10(3)/mcL. Bone marrow biopsy revealed marked hypocellularity (0-10%) with hypoplasia. The second patient is their 16 year-old brother who presented two weeks later with new-onset petechial rash and was found to have WBC 4 x10(3)/mcL, ANC 2.19 x10(3)/mcL, Hgb 6.3 gm/dL, platelet 16 x10(3)/mcL. His bone marrow biopsy demonstrated variable cellularity (10-70%), but after months of transfusion-dependence he met criteria for severe aplastic anemia. Laboratory evaluation for acquired etiologies such as infection was negative. Both patients had a shared medical history of depression briefly treated with fluoxetine, but otherwise no potential medical triggers or environmental exposures were identified. Telomere length analysis was normal and chromosomal breakage analysis was negative. Upon genetic evaluation, both patients were found to have a heterozygous variant of unknown significance of RPS19 (c.-163>T), which substitutes a moderately conserved nucleotide in the noncoding exon 1 in 5‘ untranslated region of RPS19. Although this variant has not been classified as pathogenic, three other variants in the 5‘ untranslated region of RPS19 have been reported in patients with Diamond-Blackfan Anemia (DBA). In contrast to classic DBA, these patients did not present in infancy or early childhood. Likewise, they lacked congenital anomalies or other classic phenotypic characteristics of disease. Lab studies showed normal erythrocyte adenosine deaminase levels, though it should be noted that these levels could not be obtained prior to transfusion in both patients. Given lack of other identified etiologies, however, an inherited bone marrow failure syndrome, possibly due to this variant, was presumed. With suspected but potentially unidentifiable genetic predisposition, matched sibling donor transplant was deferred and both patients underwent a matched unrelated donor bone marrow transplant with reduced-intensity conditioning.With these cases, we aim to share a unique presentation of aplastic anemia that reveals a potentially novel pathogenic variant as well as to provide our approach to medical management in pediatric aplastic anemia in the setting of uncertainty. Identification of other patients with bone marrow failure and this genetic variant will be important to determine its pathogenicity. DisclosuresNo relevant conflicts of interest to declare.

Somatic Mutations Associated with Myeloid Transformation of RUNX1 -Mutated Familial Platelet Disorders with Propensity to Myeloid Malignancies Using Targeted Next-Generation Sequencing

INTRODUCTIONRUNX1 is a master transcription factor associated with hematopoiesis. Germ-line RUNX1 mutations are associated with familial thrombocytopenia and platelet disorders with bleeding phenotype and propensity to myeloid malignancies (FPDMM), such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Although only 40 families with germ-line RUNX1 mutations have been described, its autosomal dominant inheritance pattern and the finding that 50% of the families with more than one first degree relative with MDS and/or AML had RUNX1 mutations underscore the importance of this entity.Despite the elevated frequency of transformation to AML/MDS the array of somatic mutations involved in this process is not fully characterized. Here we describe three patients from two families who had a diagnosis of FPDMM, progressed to MDS and/or AML and had DNA samples available for Next-Generation Sequencing (NGS). METHODSWe identified five patients from two different family pedigrees with AML/MDS between 2014 and 2016. We've had access to DNA samples from three of these patients extracted from one of three sources (buccal swab, peripheral blood leukocytes, and bone marrow) throughout their follow-up. Patients agreed with sample collection after informed consent, according to the Declaration of Helsinki.NGS was performed using a custom-designed 48 gene panel related to myeloid malignancies, using the IonTorrent® sequencing platform as previously described (PMID: 28486043). RESULTSThe pedigrees of both families are described in Figure 1. Patient I-2 from pedigree 1 was diagnosed with acute lymphoblastic leukemia at age 57 and died shortly after. Her son, patient II-3 came to us initially with thrombocytopenia (80,000-100,000/ μl) and mild bleeding symptoms (bleeding assessment tool score: 3) 12 years prior to his AML diagnosis. He also had a colorectal cancer (treated surgically) diagnosed 6 months prior. At AML diagnosis, he had a normal karyotype and underwent standard induction chemotherapy and achieved a complete response. He received one cycle of consolidation with high-dose cytarabine and died shortly after due to metastatic colorectal cancer. His oral epithelial cell DNA sample from the beginning of follow-up was positive for a RUNX1 p.Arg166Ter mutation. Bone marrow (BM) DNA sample from the AML diagnosis showed an additional p.Arg204Ter RUNX1 mutation and an additional p.Gln139fs NFE2 mutation.Patients III-4 and III-5 from pedigree 2 belonged to a family with an extensive previous history of thrombocytopenia and AML. Patient III-5 came to us with thrombocytopenia (50,000-70,000/μl) 2 years prior his AML diagnosis. BM DNA obtained at this time was positive for a p.Arg201Ter RUNX1 mutation and for a p.Pro95Arg SRSF2 mutation. At AML diagnosis, his karyotype was normal and BM DNA was positive for a p.Gly12Asp NRAS mutation in addition to the aforementioned mutations. He underwent three cycles of induction and received a matched unrelated donor bone marrow transplant (BMT) while in refractory disease. He achieved a complete remission that lasted a year and is currently under treatment with hypomethylating agents. His oral epithelial cell DNA sample obtained prior his BMT was only positive for the RUNX1 p.Arg201Ter mutation.Patient III-4 had been followed up for thrombocytopenia for three years and presented to us with pancytopenia and multilineage dysplasia. BM DNA at the onset of pancytopenia showed a p.Arg201Ter RUNX 1 mutation, and emerging TET2 Ser471fs and NRAS Gly12Asp mutations. These findings are summarized in Table 1. CONCLUSIONSWe report a longitudinal DNA sequencing follow-up of three patients with FPDMM. Our findings highlight the heterogeneity of genetic pathways to myeloid transformation in FPDMM. Some of these, as loss of the functioning RUNX1, have already been described. However, here we report for the first time the association of NFE2 and NRAS mutations with myeloid transformation in FPDMM. [Display omitted] DisclosuresOzelo:Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behing: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

Probability of Finding a Matched Unrelated Donor for An Asian Indian Patient Who Needs a Stem Cell Transplant.

Abstract 4343In March 2008 we initiated a matched unrelated donor (MUD) bone marrow transplant program. Forty three searches have been performed through the National Marrow Donor Program USA (NMDP) and through the German Registry (DKMS) and completed data is available on 17 patients. High resolution HLA typing for A, B, DRB1, C and DQB1 alleles was done by Histogenetics (USA), NMDP or DKMS. Of the 17 patients for whom the search process was completed we identified a 10/10 matched donor for 7 patients, a 9/10 for 7 patients and an 8/10 for one patient. The 8/10 mismatch was at the C and DQB1 loci. Thus 15 of 17 (88%) had a suitable donor identified. After the preliminary search 2 patients were unlikely to have a donor. Of the15 matched donors, 4 were Caucasian and 11 were Asian. HLA is determined by the racial background of the individual and therefore the probability of finding a high resolution allele matched donor for an Asian Indian would have been low in registries that are predominantly Caucasian. Identification of matches from among the primarily Caucasian donor pool is interesting and may reflect a Caucasoid background in some of the population in the sub continent. In 11 out of the 17 completed searches an Asian donor was identified (61%). The NMDP has 7.5 million donors of which 553,000 are Asian and Pacific Islanders, 141,462 are South Asian, and 36,790 are Southeast Asian. These data exclude Asian donors reported as being from multiple races. Thus there was a 61% probability of finding a matched donor from among the 141,462 South Asian donors registered with the NMDP.Eleven patients have had a MUD transplant (Acute Myeloid Leukemia: 8, Acute Lymphatic Leukemia: 2 and Myelofibrosis: 1): 3 patients died before engraftment, 8 engrafted, 5 remain in remission, 2 have relapsed and one died of sepsis 100 days post transplant. The remaining four patients with matched donors are awaiting transplant.Since identification of a well-matched donor (allele matched at HLA-A, B, C, DRB1) is important for good outcome after MUD transplantation, these early search data for Indian patients suggest the need for a greater number of donors in India to be available and HLA typed in order to increase the probability of finding a suitable match for patients needing a MUD transplant.Number of SearchesDonor 10/10Donor 9/10Donor 8/10No DonorDonor M/FDonor C/ADonor CMV +/-/?Matched donor able to proceed to collection Yes/NoTransplanted187 [39%]7 [39%]1 [6%]3 [17%]12/34/119/5/411/411C- Caucasian A- Asian Disclosures:No relevant conflicts of interest to declare.

76. Hematocolpos caused by Vulvovaginal Graft-Versus-Host Disease

<h3>Background</h3> One of the mainstays of treatment of Diamond-Blackfan anemia after failure of initial supportive care is allogeneic transplantation. Of the many sequelae of allogeneic hematopoetic stem cell transplantation in female survivors, graft-vs-host disease of the vulva and vagina remains one of the most common and destructive to quality of life. Labial fusion and adhesions, urethral obstruction, vaginal scarring and more uncommon - hematocolpos - are some of the presentations of severe disease. In this case report, we will discuss the treatment hematocolpos as a sequelae of GVHD following allogeneic transplantation. <h3>Case</h3> 16 year old with Diamond-Blackfan anemia status post HLA-matched unrelated donor bone marrow transplant presented 7 months post-transplant with 2 days of low abdominal pain. Pain was 8/10, intermittent, nonradiating, worse with movement and completion of urination and improved with heat packs and oral pain medication. Menarche was at age 15, and she experienced one period prior to transplant which lasted 4 days with moderate flow and no pain. Pretransplant, she had received Depot Lupron and then maintained on norethindrone acetate 5mg daily which was increased after she developed breakthrough bleeding following transplant and then stopped taking 4 months after transplant. Following transplant, she developed secondary amenorrhea consistent with hypothalamic suppression. On presentation, she had GVHD with skin, oral and ocular involvement, normal abdominal exam and a pelvic exam with Tanner stage IV development, labia majora without posterior fusion, rugation, or hyperpigmentation, and labia minora without adhesions or lesions. The distal vagina was present with patent hymen, and a Q-tip was unable to be passed beyond 2cm into the vagina. Transvaginal ultrasound was notable for a complex cystic lesion continuous with the uterine edometrium and upper vagina, demonstrating an air-fluid level measuring 5.9 × 5.9 × 5.4cm, consistent with moderate hematocolpos. Left and right ovaries unremarkable. MRI corroborated these findings. She has undergone 3 separate exams under anesthesia with lysis of adhesions but remains nonadherent to topical steroid or estrogen therapy. She takes continuous combined pills for menstrual suppression. <h3>Comments</h3> This patient highlights an uncommon instance of stenotic vaginal, without vulvar, GVHD. With an absence of external symptoms of GVHD on her genitals, diagnosis may have been delayed. The patient's discomfort with topical therapy necessitates the use of alternative treatment options, which are limited. Menstrual suppression addresses the hematocolpos, but does not address the adhesions, which may impair both future sexual intimacy and overall quality of life.

A study assessing the feasibility of randomization of pediatric and young adult patients between matched unrelated donor bone marrow transplantation and immune-suppressive therapy for newly diagnosed severe aplastic anemia: A joint pilot trial of the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium.

Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.

Non-Myeloablative Bone Marrow Transplant with Post-Transplant Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Transfusion Dependent Thalassemia: Results of an International Consortium (VGC2)

<h3>Background</h3> Post-transplant cyclophosphamide (PTCy) enables allogeneic hematopoietic cell transplant (Allo-HCT) across the human leukocyte antigen barrier. Allo-HCT for severe transfusion dependent thalassemia is restricted in its application due to limited donor availability, graft rejection, and regimen-related toxicities. We explored the use of a common non-myeloablative (NMA) conditioning regimens with PTCy based graft-versus-host disease (GvHD) prophylaxis for matched related, haploidentical, and unrelated donors in the setting of a collaborative consortium. <h3>Methods</h3> A multicenter learning collaboration involving 3 centers used an augmented NMA conditioning with PTCy developed by John Hopkins group (Bolaños-Meade, Blood 2012). All patients received common conditioning regimen consisting of ATG 4.5 mg/kg, fludarabine 150 mg/m², cyclophosphamide 29 mg/kg, thiotepa (10 mg/kg on day -7) and TBI 200 cGy. Graft versus host disease (GvHD) prophylaxis was PTCy 50 mg/kg on days +3 and +4, MMF, and sirolimus. To improve engraftment rates, all patients received preconditioning with hydroxyurea 30mg/kg x 60 days (Figure 1). Most patients received G-primed bone marrow as stem cell source. Two patients received matched related donor (MRD), 4 patients haploidentical, and 3 patients matched unrelated donor (I-MUD, 2-mismatched MUD) bone marrow transplants (Figure 2). <h3>Results</h3> A total of 9 patients with transfusion dependent thalassemia were included with a median follow-up time of 371 days. One case of primary graft failure was seen in the haploidentical cohort at D+32; 89% (8/9) patients successfully engrafted. Two cases each of mild gut and skin acute GvHD and one case each of limited gut and skin chronic GvHD were seen in transplanted patients. No cases of grades III-IV acute or severe, chronic GvHD were seen. All patients are alive, thalassemia free survival (TFS) was 100% in the MRD and M/MUD recipients, but 75% (3/4) in the haploidentical cohort. There was no statistical difference between groups in regards to neutrophil or platelet engraftment, age, TNC or CD34+ cell dose. No engrafted patient required long-term immunosuppression therapy, and all remain transfusion independent. <h3>Conclusion</h3> We have shown the feasibility of NMA conditioning with PTCy plus thiotepa for severe transfusion dependent thalassaemia. A phase II study will help determine the optimal regimen with least toxicity and improved thalassaemia free survival.

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

[Background] We previously demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1) was recommended for adult patients wih Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched related (Leukemia 2011;25:259-265) or unrelated donor (Bone Marrow Transplant 2013;48:1077-1083). However, pediatric-inspired high-intensity chemotherapy dramatically improved the prognosis of adult patients with Ph-negative ALL. Therefore, the optimal treatment strategy for Ph-negative ALL in CR1 has not been established in the era of high-intensity chemotherapy. [Methods] Outcomes of patients with Ph-negative ALL who underwent HSCT from HLA-matched related or unrelated donor in CR1 performed between 2002 and 2011 (HSCT-MRD group and HSCT-MUD group, respectively) were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT). Patients aged between 16 and 24 and between 25 and 65 were analyzed separately, and their outcomes were compared with those of patients who did not receive HSCT in CR1 in clinical studies by Japan Adult Leukemia Study Group (JALSG), ALL-202U study in which patients received chemotherapy designed for pediatric patients (Blood Cancer J 2014;4:e252)(202U group) and ALL-202O study in which patients were randomly assigned to receive adult-type chemotherapy with high-dose or intermediate-dose methotrexate (MTX) therapy (Leukemia 2018;32:626-632)(202O group), respectively. Median durations between diagnosis to HSCT were obtained from the TRUMP data, and only patients who were disease-free more than each median duration were included from the JALSG studies. Risk stratifications were performed based on the white blood cell (WBC) count and cytogenetics. [Results] In patients aged less than 25 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 188 days. Overall survival (OS) in 202U group (N = 93) was significantly superior compared with OS in HSCT-MRD group (N = 102) (OS at 5 years: 81.8% vs 67.8%, P = 0.016) (Figure 1(A)), and which was attributed to the higher non-relapse mortality in HSCT-MRD group (NRM at 5 years: 1.4% vs 9.5%, P = 0.015). Disease-free survival (DFS) and relapse rate (RR) were similar between two groups (DFS at 5 years: 70.2% vs 62.5%, P = 0.115, and RR at 5 years: 28.4% vs 28.4%, P = 0.689). Higher OS was preserved in younger (&lt;21) and standard-risk patients. In patients aged less than 25 who underwent HSCT from unrelated donor, the median duration between diagnosis to HSCT was 246 days. OS in 202U group (N = 92) was similar with OS in HSCT-MUD group (N = 51) (OS at 5 years: 81.6% vs 82.7%, P = 0.772). RR in HSCT-MUD group was lower (RR at 5 years: 16.7%) than that in HSCT-MRD group. In patients aged more than 24 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 158 days. OS rate was not different between 202O group (N = 147) and HSCT-MRD group (N = 152) (OS at 5 years: 57.0% vs 60.2%, P = 0.114) (Figure 1(B)). The lower RR was counterbalanced by the higher NRM in HSCT-MRD group (RR at 5 years: 51.6% vs 30.0%, P &lt; 0.001, and NRM at 5 years: 4.1% vs 15.2%, P = 0.015). No difference in OS was demonstrated among any subgroups. Superior DFS in HSCT-MRD group was observed only in high-risk patients (DFS at 5 years: 26.5% vs 57.2%, P = 0.003), but it diminished when only patients who actually received high-dose MTX were included in 202O group (DFS at 5 years: 36.4% vs 57.2%, P = 0.092). In patients aged more than 24 who underwent HSCT from unrelated donor, the median duration between diagnosis to HSCT was 214 days. OS rate was not different between 202O group (N = 138) and HSCT-MUD group (N = 104) (OS at 5 years: 60.0% vs 65.8%, P = 0.563). Superior DFS in HSCT-MUD group was observed even in all patients (DFS at 5 years: 47.2% vs 64.2%, P = 0.029). RR in HSCT-MUD group was lower (RR at 5 years: 14.3%) than that in HSCT-MRD group. [Discussions &amp; Conclusions] High-intensity chemotherapy may change the role of HSCT for Ph-nagative ALL. Improved outcomes in HSCT-MUD group were observed, and it was partially because patients who had long CR before HSCT could underwent HSCT from MUD in CR1. Disclosures Kako: Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria. Tanaka:Bristol-Myers Squibb: Research Funding. Ichinohe:JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kurahashi:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria. Usui:Alexion Pharmaceuticals: Other: Personal Fees; Bristol-Myers Squibb: Other: Personal Fees, Research Funding; Kyowa-Hakko-Kirin Co.Ltd.: Other: Personal Fees; Astellas Pharma Inc.: Other: Personal Fees; Huya Bioscience International: Other: Personal Fees; Nippon Shinyaku Co.: Other: Personal Fees; SymBio Pharmaceuticals: Other: Personal Fees; Celgene Corporation: Other: Personal Fees; Pfizer: Other: Personal Fees, Research Funding; Takeda Pharmaceutical Co. Ltd: Other: Personal Fees; Cmic Co: Other: Personal Fees; Otsuka Pharmaceutical Co.Ltd.: Other: Personal Fees; AbbVie Inc: Other: Personal Fees. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Matsumura:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia

AbstractAllogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Capacity Building for Pediatric Blood & Marrow Transplantation in India through Mentorship, Training Programs & International Collaboration

Introduction In 2005, India had less than 10 bone marrow transplant (BMT) centres, mostly adult BMT programs performing 300 BMT/year. There was a need to train more doctors in pediatric BMT and set up more BMT centres focussing on pediatric BMT. Here we describe how capacity for pediatric BMT was increased in India. Methods Initially send doctors to train abroad and then start a local training program with these initial mentors. Keep mentoring fellows passing out and help them go abroad to train further in pediatric BMT. Encourage them to return to home country & set up new BMT programs, become mentors themselves & start training young fellows and keep the cycle going. Results Over the course of 13 years (2005 to 2018) initial 2 mentors have trained further 68 fellows of whom 12 are still in training.  A total of 28 went abroad for further training (Fig 1). Of them 17 have returned to home country and 11 are still in training abroad. Five joined 3-year doctorate of medicine (DM) program in pediatric hemato-oncology to train further. The remaining 25 opted to train no further and join practice. More than half of the fellows; 36 are active BMT consultants and have helped set up 22 pediatric BMT programs across 9 states (Fig 2).Of these 22 centres, 4 have been  accredited for fellowship of National Boards (6 students/year). Indian Academy of Pediatrics fellowship has also started in these centres (6 students/year).One centre has started a DM program (2 students/year). This group collaborated to analyse outcome data of pediatric BMT from 8 centres across India and reported overall survival of 70% for 717 children at EBMT 2018 meeting. As per Indian stem cell transplant registry report 2018, overall BMT centres have increased to 77 from just 10 in 2005 and annual BMT have increased in India to 2000/year. Among the allogeneic BMT >50% are pediatric. In last 5 years (2012 to 2017), 3329 pediatric BMT have been performed in India (autologous-434 & allogenic-2895 including 636 haploidentical and 348 matched unrelated donor BMT). Conclusion In last decade, with mentorship, training & international collaboration, capacity to do pediatric BMT in India has improved substantially.

Comparable Survival Outcomes of Haploidentical Stem Cell Transplantation and Unrelated Bone Marrow Transplantation

Abstract Background: In the absence of an HLA matched related donor, unrelated donor hematopoietic cell transplantation (HCT) is an alternative. Recently, HLA-haploidentical HCT using posttransplant cyclophosphamide (PTCY-haplo) has been increasingly performed. Unrelated donor peripheral blood stem cell transplantation (PBSCT) program was initiated in 2011 in Japan with rather slow increase, therefore, bone marrow is the main stem cell source for HCT from unrelated donors, while PTCY-haplo is mainly PBSCT. We compared outcomes of unrelated donor bone marrow transplant (UBMT) and PTCY-haplo. Methods: This is a retrospective analysis of a registry data of the Japan Society for HCT and the Japanese Data Center for HCT using the Transplant Registry Unified Management Program (TRUMP). Patients with acute leukemia and myelodysplastic syndromes, aged between 16 and 69 years, who undergone their first HCT between 2012 and 2015 were included in the study. HLA-A, -B, -C, and -DRB1 allele-level 8/8 matched (n=1,470), 7/8 matched (n=859), and 6/8 matched (n=186) T-cell replete UBMT recipients, and 140 recipients of PTCY-haplo (PBSCT, n=133; BMT, n=6; PBSCT+BMT, n=1) were identified as subjects for analyses. Adjusted comparison of the groups on overall mortality was performed with the use of the Cox proportional-hazards regression model. For other outcomes with competing risks, Fine and Gray's proportional-hazards model for subdistribution of a competing risk was used. The models were used to estimate adjusted probabilities, with consideration of other significant clinical variables in the final multivariate models. Results: The median age for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 52(16-69), 46.5(17-68), 50(16-69), 50(16-68). According to refined disease risk index (rDRI), patients with high or very high rDRI were 32%, 54%, 34%, 34% for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Myeloablative conditioning was used in 74%, 51%, 73%, 68% of patients for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Median follow-up period of survivors for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 2.79 (0.03-5.603),1.82 (015-3.89), 3.00 (0.09-5.57), 3.17 (0.27-5.58). In adjusted comparison by multivariate analyses setting 8/8 matched UBMT as the reference, PTCY-haplo showed similar overall mortality (relative risk [RR]=0.97, 95% confidence interval [CI], 0.75-1.26, p=0.823), decreased risk of non-relapse mortality (RR=0.43, 95% CI, 0.25-0.74, p=0.003), increased risk of relapse (RR=1.57, 95% CI, 1.21-2.03, p=0.001), and decreased risk of grade II to IV acute GVHD (RR=0.68, 95% CI, 0.48-0.95, p=0.023). Relative risks for 7/8 matched and 6/8 matched UBMT were 1.08 (p=0.223) and 1.27 (p=0.032) for overall mortality, 1.29 (p=0.004) and 1.73 (p&lt;0.001) for non-relapse mortality, 0.89 (p=0.201) and 0.81 (p=0.215) for relapse, and 1.30 (p&lt;0.01) and 1.84 (p&lt;0.001) for grade II to IV acute GVHD. Other predictive variables identified for overall mortality were patient age older than 50 years old compared to younger at transplant, male sex, refined disease risk index of Intermediate, High, or Very High compared to Low, and HCT-CI total points of 1 or 3 or greater compared to 0. Adjusted probabilities for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT at two years post-transplant were 61%, 58%, 52%, 60% for overall survival, 23%, 27%, 21%, 19% for relapse, and 20%, 6%, 24%, 33% for non-relapse mortality (Figure 1). Conclusions: PTCY-haplo showed notably low non-relapse mortality which contributed to comparable short-term survival outcomes with 8/8 matched UBMT. Disclosures Ishiyama: Alexion Pharmaceuticals, Inc.: Honoraria. Ichinohe:Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Mundipharma: Honoraria; Novartis.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; MSD: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding.

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long‐term immunosuppression for many years, suggesting permanent donor‐specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Diagnosis and Treatment of Aplastic Anemia.

Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long-term clonal complications.

Prognostic Value of the Hematopoietic Cell Transplantation Comorbidity Index for Patients Undergoing Reduced-Intensity Conditioning Cord Blood Transplantation

The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has been validated as a tool for evaluating the risk of treatment-related mortality (TRM) in HLA-matched sibling and matched unrelated donor bone marrow and peripheral blood stem cell transplantation patients. However, the role of the HCT-CI after cord blood transplantation (CBT) has not been fully investigated. In this analysis, we sought to evaluate the predictive value of the HCT-CI in patients undergoing reduced-intensity conditioning (RIC) CBT. Between 2006 and 2013, HCT-CI scores were prospectively tabulated for patients with hematologic malignancies sequentially enrolled on multicenter RIC CBT studies coordinated by the Fred Hutchinson Cancer Research Center: 151 patients with acute myeloid leukemia/myelodysplastic syndrome (n = 101), chronic myeloid leukemia (n = 3), acute lymphocytic leukemia (n = 24), non-Hodgkin lymphoma (n = 8), Hodgkin lymphoma (n = 3), and other hematologic malignancies (n = 12) underwent RIC CBT and were included. Two patients received a single CBT and the remaining 149 received a double CBT. All patients received cyclosporine and mycophenolate mofetil for graft-versus-host disease prophylaxis. Median HCT-CI for the whole group was 3 (range, 0 to 8). Using the HCT-CI categories of low (0), intermediate (1 or 2), and high risk (>3), there was no significant difference in TRM between the 3 groups. However, when the patients were divided into 2 groups, HCT-CI ≤ 3 or > 3, the incidence of TRM at 3 years after transplantation was 26% (95% confidence interval [CI], 17 to 36) in the HCT-CI ≤ 3 group versus 50% (95% CI, 30 to 67) in the HCT-CI > 3 group (P = .01). Overall survival for patients with HCT-CI ≤ 3 was 40% (95% CI, 27 to 51) versus 29% in patients with HCT-CI >3 (95% CI, 12 to 48) (P = .08). Our study demonstrates that HCT-CI score > 3 is associated with an increased risk of TRM at 3 years after transplantation in patients undergoing RIC CBT. Because of the significant risk of TRM in patients with HCT-CI > 3 compared with risk for those with HCT-CI ≤ 3, patients with an HCT-CI score >3 should be counseled before undergoing RIC CBT.

Hematopoietic stem cell transplantation for acquired aplastic anemia.

There has been a steady improvement in outcomes with allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA), because of progress in optimization of the conditioning regimens, donor hematopoietic cell source, and supportive care. Here, we review recently published data that highlight the improvements and current issues in the treatment of SAA. Approximately one-third of aplastic anemia patients treated with immune suppressive therapy (IST) have acquired mutations in myeloid cancer candidate genes. Because of the greater probability for eventual failure of IST, human leukocyte antigen (HLA)-matched sibling donor BMT is the first-line of treatment for SAA. HLA-matched unrelated donor (URD) BMT is generally recommended for patients who have failed IST. However, in younger patients for whom a 10/10-HLA-allele matched URD can be rapidly identified, there is a strong rationale to proceed with URD BMT as first-line therapy. HLA-haploidentical BMT using posttransplant cyclophosphamide conditioning regimens is now a reasonable second-line treatment for patients who failed IST. Improved outcomes have led to an increased first-line role of BMT for treatment of SAA. The optimal cell source from an HLA-matched donor is bone marrow. Additional studies are needed to determine the optimal conditioning regimen for HLA-haploidentical donors.

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

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

Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT

Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT. Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome. In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations. Disclosures Niederwieser: Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Glass: Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid: Janssen Cilag: Other: Travel grand; Neovii: Consultancy.