Unrelated Bone Marrow Transplantation Research Articles

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.

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.

Three resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation

BackgroundBone marrow transplantation is now an established treatment for some hematopoietic disorders and hematopoietic malignancies, and secondary solid tumors that develop after bone marrow transplantation have begun to attract attention.Case presentationHerein, we report 3 cases of esophageal carcinoma that developed after bone marrow transplantation. Case 1: 40-year-old female received cyclophosphamide and total body irradiation at 12 Gy for acute myeloid leukemia, followed by related bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as pulmonary complications and was administered cyclosporine. Nine years after the transplantation, she was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. She died of the primary disease 17 months after the surgery. Case 2: A 45-year-old male patient received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy for acute lymphocytic leukemia, followed by related bone marrow transplantation. He developed chronic graft-versus-host disease manifesting as liver dysfunction. Fifteen years after the transplantation, he was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. Seven months after the surgery, he died of the primary disease. Case 3: A 30-year-old female patient received cyclophosphamide and total body irradiation at 3 Gy for Fanconi anemia, followed by unrelated bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as a rash and was administered tacrolimus and methotrexate. Fifteen years after the transplantation, she was diagnosed as having esophageal carcinoma Stage III and underwent radical surgery. She died of sepsis 7 months after the surgery.ConclusionThe esophageal carcinomas developing after bone marrow transplantation had the characteristics of secondary solid tumors in all 3 patients, such as early onset, after total body irradiation, association with chronic graft-versus-host disease, and history of use of immunosuppressive drugs. Patients undergoing bone marrow transplantation require long-term follow-up after the transplantation, considering the possible development of secondary solid tumors, and in regard to secondary solid tumors developing in the gastrointestinal tract, it must be borne in mind that the risk of esophageal carcinoma is particularly high.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Effect of donor type on volume of blood transfusions required after allogeneic hematopoietic cell transplantation.

We reviewed blood product use in 729 consecutive allogeneic hematopoietic cell transplantation (allo-HCT) recipients at our center to assess the volume of red blood cells (RBCs) and platelets required after allo-HCT. The median number of bags required by day 30 was 4 for RBCs (range 0-22) and 9.5 for platelets (0-53). Multivariate analysis showed that related peripheral blood stem cell transplantation (PBSCT) required a significantly lower RBC transfusion volume by day 30 compared to unrelated bone marrow transplantation (UBMT). PBSCT from haplo-identical related donors and cord blood transplantation (CBT) required a significantly greater RBC transfusion volume. For platelet transfusion, related and unrelated PBSCT required a significantly lower volume than UBMT, and CBT a greater volume. Other factors independently associated with greater RBC transfusion volume were male sex, disease status other than complete remission, and major ABO mismatch. For platelet transfusion, these were male sex, disease status, and HCT-specific comorbidity index of 1. Although the burden of blood transfusions may not be the most important factor when choosing a donor type, our findings may provide a foundation for nationwide strategies to prepare blood products and inform aspects of national healthcare expenditures.

Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions

The efficacy and toxicity of donor leukocyte infusions (DLI) after unrelated donor bone marrow transplantation (BMT) is largely unknown. We identified 58 recipients of unrelated DLI (UDLI) for the treatment of relapsed disease from the National Marrow Donor Program database. A retrospective analysis was performed to determine response, toxicity, and survival after UDLI and to identify factors associated with successful therapy. UDLI was administered for relapsed chronic myelogenous leukemia (CML) (n = 25), acute myelogenous leukemia (AML) (n = 23), acute lymphoblastic leukemia (ALL) (n = 7), and other diseases (n = 3). Eight patients were in complete remission (CR) before UDLI, and 50 were evaluable for response. Forty-two percent (95% confidence interval [CI], 28%-56%) achieved CR, including 11 of 24 (46%; 95% CI, 26%-66%) with CML, 8 of 19 (42%; 95% CI, 20%-64%) with AML, and 2 of 4 (50%; 95% CI, 1%-99%) with ALL. The estimated probability of disease-free survival (DFS) at 1 year after CR was 65% (95% CI, 50%-79%) for CML, 23% (95% CI, 9%-38%) for AML, and 30% (95% CI, 6%-54%) for ALL. Acute graft-versus-host disease (GVHD) complicated UDLI in 37% of patients (grade II-IV, 25%). A total of 13 of 32 evaluable patients (41%) developed chronic GVHD. There was no association between cell dose administered and either response or toxicity. In a multivariable analysis, only a longer interval from BMT to relapse and BMT to UDLI was associated with improved survival and DFS, respectively. UDLI is an acceptable alternative to other treatment options for relapse after unrelated donor BMT. (Blood. 2000;95:1214-1221)

Steep neutrophil recovery following unrelated bone marrow transplantation is a major risk factor for the development of acute graft-vs-host disease-a retrospective study.

The speed of neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. We retrospectively evaluated the slope of neutrophil recovery (N slope) in 120 patients who underwent a first unrelated bone marrow transplantation with granulocyte-colony-stimulating factor support between 2009 and 2018. The median N slope was 205.5/µl/day. We classified patients into low (n=59) and high (n=61) N slope groups with a cutoff value of 200/µl/day. The high N slope group correlated with older patients, RIC regimen, high CD34+ cells, and recent transplantation. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was significantly higher in the high N slope group than in the low N slope group (44.3% vs. 16.9%, P<0.001). In multivariate analysis, high N slope was identified as a significant independent risk factor for grade II-IV aGVHD, irrespective of the involved organs. There were no differences in relapse, nonrelapse mortality, or overall survival between the two groups. In conclusion, the difference in N slope after allo-HCT may predict the risk of aGVHD. Prevention and treatment of GVHD according to the changes in the neutrophil count may improve post-transplant complications.

Costs of Cord Blood Transplantation Are Higher Than Other Graft Sources in Patients with Acute Leukemia and Myelodysplastic Syndrome Treated at Pediatric Centers

In this commentary, we discuss the reasons why umbilical cord blood (UCB) allogeneic stem cell transplants are more expensive than matched related and matched unrelated peripheral blood and bone marrow transplants in patients treated at pediatric centers. We compare results of our previously published study with the recently published study from the Center for International Bone Marrow Transplant and Research/Pediatric Health Information System and also highlight the factors that contribute to increased costs of UCB transplants.

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.

Updated Comparison of 7/8 HLA Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Umbilical Cord Blood Transplantation as Alternative Donors in Adults with Acute Leukemia.

The outcomes of 7/8 allele-matched unrelated bone marrow transplantation (7/8 UBMT) and umbilical cord blood transplantation (UCBT) have been improving. We retrospectively analyzed adults with acute leukemia who underwent their first 7/8 UBMT or UCBT in Japan. Between January 2008 and December 2017, a total of 4150 patients were recorded, including 488 who underwent 7/8 UBMT and 3662 who underwent UCBT. Only 32 patients with 7/8 UBMT had graft-versus-host-disease (GVHD) high-risk HLA mismatched pairs. Overall survival at 3 years was 54% for 7/8 the UBMT group and 46% for the UCBT group, a nonsignificant difference in multivariate analysis (hazard ratio [HR], 1.01; 95% confidence interval [CI], .88 to 1.17; P=.89). The 7/8 UBMT and UCBT groups showed a similar nonrelapse mortality rate (HR, 1.16; 95% CI, .96 to 1.45; P=.16) and relapse rate (HR, .85; 95% CI, .71 to 1.02; P=.08). However, the UCBT group had a lower risk of grade II-IV acute GVHD (HR, .76; 95% CI, .65 to .88; P < .001) and chronic GVHD (HR, .77; 95% CI, .66- .91; P=.002) compared with the 7/8 UBMT group. In stratified analyses combining disease risk with conditioning intensity, 7/8 UBMT showed superior overall survival to UCBT in standard risk and myeloablative conditioning (HR, .72; 95% CI, .56 to .93; P=.014). Both 7/8 UBMT and UCBT are appropriate alternative donor procedures. The stem cell source can be selected on the basis of disease risk, patient tolerability, or concerns regarding GVHD.

GVHD-free, relapse-free survival provides novel clues for optimizing allogeneic-HSCT for adult T-cell leukemia/lymphoma

The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult T-cell leukemia/lymphoma (ATL) is still unsatisfactory. To illustrate the advantages and disadvantages of each donor source, we performed a nationwide retrospective study of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) of patients with allo-HSCT-treated ATL. One-year GRFS did not significantly differ between patients who received related bone marrow transplantation (R-BMT; 26%, n = 117), related peripheral blood stem cell transplantation (R-PBSCT; 22%, n = 225), unrelated bone marrow transplantation (UR-BMT; 26%, n = 619), and cord blood transplantation (CBT; 21%, n = 359; p = 0.09). This was attributable to a low incidence of systemically-treated chronic GVHD after CBT (9% at 1 year) and reduced non-GVHD/relapse mortality after R-PBSCT (9% at 1 year). Among patients transplanted in complete remission (CR), 1-year overall survival after CBT (52%, n = 132) was not inferior to that after R-BMT (55%, n = 51), R-PBSCT (57%, n = 79), and UR-BMT (58%, n = 280; p = 0.15), and relapse rates were equivalent among the four sources (p = 0.19). Our results suggest that all donor sources are feasible for CR patients and that GRFS provides important clues toward optimizing allo-HSCT for ATL.

Soluble Interleukin-2 Receptor Index Predicts Outcomes After Cord Blood Transplantation

BackgroundOur previous study demonstrated that the soluble interleukin-2 receptor (sIL-2R) index, defined as the ratio of serum sIL-2R levels at neutrophil engraftment to that before conditioning, is a biomarker that can predict acute graft-vs-host disease (GVHD) after unrelated bone marrow transplantation. In the present study, we evaluated the significance of the sIL-2R index among patients who underwent cord blood transplantation (CBT). MethodsWe retrospectively analyzed 31 patients who underwent single-unit CBT as their first transplantation for hematologic malignancies. ResultsThe median sIL-2R index was 4.2. The cumulative incidence of grade II to IV acute GVHD was not associated with the sIL-2R index. However, the cumulative incidence of relapse at 3 years after transplantation was significantly lower, with an sIL-2R index ≥ 3.7 than with an index < 3.7 (12.8% vs 50.0%; P = .04). As a result, the probability of overall survival at 3 years after transplantation was significantly higher in the former group than in the latter (79.8% vs 20.0%; P < .01). Only the dose of corticosteroid administered in the pre-engraftment period influenced the sIL-2 index. ConclusionThe sIL-2R index can predict the incidence of relapse and probability of survival after CBT, possibly reflecting a graft-vs-leukemia effect.

Isolation of a novel intertypic recombinant human mastadenovirus B2 from two unrelated bone marrow transplant recipients.

Human adenoviruses (HAdV) are well-known opportunistic pathogens of immunocompromised adult and pediatric patients but specific associations between HAdV species or individual HAdV types and disease are poorly understood.In this study we report the isolation of a novel HAdV-B2 genotype from two unrelated immunocompromised patients, both recipients of a hematopoietic cell transplant. In both patients, the course of HAdV infection is consistent with a scenario of reactivation of a latent virus rather than a primary opportunistic infection.Archived HAdV PCR-positive plasma, urine, and stool specimens were processed for virus isolation and detailed molecular characterization. Virus isolates were recovered from patient 1 from PCR-positive urine specimens obtained at days 103 and 116 after transplant in association with gross hematuria, and from a stool specimen obtained 138 days after transplant in association with diarrhea. An isolate was recovered from patient 2 from a PCR-positive urine specimen. Hexon and fiber gene amplification and sequencing were carried out for initial molecular typing, identifying the isolates as an intertypic recombinant with a HAdV-11-like hexon gene and a HAdV-77-like fiber gene. Comprehensive restriction fragment length polymorphism (RFLP) analysis was performed on viral DNA purified from urine and stool isolates, and next generation whole genome sequencing was carried out on purified viral genomic DNA. The genomes of the two isolated strains are 99.5% identical and represent the same RFLP genomic variant. The identified virus is a novel HAdV-B2 genotype designated HAdV-78 exhibiting a HAdV-11-like penton base, a HAdV-11-like hexon and a HAdV-77-like fiber (P11H11F77).

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients.

Heme oxygenase-1 (HO-1), an intracellular enzyme that catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exerts anti-inflammatory and cytoprotective effects against endothelial cell injury. The HO-1 promoter gene has one important single-nucleotide polymorphism (SNP) rs2071746 (-413A>T) that is functional, and the A allele has been reported to be associated with higher HO-1 expression levels than the T allele. We investigated the influence of the HO-1 rs2071746 SNP on the transplant outcomes in 593 patients with hematological malignancies undergoing unrelated, human leukocyte antigen (HLA)-matched, T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. In patients with high-risk diseases, the donor A/A or A/T genotype was associated with better 5 year overall survival (35% vs. 25%; p = 0.03) and 5 year disease-free survival (35% vs. 22%; p = 0.0072), compared to the donor T/T genotype. These effects were not observed in patients with low-risk diseases. The current findings therefore indicate that HO-1 rs2071746 genotyping could be useful for selecting donors and tailoring transplant strategies for patients with high-risk hematologic malignancies.

Different Immune Reconstitution between Cord Blood and unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.

A Machine Learning Approach Deciphers the Effects of Immune Parameters on Clinical Outcomes after HLA-Haploidentical and HLA-Matched Allogeneic Bone Marrow Transplantation with Posttransplant Cyclophosphamide

Background We previously demonstrated comparable immune reconstitution after HLA-matched sibling (MSD), HLA-matched unrelated (MUD), and HLA-haploidentical (haplo) bone marrow transplantation (BMT) with posttransplant cyclophosphamide (PTCy). Here, we use machine learning algorithms to identify predictive immunologic variables, providing insight for future translational interventions. Methods We assessed 11 pre-transplant factors, 22 immune subsets, and 7 serum markers at day 28 and day 56 post-BMT in 70 patients who engrafted after myeloablative conditioned (MAC) haplo BMT with PTCy (50mg/kg on days +3 and +4), mycophenolate mofetil (days +5-35), and tacrolimus (days +5-180) and 74 patients who engrafted after MAC HLA-matched BMT with PTCy (50mg/kg on days +3 and +4). Classification and regression tree machine based learning with nodal selection was applied to detect risk groups for four outcomes: overall survival (OS), progression-free survival (PFS), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Results When compared with cytomegalovirus (CMV) seronegative recipients, CMV seropositive recipients had higher CD3+ T cells, effector memory (EM) CD4+ T cells, T effector memory expressing RA (TEMRA) CD4+ T cells, CD8+ T cells, EM CD8+ T cells, and TEMRA CD8+ T cells at early time points after both BMT platforms (not shown). Pre-BMT disease status and natural killer (NK) cell count at day 28 emerged as predictive variables for survival. Two-year OS and PFS for patients in complete remission (CR) with NK cells >54 cells/µL were 98% and 89%, in CR with NK cells 55 cells/µL, the CuI of aGVHD was 18% in those with CXCL-9 Conclusion Machine learning using immune cellular and soluble markers can be successfully applied to identify risk factors for BMT outcomes. High CD4+ counts and CXCL-9 levels at day 28 predicted aGVHD and high reg3α at day 56 predicted cGVHD. Both CXCL-9 and reg3α represent potential therapeutic targets. Finally, disease status and NK cell counts at day 28 predicted OS and PFS. These data support research to determine what influences NK cell recovery as well as to investigate NK cell therapy for recipients with active disease or for those with poor early NK cell reconstitution.

Steep Neutrophil Recovery Following Unrelated Bone Marrow Transplantation Is a Major Risk Factor for the Development of Acute Graft-Vs-Host Disease

Background: Neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. Some cases have a rapid increase in neutrophils and early engraft, while others show slow increase after neutrophils appearance and take time until engraftment. Such differences in neutrophil recovery may reflect the composition of the graft and affect the complications or prognosis after allo-SCT, though it has not been well documented in the literature. In this study, we retrospectively analyzed the influence of the slope of neutrophil recovery (N slope) following allo-HCT on post-transplant complications and prognosis. Methods: This study was a retrospective analysis of 120 patients with hematopoietic diseases who undergone first unrelated bone marrow transplantation at Jichi Medical University between January 2009 and December 2018. Patients who failed to achieve engraftment or did not receive granulocyte-colony stimulating factor were excluded. The N slope was defined as the increase of neutrophil counts from the last day of lowest neutrophil count after transplantation to the date of neutrophil engraftment. We evaluated the predictive value of N slope for acute graft-versus-host disease (GVHD) using the area under the receiver operating characteristic (ROC) curve and determined the cut-off value to maximize the sum of the sensitivity and specificity. Results: The median N slope was 205.5 /µL/day (range 26.4-7574). An ROC analysis showed that a cut-off value of N slope for grade II-IV acute GVHD was 207.5 /µL/day (sensitivity 0.73, specificity 0.6, AUC = 0.67, 95 % confidence interval (CI) = 0.59-0.79). Then, we classified patients into the low (n = 59) and high (n = 61) N slope groups according to the cut-off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, higher infused CD34+ cells ≥ 1.5 × 106/kg, and former transplantation between 2009 and 2013 compared with the low N slope group (p = 0.028, p = 0.003, p = 0.036 and p = 0.025, respectively). Cumulative incidence of grade II-IV acute GVHD at day 100 was significantly higher in the high N slope group than the low N slope group (44.3 % vs. 16.9%, p = 0.0007). With regard to the risk factors for grade II-IV acute GVHD, male, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation between 2009 and 2013 were significant in univariate analysis. In multivariate analysis, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation were identified as significant independent risk factors (hazard ratio (HR) 3.6, 95%CI 1.7-7.7, p = 0.001; HR 2.8, 95%CI 1.5-5.3, p = 0.002; HR 3.0; 95%CI 1.5-6.1, p = 0.02;, respectively). Cumulative incidence of grade III-IV acute GVHD at day 100 and chronic GVHD at 2 years did not differ in the high and low N slope groups (10.8 % vs. 5.1 %, p = 0.328; 63.3 % vs. 50.1 %, p = 0.12, respectively). In addition, there was no difference in relapse, non-relapse mortality and overall survival between the two groups (p = 0.76, p = 0.32, p = 0.65, respectively). Conclusion: The current study showed that a steeper slope of neutrophil recovery following HCT was associated with increased acute GVHD, though it did not affect relapse, NRM and OS. Early diagnosis and therapeutic intervention for acute GVHD may improve the outcome of patients with rapid neutrophil recovery. Disclosures Kanda: Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Takara-bio: Consultancy, Honoraria; CSL Behring: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Mochida: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Otsuka: Research Funding; MSD: Research Funding; Takara-bio: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Nippon-Shinyaku: Research Funding; MSD: Research Funding; Asahi-Kasei: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Pfizer: Research Funding; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Celgene: Consultancy, Research Funding; Otsuka: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Taiho: Research Funding; Taisho-Toyama: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Graft-Versus-Host Disease-Free, Relapse-Free Survival in Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma Provides a Novel Donor Selection Paradigm

Background: Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can provide sustained remission for adult T-cell leukemia/lymphoma (ATL), its prognosis is still unsatisfactory. Alternative donor sources are often utilized in allo-HSCT for ATL, but advantages and disadvantages of each donor source have not been fully elucidated. Graft-versus-host disease (GVHD) -free, relapse-free survival (GRFS) has been proposed as a novel and clinically meaningful endpoint of allo-HSCT. Whereas GVHD has been relatively accepted in ATL to induce substantial graft-versus-tumor (GVT) effects, severe GVHD is associated with non-relapse mortality and disturbs quality of patients' life. Analyses of GRFS may illustrate important aspects to optimize the balance between regulating GVHD and enhancing GVT effects in ATL patients. Patients and methods: We retrospectively analyzed the data of 1363 patients with ATL who received first allo-HSCT from 2006 through 2015 in Japan. Data were collected from the nationwide database maintained by the Japan Society of Hematopoietic Cell Transplantation. The probability of OS and GRFS was estimated according to the Kaplan-Meier method, and univariate comparisons among the groups were performed using the log-rank test. The Cox proportional hazard model was used for the multivariate analysis of OS and GRFS. Results: Median age was 57 years-old (range: 20-78) and median observation period of survivors was 3.1 years (range: 0.0-10.5). One-year OS and GRFS were 45% and 24%, respectively. OS of cord blood transplantation (CB) (37% at 1 year, n = 359) was worse than those of related bone marrow transplantation (R-BM) (48%, n = 121), related peripheral blood stem cell transplantation (R-PB) (50%, n = 264) and unrelated bone marrow transplantation (UR-BM) (47%, n = 619) (p &lt; 0.001). However, in the cases of complete remission (CR) at allo-HSCT, OS of CB (n = 132) was 52% at 1 year and not inferior to those of R-BM (54%, n = 52), R-PB (57%, n = 88) and UR-BM (58%, n = 280) (p = 0.14). The cumulative incidence of relapse in CB was 47% at 1 year and higher than those of R-BM (40%), R-PB (43%) and UR-BM (35%) (p = 0.002). However, in CR cases, the cumulative incidences of relapse were lower in UR-BM (21% at 1 year) and CB (26%) than those in R-BM (31%) and R-PB (31%), though not significant (p = 0.21). Notably, there were no significant differences in GRFS of CB, R-BM, R-PB and UR-BM (21%, 25%, 21% and 26% at 1 year, p = 0.08, Figure 1A). It was attributed to low incidence of chronic GVHD which needed systemic therapy in CB (9% at 1 year, R-BM: 22%, R-PB: 28% and UR-BM: 18%, p &lt; 0.001, Figure 1B) and low incidence of non-GVHD/relapse mortality in R-PB (9% at 1 year, CB: 20%, R-BM: 13% and UR-BM: 16%, p &lt; 0.001, Figure 1C). In R-BM and UR-BM, there were no significant differences as for OS and GRFS between HLA-matched and HLA-mismatched transplantations. In R-PB, OS of HLA haploidentical transplantation (Haplo, n = 36) was 39% at 1 year and tended to be inferior to those of HLA 6/6-matched (53%, n = 183) and HLA 5/6-matched transplantation (49%, n = 45) (p = 0.11). There was no significant difference as for GRFS among these 3 groups (Haplo: 22%, 6/6-matched: 20%, 5/6-matched: 27% at 1 year, p = 0.69). Finally, multivariate analysis revealed that male sex, higher age (&gt; 50 years), worse PS (&gt; 1) and non-CR at allo-HSCT were associated with lower OS and GRFS. Importantly, donor sources and HLA mismatch were not associated with OS and GRFS. Conclusions: Our results imply that all donor sources are feasible for CR cases and can be selected depending on their clinical characteristics such as frailty and history of infection. While the main issue of CB is high non-GVHD/relapse mortality, it is warranted to suppress severe GVHD in R-PB. Thus, GRFS provides important clues to improve the outcome of allo-HSCT for ATL. Figure Disclosures Shindo: Novartis: Research Funding. Nakano:Novartis: Honoraria. Ichinohe: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; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Impact of Different Doses of Fludarabine in Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation

Background: The purine analog fludarabine (Flu) is recognized as an agent having strong immunosuppressive effects and plays a central role in reduced-intensity conditioning (RIC) and myeloablative reduced-toxicity conditioning (RTC) regimens because of limited nonhematologic toxicities. Combinations of Flu and busulfan (Bu) (FB group) or melphalan (Mel) (FM group) are the commonly used as RIC and RTC regimens. Flu inhibits lymphocyte proliferation, induces apoptosis of hematologic malignant cells and has a synergistic tumor-killing effect with alkylating agents such as Bu and Mel. Few reports assess the impact of different dose of Flu on the clinical outcome. In this study, to compare the impact of Flu doses in RIC or RTC, we retrospectively analyzed clinical outcomes in patients who received FB or FM conditioning by using nationwide registration data of Japan Society for Hematopoietic Cell Transplantation. Method: Patients aged 16 years of older with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia and malignant lymphoma, who received FB or FM conditioning regimen, and who underwent bone marrow transplantation from an unrelated donor between 2007 and 2016 were included in this study. We excluded patients who received oral Bu. Also, patients who had renal dysfunction in Hematopoietic Cell Transplantation-Comorbidity Index was excluded because Flu dose needs an adjustment due to renal function. As a result, 2809 patients were included in this study. All transplantation data in the present study were obtained from the Transplant Registry Unified Management Program (TRUMP), which included clinical data of hematopoietic cell transplantation performed in Japan. Result: In the FB group (n=1647), high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were used in 1334 and 313 patients, respectively. The probabilities of 3-year OS and PFS in the HFB group were significantly higher than that in the LFB group (49% vs 38%, P&lt;0.001; 44% vs 35%, P=0.007). The cumulative incidences of relapse at 3 years were 30.4% and 36.6% (P=0.058), and NRM at 3 years were 25.1% and 28.1% (P=0.24) in the HFB and LFB groups, respectively. In multivariate analysis for OS and relapse, Flu doses was identified as an independent prognostic factor (HR 0.82, P=0.03; HR 0.8, P=0.043). In the FM group (n=1162), high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were used in 118 and 1044 patients, respectively. There was no significant difference in the OS, relapse and NRM rates between HFM and LFM (at 3 years, 51.4% vs 48.5%, P=0.596; 22.4% vs 27.0%, P=0.362; 30.7% vs 30.3%, P=0.783). Conclusion: In this large study, we suggested that high-dose Flu was associated with favorable outcome in the FB group, but not in the FM group. Prospective studies and further investigations are needed to clarify the benefit of high-dose Flu in the setting of FB regimen. Disclosures Ozawa: Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria. Kanda:Daiichi Sankyo Company: Honoraria; Bristol-Meyers Squib: Honoraria; Celgene: Honoraria; MSD: Honoraria; JCR Pharmaceuticals: Honoraria; Takeda: Honoraria; Otsuka: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai: Honoraria; Astellas: Honoraria; Novartis: Honoraria; NextGeM Incorporation: Patents &amp; Royalties: 2019-011392. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL 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.