[Successful immunosuppressive therapy in female hemophilia A developing inhibitor after perioperative administration of factor VIII products].

A 62-year-old woman was diagnosed as a hemophilia A carrier (factor VIII activity 35%) on preoperative examination of an ovarian tumor. A total of 35,600 units of recombinant factor VIII products was administered perioperatively. On postoperative day 95, a subcutaneous hematoma formed and immunosuppressive therapy with prednisolone was started based on an APTT of 66 seconds, factor VIII (FVIII) activity of 3%, and FVIII inhibitor of 1 BU/ml. During this treatment, the patient was hospitalized due to ankle joint bleeds and required hemostatic treatment, but the inhibitor disappeared and FVIII activity recovered to 30% after postoperative day 438 with cyclophosphamide. F8 analysis revealed the patient carried a heterozygosity of p.Arg391Cys, which has previously been categorized as cross-reacting material (CRM)-positive severe hemophilia A. No high-risk mutations for inhibitor development were found. We also report the results of a desmopressin acetate hydrate test administered to the patient to prepare for future treatment in case of hemorrhage, since high-dose FVIII administration may have been a factor in inhibitor development.

Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

[Allogeneic hematopoietic stem cell transplantations for relapsed and refractory acute lymphoblastic leukemia following inotuzumab ozogamicin treatment].

Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.

[FLT3-ITD and NPM1 mutation positive acute myeloid leukemia with cuplike blasts mimicking acute promyelocytic leukemia].

FMS-like tyrosine kinase 3 (FLT3) inhibitors improve the prognosis of FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML). Case 1 is a 47-year-old male patient who presented with a white blood cell count (WBC) of 95,700/ml with 94% blast accompanied by cuplike nuclei, lactate dehydrogenase (LDH) of 2,434 IU/l, fibrin degradation products (FDP) of 476 mg/ml, and a bone marrow examination that revealed blastic marrow with chromosome 46, XY, positive FLT3-ITD, and positive nucleophosmin 1 (NPM1) mutation type A. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and human leukocyte antigen-DR isotype (HLA-DR). The patient had no response to idarubicin combined cytarabine; however, qiuzartinib administration resulted in the first complete remission. Case 2 is a 71-year-old female patient, who presented with 94,900/ml of WBC with a 91% blast accompanied with cup-like nuclei, LDH of 19,03 IU/l, FDP of 112 mg/ml, and a peripheral blood examination that revealed chromosome 46, XX, positive FLT3-ITD, and positive NPM1 mutation type B. Flow cytometry revealed that blasts were positive for CD33 and negative for CD34, CD117, and HLA-DR. She had a partial response to venetoclax combined with azacytidine, and qiuzartinib administration resulted in the first complete remission. Both cases were CD34- and HLA-DR-negative with disseminated intravascular coagulation mimicking acute promyelocytic leukemia (APL). Additionally, recognizing the cuplike blasts is useful to differentiate FLT3 mutant AML from APL for the proper use of FLT3 inhibitors.

[Use of pegylated granulocyte colony-stimulating factor in dose-adjusted EPOCH-R therapy].

Dose-adjusted (DA)-EPOCH-R causes profound neutropenia requiring relatively long hospital stays with multiple doses of granulocyte colony-stimulating factor (G-CSF). A single-dose pegylated G-CSF (PEG-G-CSF) has been used for the treatment of chemotherapy-induced neutropenia. We retrospectively examined 15 patients (median age 61, range 33-75 years) treated with DA-EPOCH-R. In the first cycle of the DA-EPOCH-R therapy, a G-CSF preparation was used, and since the second cycle, the G-CSF and PEG-G-CSF use groups were divided. The median length of hospitalization after starting chemotherapy in the second-cycle DA-EPOCH-R was significantly shorter with PEG-G-CSF group (n=9) of 9 (7-13) days compared with G-CSF group (n=6) of 18 (15-22) days (P<0.001). Risk factors of febrile neutropenia, such as bone marrow invasion, performance status, serum albumin, and history of febrile neutropenia at the first DA-EPOCH-R cycle or previous chemotherapy were not significantly different for both groups, and the incidence of febrile neutropenia in PEG-G-CSF and G-CSF groups was 2.6% and 46.9%, respectively. These analyses suggest that PEG-G-CSF can be combined with DA-EPOCH-R without compromising treatment outcomes as compared with the daily dose of G-CSF.

Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Poor-Prognosis Cytogenetics in First Complete Remission.

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P = .011 and P = .025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P = .082 and P = .062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.

Outcome of allogeneic hematopoietic stem cell transplantation for mycosis fungoides and Sézary syndrome.

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.

Successful correction of factor V deficiency of patient-derived iPSCs by CRISPR/Cas9-mediated gene editing.

BACKGROUND: Factor V (FV) deficiency is a monogenic inherited coagulation disorder considered to be an ideal indication for gene therapy. To investigate the possibility of therapeutic application of genome editing, we generated induced pluripotent stem cells (iPSCs) from a FV-deficient patient and repaired the mutation of factor V gene (F5) using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9). METHODS: The patient's peripheral blood mononuclear cells were reprogrammed for iPSCs. The targeting vector was designed with homology arms against F5 containing the corrected sequence. Cas9 ribonucleoprotein (RNP) complex and targeting vector were electroporated into iPSCs. Gene-edited iPSCs were differentiated into hepatocyte-like cells (HLCs). RESULTS: The mutation of F5 in patient-derived iPSCs was repaired by CRISPR/Cas9. In concentrated culture supernatants of patient-derived iPS-HLCs, neither FV antigen nor activity was detected, while in those of gene-corrected iPS-HLCs, FV antigen and specific activity were 67.0 ± 13.1 ng/mL and 173.2 ± 41.1 U/mg, respectively. CONCLUSIONS: We successfully repaired the mutation of F5 using the CRISPR/Cas9 and confirmed the recovery of FV activity with gene-corrected iPS-HLCs. Gene-edited iPSCs are promising for elucidating the pathophysiology as well as for a modality of gene therapy.

[Interleukin-6-producing paraganglioma mimicking multicentric Castleman disease].

Multicentric Castleman disease (MCD) comprises a heterogeneous group of lymphoproliferative disorders. Interleukin 6 (IL-6) plays an important role in the MCD pathophysiology. Here, we report the case of a 17-year-old Japanese man who presented with fever, headache, fatigue, and weight loss, with normal blood pressure. A movable mass was palpated in his lower abdomen. Laboratory tests revealed microcytic anemia and hypoalbuminemia, with elevated IL-6, sIL-2R, and vascular endothelial growth factor. Computed tomography of the abdomen demonstrated a 55-mm-diameter pelvic tumor and enlarged mesenteric lymph nodes. MCD was suspected, and the pelvic tumor resected. After the operation, his blood pressure rose slowly, and resulted to seizures of posterior reversible encephalopathy syndrome. Evaluation of hypertension revealed that plasma norepinephrine and normetanephrine concentrations were elevated, and pathological examinations showed that the resected tumor was positive for IL-6 and chromogranin-A. Therefore, we diagnosed the patient with IL-6-producing paraganglioma with MCD-mimicking symptoms. Moreover, IL-6-producing pheochromocytoma and paraganglioma should be included in differential diagnoses of MCD, even in normotensive patients.

High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

A case of 8p11 myeloproliferative syndrome with BCR-FGFR1 gene fusion presenting with trilineage acute leukemia/lymphoma, successfully treated by cord blood transplantation.

The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11-12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11-12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date.

[Amebic colitis and liver abscess complicated by high serum procalcitonin in acute myeloid leukemia].

We present a case of amebic colitis and liver abscess complicated by acute myeloid leukemia (AML) with high serum procalcitonin (PCT). A 61-year-old Japanese man seen at our hospital for severe diarrhea and high fever was found to have multiple ulcers in the transverse and sigmoid colon and rectum by colonoscopy and biopsies were conducted. Immature leukocytes with mild anemia and thrombocytopenia were seen in peripheral blood, necessitating bone marrow aspiration and biopsy that yielded a diagnosis of AML (FAB M4Eo). Serum C-reactive protein and PCT were extremely elevated. Blood cultures for bacteria and fungi were negative. Multiple low-density areas in the liver were found in abdominal computed tomography. Histological colon biopsy findings revealed amebic colitis, strongly suggesting amebic liver abscess. Metronidazole treatment was initiated for amebiasis and subsequent standard chemotherapy for AML was followed after fever was lowered. Hematological and cytogenetic CR was maintained with good clinical condition. Few case reports have been published in Japan to date on amebic colitis and liver abscess complicated by AML and no reports have been made on PCT elevation caused by amebiasis. In conclusion, differential diagnosis of amebiasis is necessary in addition to that of bacterial or fungal infection in serum PCT elevation.

Factor VII Deficiency Due to Compound Heterozygosity for the p.Leu13Pro Mutation and a Novel Mutation in the HNF4 Binding Region (-58G>C) in the F7 Promoter.

We investigated the molecular basis of factor VII (FVII) deficiency in a Japanese patient and identified compound heterozygous mutations. Factor VII activity and antigen levels in the patient were less than 5.0% and 6.5% of controls, respectively. All exons, exon-intron boundaries, and the 5' promoter region of F7 from genomic DNA were amplified using polymerase chain reaction (PCR). Sequencing analysis of PCR fragments revealed that the patient was heterozygous for a known T to C substitution at nucleotide position 38, which resulted in the p.Leu13Pro missense mutation (Factor VII Morioka) in the signal peptide region, and a novel mutation in the 5' promoter region (-58G>C). An electrophoretic mobility shift assay showed that the mutation in the promoter region reduced the binding of hepatocyte nuclear factor (HNF). It is presumed that the reduced binding of HNF-4 to the F7 promoter region reduces F7 transcription and thus reduces the synthesis and expression of FVII.

A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.

Risks of Muscle Atrophy in Patients with Malignant Lymphoma after Autologous Stem Cell Transplantation.

OBJECTIVE: Muscle atrophy is associated with autologous stem cell transplantation (ASCT)-related outcomes in patients with malignant lymphoma (ML). However, the impact of ASCT on muscle mass remains unclear in patients with ML. The aims of this study were to investigate changes in muscle mass and risk profiles for muscle atrophy after ASCT. METHOD: We enrolled 40 patients with refractory ML (age 58 [20-74] years, female/male 16/24, body mass index (BMI) 21.1 kg/m2 [17.1-29.6]). Psoas muscle mass was assessed using the psoas muscle index (PMI) before and after ASCT. STATISTICAL ANALYSIS USED: Independent factors associated with a severe decrease rate of change in PMI were evaluated by decision-tree analysis, respectively. RESULTS: PMI was significantly decreased after ASCT (4.61 vs. 4.55 cm2/m2; P=0.0425). According to the decision-tree analysis, the regimen was selected as the initial split. The rates of change in PMI were -5.57% and -3.97% for patients administered MCEC and LEED, respectively. In patients who were administered LEED, the second branching factor was BMI. In patients with BMI < 20.3 kg/m2, the rate of change in PMI was -7.16%. On the other hand, the rate of change in PMI was 4.05% for patients with BMI ≥ 20.3 kg/m2. CONCLUSION: We demonstrated that muscle mass decreased after ASCT in patients with ML. Patients who received MCEC and patients with low BMI were at risk for a decrease in muscle mass.

Adding melphalan to fludarabine and a myeloablative dose of busulfan improved survival after allogeneic hematopoietic stem cell transplantation in a propensity score-matched cohort of hematological malignancies.

Fludarabine and a myeloablative dose of busulfan (Flu/Bu4) can improve prognosis after allogeneic hematopoietic stem cell transplantation (HSCT) with melphalan (Mel). We investigated the prognostic impact of adding Mel to Flu/Bu4 by comparing between Flu/Bu4/Mel and Flu/Bu4 groups. This study included 846 propensity score (PS)-matched patients who received either Flu/Bu4/Mel (n = 423) or Flu/Bu4 (n = 423) from 2394 patients enrolled in a multicenter prospective registry, from January 2010 to December 2016. The primary endpoint (5-year overall survival [OS]), and the prognostic impact of adding Mel was evaluated using Cox regression analysis. The study population median age was 58 (interquartile 50-64) years and 61.0% were male. Patient characteristics were well-balanced between groups. Five-year OS was 34.2% (95% confidence interval [CI]: 27.3-41.1%) and 30.1% (24.8-35.6%) in the Flu/Bu4/Mel and Flu/Bu4 groups, respectively (log-rank P = 0.019). The adjusted hazard ratio of adding Mel was 0.77 (95% CI: 0.62-0.96) (P = 0.022) for the 5-year OS, and this attributed to a lower incidence of 5-year relapse (0.71, 0.56-0.90, P = 0.005) and relapse associated mortality (0.73, 0.57-0.95, P = 0.018). There was no statistical difference in 5-year non-relapse mortality between groups (log-rank P = 0.855). Flu/Bu4/Mel was associated with better 5-year OS compared to Flu/Bu4 in a PS-matched cohort after allogeneic HSCT.

Prednisolone-responsive primary sclerosing cholangitis with autoimmune hemolytic anemia: a case report and review of the literature.

We report a case of primary sclerosing cholangitis (PSC) with autoimmune hemolytic anemia (AIHA). A 47-year-old woman was diagnosed with PSC. One year later, she was admitted to our hospital for jaundice and fatigue. Magnetic resonance cholangiopancreatography (MRCP) showed worsening of the biliary stricture, and rapidly progressive anemia developed simultaneously. Based on the various laboratory findings, she was diagnosed with AIHA. The administration of prednisolone improved not only the anemia but also the biliary stricture. This case is impactful, as there are few case reports of PSC with AIHA. In addition, we were able to observe the changes in imaging findings using MRCP over time.

Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion.

BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a neoplasm of lymphoblasts committed to the B-cell lineage that lack the BCR-ABL1 translocation but show a pattern of gene expression very similar to that seen in ALL with BCR-ABL1 with poor prognosis. A 22-year-old female was diagnosed with common-B-cell-ALL positive for CD10, CD19, CD22, CD79a, CD34, HLA-DR, and TdT in January 2017, and achieved complete remission (CR) with induction therapy, followed by consolidation therapy and maintenance therapy. In March 2020, 6 months after the completion of maintenance therapy, she relapsed. Inotuzumab ozogamicin (IO) was administered, and on day 28, bone marrow evaluation showed a morphologic CR. She had an HLA-identical sibling, and transplantation in her 2nd CR was planned. Because her ALL had been identified as BCR-ABL1-like ALL with CCDC88C-PDGFRB fusion, she was treated with imatinib for 2 months accompanied by 2 intrathecal methotrexate therapies, and 1 course of L-asparaginase, vincristine, and prednisolone in an outpatient setting. MRD analysis revealed potent efficacy of 2 months imatinib therapy; IgH MRD decreased from 1 × 10-2 to 1 × 10-3, and CCDC88C-PDGFRB/104ABL from 37.3 to 0. It is earnestly desired that well-designed clinical trials of TKI in ABL class-mutant BCR-ABL1-like ALL be conducted in Japan.

Single Cord Blood Transplantation Versus Unmanipulated Haploidentical Transplantation for Adults with Acute Myeloid Leukemia in Complete Remission.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative post-remission therapy for adult patients with acute myeloid leukemia (AML) in complete remission (CR). The availability of alternative human leukocyte antigen (HLA)-mismatched donors, such as cord blood and haploidentical related donors, could allow patients to receive allogeneic HCT who are without an HLA-matched sibling or unrelated donor. The use of these alternative donors is preferable for patients with advanced disease due to the rapid availability. However, comparative data for cord blood transplantation (CBT) and haploidentical related donor transplantation (haplo-HCT) are limited for adult patients with AML in CR. We sought to compare overall survival (OS); leukemia-free survival (LFS); graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); and chronic GVHD-free, relapse-free survival (CRFS) between single-unit CBT (SCBT) and haplo-HCT recipients for adult patients with intermediate- or poor-risk AML in CR. We retrospectively analyzed and compared the results of allogeneic hematopoietic cell transplantation in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan. Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients (P < .001 for neutrophil, P < .001 for platelet). SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT (P = .013 for grades II to IV acute GVHD; P = .006 for extensive chronic GVHD). Haplo-HCT recipients developed a higher incidence of cytomegalovirus (CMV) antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD (hazard ratio [HR], 1.17; 95% confidence interval [CI], .88 to 1.57; P = .26), relapse incidence (HR, 1.09; 95% CI, .76 to 1.58; P = .61), non-relapse mortality (HR, .83; 95% CI, .58 to 1.18; P = .32), OS (HR, .92; 95% CI, .70 to 1.20; P = .56), LFS (HR, .94; 95% CI, .73 to 1.21; P = .67), GRFS (HR, 1.12; 95% CI, .90 to 1.40; P = .27), or CRFS (HR, 1.15; 95% CI, .92 to 1.44; P = .19) between the two donor types. In the propensity score matching analysis, which identified 180 patients in each cohort, there were no significant differences in transplant outcomes between the two donor types, except for delayed neutrophil (P < .001) and platelet recovery (P < .001) and a higher incidence of grades II to IV acute GVHD (P = .052) in SCBT. SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients.

Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia.

To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX15-10-10, 415; MTX10-7-7, 294; MTX5-5-5, 71; MMF, 108) were included. In multivariate analyses with MTX15-10-10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX10-7-7 group, and similarly better in MMF group compared with MTX15-10-10. All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX15-10-10 or Tac plus MMF.