Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy.

The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.

Prognostic impact of complex karyotype on post-transplant outcomes of myelofibrosis.

Chromosomal abnormalities in the role of prognostic factor for transplant patients with myelofibrosis (MF) are not fully investigated. Regarding complex karyotype (CK), we retrospectively analyzed 241 patients with primary and secondary MF who received a first allogeneic hematopoietic cell transplantation (HCT). Based on an unfavorable karyotype in the Dynamic International Prognostic Scoring System, we compared the outcomes in 3 groups: favorable karyotype, unfavorable karyotype including CK (unfavorable-CK(+)), and unfavorable karyotype not including CK (unfavorable-CK(-)). Overall survival was significantly shorter in the unfavorable-CK(+) group (hazard ratio (HR) 2.49, 95% CI: 1.46-4.24, P < 0.001), whereas there was no difference between the unfavorable-CK(-) group and the favorable group (HR 0.57, 95% CI: 0.20-1.59, P = 0.28). In addition, a significantly higher proportion of patients in the unfavorable-CK(+) group did not achieve complete remission after HCT (P = 0.007). The cumulative incidence of disease progression was significantly higher in the unfavorable-CK(+) group (HR 2.5, 95% CI 1.6-3.92, P < 0.001), whereas that in the unfavorable-CK(-) group was comparable to that in the favorable group (HR 0.49, 95% CI 0.12-1.94, P = 0.31). Further investigations will be needed to clarify the impact of CK on transplant outcomes in MF.

HLA 1-3 antigen-mismatched related peripheral blood stem cells transplantation using low-dose antithymocyte globulin versus unrelated cord blood transplantation.

Little information is available regarding whether unrelated cord blood transplantation (CBT) or an HLA 1-3 antigen-mismatched related donor peripheral blood stem-cell transplantation (PBSCT) using low-dose anti-thymocyte globulin (ATG) is superior as an alternative transplantation for patients who lack an HLA-matched sibling or unrelated donor. Therefore, we evaluated 7861 patients with hematologic malignancies (aged 0 to 70 years) who received either a CBT without ATG (CBT-no ATG, n = 7034) or an HLA 1-3 antigen-mismatched related donor PBSCT using low-dose ATG (PBSCT-ATG, n = 827). CBT-no ATG was associated with significantly better overall survival (OS) than the use of a PBSCT-ATG (hazard ratio [HR], 0.77; p < .001), although PBSCT-ATG patients with an HLA 1 antigen-mismatch showed OS comparable to that in the CBT-no ATG group. Neutrophil and platelet engraftment was significantly delayed, whereas the incidences of nonrelapse mortality, and severe graft-versus-host disease (GVHD) were significantly lower in the CBT-no ATG group. The incidences of relapse and chronic GVHD were comparable between these donors. In conclusion, CBT-no ATG may be a better alternative than HLA-mismatched related donor PBSCT using low-dose ATG. Notably, HLA 2-3 antigen mismatch-related transplantation with low-dose ATG had significant adverse effects on transplantation outcomes.

Single cord blood transplantation for acute myeloid leukemia patients aged 60 years or older: a retrospective study in Japan.

The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)-based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil-based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection.

Impact of Homozygous Conserved Extended HLA Haplotype on Single Cord Blood Transplantation: Lessons for Induced Pluripotent Stem Cell Banking and Transplantation in Allogeneic Settings.

Induced pluripotent stem cells (iPSCs) have been applied to clinical regenerative cell therapy. Recently, an iPSC banking system to collect HLA haplotype (HP) homozygous (homo) cells for iPSC transplantation in allogeneic settings was proposed, and tissue transplantation generated from iPSC through banking has just began. We analyzed 5017 single cord blood transplantation (CBT) pairs with HLA-A, -B, -C, -DRB1 allele typing data and found 39 donor HLA homo donor to patient HLA heterozygous (hetero) pairs. Of note, all 39 HLA homo to hetero pairs engrafted neutrophils, except 1 early death pair, and all 30 assessable pairs engrafted platelets. Acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV occurred in 17 and 3 of 38 assessable pairs, respectively. Competing risk regression analysis revealed a favorable risk of neutrophil engraftment and higher risk of acute GVHD compared with HLA-matched CBTs. Thirty-seven of 39 homo to hetero pairs had conserved extended HLA HPs (HP-1, n = 18; HP-2, n = 8; HP-3, n = 7; HP-4, n = 4; HP-5, n = 1) that were ethnicity-specific, and at least 1 of 2 patient HLA-A, -B, -C, and -DRB1 alleles in each locus were invariably shared with the same donor HP in 35 pairs. These findings confirmed our preliminary results with 6 HLA homo CBTs, and a trend of high incidence of acute GVHD was newly observed. Importantly, they imply the possibility that HLA-homo iPSC transplantation provides favorable engraftment and accordingly imply the merit of banking iPSC with homozygous major conserved extended HLA HPs.

Low incidence of posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation in patients with lymphoma treated with rituximab.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma is unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = .98). Year of HSCT after 2010 (hazard ratio [HR] = 5.6, 95% confidence interval [CI], 1.48-21.3), antithymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = .10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients.

Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT.

[Toxoplasmosis-associated central nervous system vasculitis accompanied by multiple cerebral hemorrhages developing subsequent to cord blood transplantation].

A 57-year-old man with high-risk myelodysplastic syndrome underwent umbilical cord blood transplantation. He began receiving steroids on day 14 for acute graft-versus-host disease, and experienced dizziness on day 75 during gradual dose reduction. Multiple hemorrhages were observed in the cerebrum, cerebellum, and brainstem. His bleeding increased, and he underwent a brain biopsy on day 91. Subsequently, he was diagnosed with central nervous system vasculitis (CNSV) on the basis of the observed aggregation of mature CD3+ lymphocytes around small vessels and vascular wall invasion by lymphocytes and macrophages. After receiving high-dose steroid therapy, cerebral hemorrhage stopped; however, dysphasia occurred on day 113 and the patient died of cerebral edema on day 128. Toxoplasma DNA and tachyzoites were detected in the brain biopsy specimen during additional examinations; therefore, we suspected that the toxoplasmosis was related to the onset of CNSV. CNSV is a rare, rapidly progressing disease that may present as a fatal post-transplantation central nervous system complication. Investigating the causes of CNSV, including CNSV associated with toxoplasmosis, is critically important for improving the prognosis of patients with CNSV.

Cord blood transplantation for adult mature lymphoid neoplasms in Europe and Japan.

ABSTRACT: To clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (≥50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high-very high: 49% vs 14%) were included in the Japanese registry. High-very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)-containing conditioning contributed to superior OS both in Europe (vs TBI-reduced-intensity conditioning [RIC], non-TBI-RIC: HR, 1.93; P < .001; non-TBI-Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non-TBI-RIC: HR, 1.71; P < .001; non-TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (≥2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.

Incidence, Etiology, Risk Factors, and Outcomes of Bloodstream Infection after a Second Hematopoietic Stem Cell Transplantation.

Objective Infections after a second hematopoietic stem cell transplantation (HSCT) occur commonly and are associated with high mortality. However, studies on bloodstream infection (BSI) after a second HSCT are lacking. We therefore evaluated the details of BSI after a second HSCT. Methods We retrospectively evaluated the incidence, etiology, risk factors, and outcomes of BSI after a second HSCT. Patients Fifty-two adult patients with hematological malignancies who underwent allogeneic HSCT, including cord blood transplantation (CBT; n=33), as the second transplantation were enrolled. The second transplantation was limited to allogeneic HSCT. Patients who underwent HSCT for graft failure were excluded. Results The median HSCT interval was 438 (range: 39-3,893) days. Overall, 31 (59.6%) patients received autologous HSCT as the first HSCT. The cumulative incidence of BSI was 40.4% at 100 days after the second HSCT, with Gram-positive bacteria accounting for the majority (30.8%) of pathogens. Overall, 92.0% of BSIs occurred during the pre-engraftment period, and Enterococcus faecium accounted for 29.6% of pathogens. On a multivariate analysis, CBT was most closely associated with pre-engraftment BSI after the second HSCT (hazard ratio: 3.43, 95% confidence interval: 1.05-11.23, p=0.042). The 1-year survival rate after the second HSCT was lower in patients with BSI than in patients without BSI (p=0.10). Conclusion BSI is common after a second HSCT, especially with CBT. During the pre-engraftment period, BSI caused by pathogens such as E. faecium should be anticipated and appropriately treated to improve transplant outcomes.

Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation.

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n = 4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6 × 107/kg and .8 × 105/kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection.

Ideal Body Weight Is Useful For Predicting Neutrophil Engraftment and Platelet Recovery for Overweight and Obese Recipients in Single-Unit Cord Blood Transplantation.

Because cord blood (CB) units are usually selected based on the cell dose per kilogram, overweight (body mass index [BMI] ≥25 kg/m2to < 30 kg/m2) and obese (30 kg/m2 ≤ BMI) recipients tend to have difficulty in getting appropriate CB units. In general, actual body weight (ABW) is used for CB unit selection. However, ideal body weight (IBW) has been reported to be more closely correlated with successful engraftment after autologous, allogeneic bone marrow, and peripheral blood stem cell transplantation than ABW. We conducted this analysis to clarify the threshold of CD34+ cell doses based on ideal body weight (CD34IBW) and to compare the outcomes among the groups stratified by the threshold according to actual body weight (CD34ABW) and CD34IBW for overweight and obese recipients in cord blood transplantation (CBT). We retrospectively analyzed 650 overweight and obese recipients who received single-unit CBT. To focus on the recipients who received a low CD34+ cell dose/kg, those who received 1.5×105 CD34+ cells/ABW or more were excluded. Using a cut-off of 0.8×105 CD34+ cells/kg, we compared the outcomes in 3 groups with low CD34ABW and low CD34IBW (CD34Low/Low), low CD34ABW but high CD34IBW (CD34Low/High), and high CD34ABW and high CD34IBW (CD34High/High). Hematopoietic recoveries were significantly delayed in the CD34Low/Low group compared with those in the CD34Low/High group (hazard ratio [HR] 0.67 for neutrophil, P < .001; HR 0.72 for platelet, P = .014), whereas those were comparable in the CD34Low/High and CD34High/High groups (HR 1.22 for neutrophil, P = .16; HR 1.29 for platelet, P = .088). Moreover, the CD34Low/High group demonstrated longer overall survival than the CD34Low/Low group (HR 1.48, P = .011) and comparable survival to the CD34High/High group (HR 0.93, P = .68). This finding may address the lack of availability of CB units for some overweight and obese recipients for whom suitable donors are unavailable. Further investigations are warranted to evaluate the appropriateness of ABW and IBW.

Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia.

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998-2007 vs 2008-2013 vs 2014-2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch.

The impact of the killer immunoglobulin-like receptor (KIR)-ligand mismatch between donor and recipient in hematopoietic stem cell transplantation is controversial. Recently, it has been suggested that their effect on cord blood transplantation (CBT) differs among types of mismatched KIR-ligand and graft-versus-host disease (GVHD) prophylaxis. To investigate their role in acute myeloid leukemia (AML), mismatch of KIR2DL1, KIR3DL1, and KIR3DL2-ligand (HLA-C2, Bw4, and A3/11) were retrospectively assessed in patients undergoing CBT with GVHD prophylaxis comprising a calcineurin inhibitor plus methotrexate (CNI/MTX) or mycophenolate mofetil (CNI/MMF). In patients who received CNI/MTX, a favorable effect of KIR-ligand mismatch on relapse was noted in HLA-C2 mismatched cases (24.8% at 3 years post-CBT [no HLA-C2 mismatch, n = 1602] vs. 15.4% [HLA-C2 mismatch, n = 161], P = 0.0116). In this group, overall survival (OS) was also superior (68.2%, P = 0.0083) compared to the other group (55.0%). Multivariate analysis results supported these findings (hazard ratio [HR] 0.61 for relapse, P = 0.017 and HR 0.72 for OS, P = 0.016). However, the KIR-ligand mismatch effect was not observed in patients with KIR-ligand mismatch types other than HLA-C2 and those using CNI/MMF for GVHD prophylaxis. These results suggest that HLA-C2 mismatch in CBT using CNI/MTX as GVHD prophylaxis may improve the outcomes of patients with AML.

Successful upfront cord blood transplantation for plasma cell leukemia in the first complete response after daratumumab therapy.

Plasma cell leukemia (PCL) is a rare and aggressive disease with a poor prognosis. Autologous or allogeneic stem cell transplantation (ASCT or allo-SCT) with intensive chemotherapy is performed for PCL, but their efficacy is still controversial. The efficacy of novel agents such as daratumumab for PCL is also unclear. Here, we report a case of PCL treated successfully with daratumumab and upfront cord blood transplantation (CBT) in the first complete response (CR). A 58-year-old man was diagnosed with PCL based on elevated abnormal plasma cells and IgD levels. After two cycles of bortezomib, lenalidomide, and dexamethasone therapy, some PCL cells remained in the bone marrow. We switched treatment to daratumumab, lenalidomide, and dexamethasone therapy and confirmed an immunophenotypic CR. We then performed CBT with fludarabine, melphalan, and total body irradiation for conditioning 3 months after diagnosis. Acute graft-versus-host disease was observed but controlled with corticosteroid therapy. The patient remained in stringent CR for 1 year after CBT. We successfully treated PCL with daratumumab followed by upfront CBT. Daratumumab was effective in PCL and could be used safely even before allo-SCT. Early use of daratumumab and early upfront allo-SCT may be a useful treatment option for PCL.

Listeria monocytogenes Bacteremia During Isatuximab Therapy in a Patient with Multiple Myeloma.

An elderly patient with multiple myeloma (MM) was being treated with several regimens and developed a severe drug eruption, necessitating the use of atovaquone instead of trimethoprim-sulfamethoxazole for pneumocystis pneumonia (PCP) prophylaxis. For progressive MM, treatment with isatuximab, an anti-CD38 monoclonal antibody, was started. During the treatment, he developed Listeria monocytogenes bacteremia and recovered quickly with ampicillin administration. CD38 is closely related to the innate immune response against L. monocytogenes, and isatuximab may increase the risk of infection. Therefore, trimethoprim-sulfamethoxazole may be useful in the prevention of not only PCP but also L. monocytogenes infection.

Haploidentical hematopoietic stem cell transplantation with one-day posttransplant cyclophosphamide and anti-thymocyte globulin for graft failure.

Patients with myelofibrosis usually have poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy, which has graft failure as a life-threatening complication. However, no consensus is available with regard to therapeutic options for patients with graft failure. Here we report a patient with myelofibrosis who underwent successful salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with one-day posttransplant cyclophosphamide (PTCy) and low-dose anti-thymocyte globulin (ATG) for graft failure. A 39-year-old Japanese male patient with rapidly progressing primary myelofibrosis underwent cord blood transplantation (CBT). Unfortunately, both the first and second CBT resulted in primary graft failures. Therefore, emergent haplo-HSCT from a sibling donor was performed with one-day PTCy (50 mg/kg on day ＋3) after conditioning with etoposide (60 mg/m2 on days -3 and -2) and rabbit anti-human thymocyte globulin (1 mg/kg on days -2 and -1). Neutrophil engraftment was achieved on day ＋13 after haplo-HSCT, and no severe infection or regimen-related toxicity was observed. Skin stage 3, gut stage 1 total grade II acute graft-versus-host disease developed. His posttransplant course had been uneventful with cutaneous chronic graft-versus-host disease (NIH score 2) and suppressed relapse. We believe that haplo-HSCT with one-day PTCy and low-dose ATG is one of the successful therapeutic options for graft failure.

Late mortality and causes of death among long-term survivors after autologous hematopoietic stem cell transplantation.

By evaluating risks of late mortality and causes of death among long-term survivors after autologous hematopoietic stem cell transplantation (HSCT) in Japan, we clarified what we should focus on during follow-up to reduce them. The study cohort included 6,780 patients who had survived for ≥2 years after the first autologous HSCT performed from 1974 to 2012 for hematological diseases. With a median follow-up of 6.0 years among survivors, overall survival probabilities at 5 and 10 years after HSCT were 92% and 83%, respectively. Eight hundred thirty deaths occurred: 451, recurrent primary diseases; 87, subsequent solid cancers; 57, subsequent hematological malignancies; 55, infections; 41, respiratory diseases; 19, cardiovascular diseases; 15, liver diseases; 10, neurological diseases; and 7, kidney/genitourinary diseases (Except small numbers of other causes and missing). According to the log-rank test, the risk of overall mortality was remarkably increased among HSCT recipients compared with the that in the general Japanese population (observed/expected ratio [O/E]=5.4; 95% confidence interval [CI], 5.0-5.8). The risks of cause-specific mortality increased with infection (O/E=6.8; 95% CI, 5.1-8.8), subsequent solid cancers (O/E=1.4; 95% CI, 1.1-1.7), subsequent hematological malignancies (O/E=14.3; 95% CI, 10.8-18.5), kidney/genitourinary diseases (O/E=3.4; 95% CI, 1.4-7.1), respiratory disease (O/E=9.0; 95% CI, 6.5-1.2), and liver diseases (O/E=2.6; 95% CI, 1.4-4.2). Long-term survivors after autologous HSCT are at an increased risk of death due to secondary cancers, infections, and any organ diseases as well as recurrence compared to the general population. When monitoring these patients in the outpatient clinic, it is important for physicians to predict a change in the patient's condition and to start treatment earlier.

Conditioning regimen with a 75% dose of standard busulfan/cyclophosphamide plus fludarabine before cord blood transplantation in older patients with AML and MDS.

In this retrospective study, we aimed to establish a conditioning regimen for older patients receiving cord blood transplantation (CBT). This study included 21 older patients [median age 65 (58-73) years] with acute myeloid leukemia and myelodysplastic syndrome who underwent single CBT following a conditioning regimen comprising fludarabine (FLU) 125-175 mg/m2, busulfan (BU) 9.6 mg/kg, and cyclophosphamide (CY) 90 mg/kg. Twelve patients (57.1%) were considered high or very high risk according to the disease risk index. Nineteen achieved neutrophil engraftment at a median of 19 days (range 14-29 days) after CBT (cumulative incidence 90.5%). During a median observation period of 24.3 months, the overall survival (OS) rates at 100 days and 2 years were 76.2% and 47.6%, respectively, with cumulative 2-year relapse and non-relapse mortality (NRM) rates of 19.0% and 38.1%, respectively. Infectious disease was the leading cause of NRM (n = 5) and occurred within 100 day post-transplantation in two patients. This suggested that the administration of a reduced BU/CY plus FLU regimen to older patients receiving CBT enables an early recovery with high neutrophil engraftment, relapse suppression, and acceptable NRM rates.