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.

The impact of GVHD on outcomes after adult single cord blood transplantation in European and Japanese populations.

The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial. In the Eurocord/ALWP EBMT and JSTCT/JDCHCT collaborative study, we evaluated the impact of GVHD on UCBT outcomes in Japanese and European registries. A total of 3,690 adult patients with acute leukemia who received their first single UCBT were included. A multivariate analysis of overall survival (OS) revealed a positive impact of grade II acute GVHD compared with grade 0-I GVHD, in the Japanese cohort (hazard ratio (HR), 0.81; P = 0.001), and an adverse impact in the European cohort (HR, 1.37; P = 0.007). A negative impact of grade III-IV acute GVHD on OS was observed regardless of registries. In the analysis of relapse, a positive impact of grade II acutes GVHD compared with grade 0-I GVHD was observed only in the Japanese cohort, regardless of disease risk. The positive impact of limited chronic GVHD on OS was observed only in the Japanese cohort. In conclusion, a positive impact of mild GVHD after a single UCBT was observed only in the Japanese cohort. This could explain the ethnic difference in UCBT outcomes and might contribute to the preference usage of UCBT in Japan.

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.

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation.

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.

Impact of event-free survival status after stem cell transplantation on subsequent survival of patients with lymphoma.

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period-matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.

Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008.

Acute lymphoblastic leukemia (ALL) is a common neoplasm in children, but less frequent in adults. Since information on clinical features and genetics of adult ALL in Japan is limited, we analyzed 215 subjects aged 16-65 years with untreated ALL enrolled in the Fukuoka Blood & Marrow Transplant Group studies ALL MRD 2002 and 2008. The prevalence of ALL was bimodal, with the larger group aged 56-65 years. Immunophenotypic characterization showed B-lineage is more frequent than T-lineage ALL (78.6 vs 13.0%), with age-related differences. The proportion with BCR-ABL1 rearrangement increased progressively with age, up to 55.7% among subjects aged over 56-65 years. Rearrangements involving the KMT2A gene, ETV6-RUNX1, and TCF3-PBX1 were rare in this study cohort. The overall incidence of hyperdiploidy was only 1.7%, and there were no cases with hypodiploidy. Overall survival varied by age and cytogenetics. Older subjects and those with BCR-ABL1 tended to have inferior outcomes. In this epidemiological study of Japanese adult ALL, the majority of subjects had B-lineage ALL, the T-cell phenotype was most frequent in those aged 16-25, and BCR-ABL1 rearrangement was very common, with prevalence increasing with age. These types of adult ALL are potentially manageable with targeted therapies.

Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation.

Cytomegalovirus (CMV) reactivation in cord blood transplantation (CBT) may result in the proliferation and maturation of natural killer (NK) cells. Similarly, a mismatch of the killer cell immunoglobulin-like receptor (KIR)-ligand induces NK cell activation. Therefore, if CMV reactivation occurs in the presence of KIR-ligand mismatch, it might improve CBT outcomes. We assessed the difference in the effect of CMV reactivation in the presence of KIR-ligand mismatch on disease relapse in the graft-versus-host direction. A total of 2840 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were analyzed. Among those with a HLA-Bw4/A3/A11 (KIR3DL-ligand) mismatch, CMV reactivation up to 100 days following CBT had a favorable impact on relapse (18.9% vs. 32.9%, P = 0.0149). However, this effect was not observed in cases without the KIR3DL-ligand mismatch or in those with or without a HLA-C1/C2 (KIR2DL-ligand) mismatch. The multivariate analysis suggested that CMV reactivation had a favorable effect on relapse only in cases with a KIR3DL-ligand mismatch (hazard ratio 0.54, P = 0.032). Moreover, the interaction effect between CMV reactivation and KIR3DL-ligand mismatch on relapse was significant (P = 0.039). Thus, our study reveals the association between KIR-ligand mismatches and CMV reactivation, which will enhance CBT outcomes.

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.

A Case of Repeated TAFRO Syndrome-Like Symptoms and Retroperitoneal Hemorrhage in a Patient With Sjögren Syndrome.

A 50-year-old Japanese man complaining of dry mouth and eyes, pale skin with cold irritation, and worsening epigastric pain was admitted to the hospital, whereupon he developed fever and anasarca. A computed tomography (CT) scan showed ascites, hepatosplenomegaly, and mildly enlarged multiple lymph nodes, and blood examination revealed renal impairment, thrombocytopenia, and high levels of C-reactive protein (CRP). He was diagnosed with Sjögren syndrome and concurrently manifested symptoms resembling TAFRO syndrome (i.e., thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)). Although the TAFRO syndrome-like symptoms progressed, he gradually recovered with immunosuppressive agents. Seven years and five months after the admission, the TAFRO syndrome-like symptoms recurred. Bone marrow biopsy specimens revealed reticulin fibrosis. Inguinal and mediastinal lymph nodes biopsy specimens revealed Castleman disease-like features. Although the symptoms indicated TAFRO syndrome, a diagnosis was not possible owing to the presence of hypergammaglobulinemia and Sjögren syndrome, which required exclusion. Corticosteroid treatment was initiated; however, it was complicated by retroperitoneal hemorrhage, probably due to microangiopathy. After additional treatment with tocilizumab and rituximab, the TAFRO syndrome-like symptoms improved and the hemorrhage progression stopped. In conclusion, TAFRO syndrome-like symptoms may recur with vascular complications and can be successfully treated with tocilizumab and rituximab during Sjögren syndrome. The etiology of TAFRO syndrome could potentially involve Sjögren syndrome, and these syndromes may co-exist.

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.

Effects of Haplotype Matching on Outcomes after Adult Single-Cord Blood Transplantation.

It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.

Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation.

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.

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.

[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.

Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

[Generalized erythema triggered by a rapid decrease of basophils in chronic myeloid leukemia treated with imatinib].

A 57-year-old woman with chronic myeloid leukemia showing severe basophilia (WBC 17.1 X 10(9)/L, basophils 23%) was treated with 400mg imatinib in June 2003. A high basophil count (WBC 10.6 X 10(9)/L, basophils 31%) was still observed after 1 week of therapy. After 9 days of therapy, she developed generalized pruritic skin erythema, chills and high fever. After terminating imatinib treatment, prednisolone therapy was initiated. The rash quickly disappeared. Four days after withdrawal of imatinib, leukocyte count was 13.0 X 10(9)/L with 3% of basophils, suggesting the possibility that rapid decrease in basophils following imatinib therapy may induce severe cutaneous reactions.