Publications by authors named "Yoshiko Atsuta"

355 Publications

Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan.

Pediatr Transplant 2021 Oct 18:e14125. Epub 2021 Oct 18.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms.

Methods: We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10).

Results: The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173).

Conclusions: Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.
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http://dx.doi.org/10.1111/petr.14125DOI Listing
October 2021

Autologous hematopoietic cell transplantation during second or subsequent complete remission of acute promyelocytic leukemia: a prognostic factor analysis.

Bone Marrow Transplant 2021 Oct 13. Epub 2021 Oct 13.

The Jikei University School of Medicine, Tokyo, Japan.

Autologous hematopoietic cell transplantation (HCT) is an effective therapy for patients with relapsed acute promyelocytic leukemia (APL). However, it remains unclear whether this procedure is equally effective for certain groups of patients. To address this question, we analyzed 296 patients with APL who had undergone autologous HCT during second or subsequent complete remission (CR2+) between 2006 and 2019. Among them, 24 patients were ≥65 years old, and 17 underwent autologous HCT during third or subsequent CR. Of the 286 patients whose measurable residual disease (MRD) data were available, 21 showed detectable MRD. The 5-year probabilities of relapse-free survival (RFS), overall survival, relapse, and nonrelapse mortality for the entire cohort were 85%, 88%, 9%, and 6%, respectively. The multivariate analysis revealed that the duration of first CR ( < or ≥2 years) was the sole factor associated with RFS (P = 0.002), but even those with CR1 duration <2 years showed a 5-year RFS of 76%. The other factors such as age, disease status, and MRD status were not predictive for the survival outcomes. Our findings demonstrate very favorable long-term results when autologous HCT is conducted during CR2 + across the various subgroups of patients with relapsed APL.
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http://dx.doi.org/10.1038/s41409-021-01501-9DOI Listing
October 2021

Peri-transplant glucocorticoids redistribute donor T-cells to the bone marrow and prevent relapse after haploidentical SCT.

JCI Insight 2021 Oct 12. Epub 2021 Oct 12.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America.

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency. This results in significant reductions in GVHD whilst promoting potent GVL effects (relapse in recipients receiving glucocorticoids, vehicle or PT-Cy was 12%, 56% and 100% respectively). Intriguingly, patients with acute myeloid leukemia not in remission that received unmanipulated haplo-SCT and peri-transplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%: 95% CI, 18%-47%) with high overall survival at 3 years (58%: 95% CI, 38-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.
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http://dx.doi.org/10.1172/jci.insight.153551DOI Listing
October 2021

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

Bone Marrow Transplant 2021 Oct 11. Epub 2021 Oct 11.

Eurocord, Hospital Saint Louis, AP-HP, IUH University Paris VII, Paris, France.

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.
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http://dx.doi.org/10.1038/s41409-021-01479-4DOI Listing
October 2021

Outcomes of third allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute leukemia after a second transplantation.

Bone Marrow Transplant 2021 Oct 8. Epub 2021 Oct 8.

Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.

Relapsed acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with poor prognosis. In a subset of patients, durable remissions can be achieved with a second allo-HSCT (allo-HSCT2). However, many patients experience relapse after allo-HSCT2 and they may be considered for a third allo-HSCT (allo-HSCT3). Nevertheless, the benefit of allo-HSCT3 remains unconfirmed. Thus, herein a retrospective analysis of 253 allo-HSCT3s in patients with relapsed/refractory acute leukemia was carried out. In total, 29 (11.5%) survived at a median follow-up of 794 days (range: 87-4 619). The 3-year leukemia-free survival and overall survival (OS) rates were 9.7% and 10.9%, respectively. Patients who maintained remission for ≥2 years after allo-HSCT2 had a significantly better 3-year OS (35.8%) than those who experienced early relapse (<1 year, 7.8%; 1-2 years, 14.0%; P = 0.004). Complete remission at allo-HSCT3, performance status score of 0-1 at allo-HSCT3, grade I acute graft-versus-host disease after allo-HSCT2, and relapse ≥2 years after allo-HSCT2 were associated with better survival in patients who received allo-HSCT3. The prognosis after allo-HSCT3 in patients with relapsed/refractory acute leukemia is generally unfavorable. However, given the lack of alternative treatment options, allo-HSCT3 may be considered in a group of patients.
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http://dx.doi.org/10.1038/s41409-021-01485-6DOI Listing
October 2021

Impact of chronic GVHD on QOL assessed by visual analogue scale in pediatric HSCT survivors and differences between raters: a cross-sectional observational study in Japan.

Int J Hematol 2021 Oct 3. Epub 2021 Oct 3.

Division of Hematology, Department of Medicine, Keio University, Tokyo, Japan.

A nationwide cross-sectional survey was conducted in long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT) in childhood to investigate the effect of chronic graft-versus-host disease (cGVHD) on quality of life (QOL) and differences in QOL assessments between raters. QOL was evaluated by a visual analogue scale (VAS). Assessments were compared between the survivor, guardian, and attending pediatrician for those aged 15 years or younger, and between the survivor and attending pediatrician for those aged 16 years or older. For cGVHD, severity scores were obtained by organ and their association with the VAS score was analyzed. The average pediatrician-rated VAS score was higher than that of other raters for both patient age groups (< 15 years and > 16 years). By organ, involvement of the skin, digestive organs, and joints in GVHD affected the VAS scores. A high joint score was associated with a low VAS score, and conversely, a high lung score was associated with a low pediatrician-rated VAS score. Our results indicate that differences between raters must be considered when evaluating QOL of HSCT survivors, because patients appeared to experience grater inconvenience and difficulties due to joint GVHD than their pediatricians perceived.
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http://dx.doi.org/10.1007/s12185-021-03227-2DOI Listing
October 2021

Altered effect of killer immunoglobulin-like receptor-ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation.

Bone Marrow Transplant 2021 Sep 24. Epub 2021 Sep 24.

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.
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http://dx.doi.org/10.1038/s41409-021-01469-6DOI Listing
September 2021

Syngeneic hematopoietic stem cell transplantation for acute myeloid leukemia: a propensity score-matched analysis.

Blood Cancer J 2021 Sep 24;11(9):159. Epub 2021 Sep 24.

Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.
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http://dx.doi.org/10.1038/s41408-021-00553-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463668PMC
September 2021

Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation.

Ann Hematol 2021 Sep 21. Epub 2021 Sep 21.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34 cell doses in a UCB unit at cryopreservation were 2.5 × 10/kg and 0.7 × 10/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34 cell dose in an UCB unit (≥ 0.7 × 10/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.
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http://dx.doi.org/10.1007/s00277-021-04664-zDOI Listing
September 2021

Dasatinib-based Two-step Induction for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood Adv 2021 Sep 13. Epub 2021 Sep 13.

Kanazawa University, Kanazawa, Japan.

The standard treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, approximately 40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities and relapse before HSCT, and older age. We evaluated dasatinib-based two-step induction with the primary endpoint of 3-year event-free survival (EFS) in this study. The first induction (IND1) was dasatinib plus prednisolone to achieve CR and the second (IND2) was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD)-negativity. Patients who achieved CR and had an appropriate donor were recommended to undergo HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate. Prophylactic dasatinib after HSCT was assigned to patients with positive pre-transplant MRD. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD-negativity after IND2. Non-relapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight (74.4%) patients underwent HSCT in CR1 and 44 (75.9%) were negative with pre-transplant MRD. At a median follow-up of 4.0 years, the 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based two-step induction was demonstrated to improve the 3-year EFS. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
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http://dx.doi.org/10.1182/bloodadvances.2021004607DOI Listing
September 2021

Prognostic value of the revised International Prognostic Scoring System five-group cytogenetic abnormality classification for the outcome prediction of hematopoietic stem cell transplantation in pediatric myelodysplastic syndrome.

Bone Marrow Transplant 2021 Sep 10. Epub 2021 Sep 10.

Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.
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http://dx.doi.org/10.1038/s41409-021-01446-zDOI Listing
September 2021

Graft-Versus-Host Disease Prophylaxis Using Low-Dose Antithymocyte Globulin in Peripheral Blood Stem Cell Transplantation-A Matched-Pair Analysis.

Transplant Cell Ther 2021 Sep 6. Epub 2021 Sep 6.

Department of Hematology, Hokkaido University Hospital, Sapporo, Japan; Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan. Electronic address:

Antithymocyte globulin (ATG) decreases chronic graft-versus-host disease (cGVHD) in peripheral blood stem cell transplantation (PBSCT); however, the optimal ATG dose has not been elucidated. We conducted a matched-pair analysis to evaluate whether low-dose ATG could inhibit cGVHD in HLA-matched PBSCT after myeloablative conditioning. A total of 70 patients who were enrolled in the JSCT-ATG15 study, a multicenter phase II clinical trial of 2 mg/kg of ATG (thymoglobulin) given on days -2 and -1, were compared with 210 patients not receiving ATG, who were matched for age, sex, disease, and calcineurin inhibitor selected from the database in Japan. The primary endpoint, cumulative incidence of extensive cGVHD at 2 years was significantly less in the ATG group than that in the non-ATG group (8.7% [95% CI, 3.5%-16.8%] versus 26.2% [95% CI, 20.3%-32.5%], P = .002). ATG significantly reduced the incidence of overall cGVHD and inhibited multiple organ involvement. The ATG group had favorable outcome compared to the non-ATG group in GVHD-free, and relapse-free survival at 2 years. In conclusion, low-dose ATG effectively inhibits chronic GVHD in PBSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.08.029DOI Listing
September 2021

Allogeneic Hematopoietic Cell Transplantation from Alternative Donors in Acute Myelogenous Leukemia: A Comparative Analysis.

Transplant Cell Ther 2021 Sep 6. Epub 2021 Sep 6.

The Jikei University School of Medicine, Tokyo, Japan.

In the absence of HLA-matched related and unrelated donors, alternative donors must be found for patients in need of allogeneic hematopoietic cell transplantation (HCT). There are at least 3 donor options: a mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and a haploidentical related donor (haplo); however, the optimal alternative donor type remains to be established. This study aimed to address how the outcomes of patients receiving these 3 alternative donor HCTs differ, and whether these outcomes change over time post-transplantation. We retrospectively analyzed Japanese nationwide transplantation registry data of adults with acute myelogenous leukemia (AML) undergoing allogeneic HCT while in first complete remission (CR) from an MMUD with a 7/8 match at the allele level (n = 601), with UCB (n = 1110), or from a haploidentical related donor (n = 221) between 2007 and 2018. For patients who underwent transplantation between 2007 and 2014, the 3-year overall survival (OS) for the MMUD, UCB, and Haplo groups was 60%, 54%, and 47%, respectively (P = .022). For those who underwent transplantation between 2015 and 2018, the 3-year OS in these groups was 60%, 66%, and 63%, respectively (P = .693). Multivariate analysis revealed that the risks of both overall mortality and nonrelapse mortality (NRM) were significantly lower in the later period than in the earlier period in the UCB group (hazard ratio [HR], 0.66 [P < .001] for OS; HR, 0.64 [P < .001] for NRM) and the Haplo group (HR, 0.58 [P = .019 for OS; HR, 0.39 [P = .004] for NRM), but not in the MMUD group (HR, 1.07 [P = .631] for OS; HR, 1.26 [P = .175] for NRM). The results of a test for interaction showed a significant difference in the effect of transplantation period on OS and NRM between the MMUD and UCB groups (P = .014 for OS; P = .004 for NRM) and between the MMUD and Haplo groups (P = .034 for OS; P = .003 for NRM). These findings demonstrate the recent improvements in the outcomes of UCB and Haplo transplantations in patients with AML in first CR that have resulted in a similar OS in patients undergoing HCT with grafts from MMUDs, UCB, and haploidentical donors in the later period of the study.
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http://dx.doi.org/10.1016/j.jtct.2021.08.027DOI Listing
September 2021

Cytomegalovirus reactivation is associated with an increased risk of late-onset invasive aspergillosis independently of grade II-IV acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation: JSTCT Transplant Complications Working Group.

Ann Hematol 2021 Sep 7. Epub 2021 Sep 7.

Division of Hematology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma, Omiya-ku, Saitama-city, Saitama, 330-8503, Japan.

There is a matter of debate about the clinical impact of cytomegalovirus (CMV) reactivation on the development of late-onset invasive aspergillosis (IA), which occurs 40 days or later after allogeneic hematopoietic stem cell transplantation (HSCT). Using a Japanese transplant registry database, we analyzed the risk factors for the development of late-onset IA in 21,015 patients who underwent their first allogeneic HSCT between 2006 and 2017. CMV reactivation was defined as the initiation of preemptive anti-CMV antiviral therapy. Overall, there were 582 cases of late-onset IA, which occurred at a median of 95 days after HSCT. The 2-year cumulative incidence was 3.4% (95% confidence interval (CI), 3.0-3.9) in patients with CMV reactivation within 40 days after HSCT and 2.5% (95% CI, 2.3-2.8) in those without it (P < 0.001). In a multivariate analysis, CMV reactivation as a time-dependent covariate was significantly associated with the development of late-onset IA (hazard ratio (HR) 1.40, P < 0.001), as well as grade II-IV acute GVHD, age > 50 and HCT-CI ≥ 3 in the entire cohort. If we focus on the subgroup without grade II-IV acute GVHD, which is generally an indication for systemic corticosteroid therapy (n = 12,622), CMV reactivation was still a significant factor for the development of late-onset IA (HR 1.37, P = 0.045) as well as age > 50 years, HCT-CI ≥ 3, and cord blood transplantation. In conclusion, CMV reactivation was associated with an increased risk of late-onset IA after allogeneic HSCT independently of acute GVHD. Close monitoring for late-onset IA is necessary for patients who develop CMV reactivation even without grade II-IV acute GVHD.
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http://dx.doi.org/10.1007/s00277-021-04660-3DOI Listing
September 2021

Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis.

Bone Marrow Transplant 2021 Sep 7. Epub 2021 Sep 7.

Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.

Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid leukemia. However, the effectiveness of Flu/Bu4 for myelodysplastic syndrome (MDS) remains poorly understood. Therefore, we retrospectively analyzed nationwide registry data in Japan from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu4 and busulfan/cyclophosphamide (Bu4/Cy) using propensity score (PS) matching. The primary endpoint was overall survival (OS). Among 2,482 MDS patients, 153 patients were assigned each to the Flu/Bu4 and Bu4/Cy groups. The 3-year OS rates were 52.7% (95% confidence interval [CI], 43.8-60.8%) and 49.5% (95% CI, 40.8-57.6%) in the Flu/Bu4 and Bu4/Cy group, respectively (P = 0.548). The 3-year progression-free survival (P = 0.858), the cumulative incidence of relapse (P = 0.536), and cumulative incidence of non-relapse mortality (P = 0.684) were not significantly different between the two groups. According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens. In conclusion, although our PS-matched cohort mainly comprised older patients who had a low hematopoietic cell transplantation-comorbidity index and low-risk disease status, Flu/Bu4 could be an alternative to Bu4/Cy for MDS patients prior to allo-HSCT.
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http://dx.doi.org/10.1038/s41409-021-01447-yDOI Listing
September 2021

Impact of HLA disparity on the risk of overall mortality in patients with grade II-IV acute GVHD on behalf of the HLA Working Group of Japan Society for Hematopoietic Cell Transplantation.

Bone Marrow Transplant 2021 Sep 3. Epub 2021 Sep 3.

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Stem cell source or HLA disparity may exert a significant impact on the overall survival (OS) after the development of aGVHD. In order to clarify this point, we performed a retrospective analysis using a database of the Japan Society for HCT. We analyzed the clinical outcomes of 10,035 patients who developed grade II-IV aGVHD. The median age of the patients was 48 years. The probability of 2-year OS after the onset of grade II-IV aGVHD in the study cohort was 54.1%. The multivariate analysis showed that the HLA ≥2-loci mismatched related donor and HLA 1-locus mismatched unrelated donor were significantly associated with an inferior OS after grade II-IV aGVHD. In a subgroup analysis, peripheral blood stem cells and HLA disparity were associated with an inferior OS in patients who received related or unrelated HCT. Thus, the clinical outcome after grade II-IV aGVHD significantly varied as per the combination of the presence of HLA disparity and stem cell source. Further research using other databases is necessary to confirm our findings.
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http://dx.doi.org/10.1038/s41409-021-01443-2DOI Listing
September 2021

The differential effect of disease status at allogeneic hematopoietic cell transplantation on outcomes in acute myeloid and lymphoblastic leukemia.

Ann Hematol 2021 Sep 3. Epub 2021 Sep 3.

The Jikei University School of Medicine, Tokyo, Japan.

This study aimed to compare the effect of disease status at the time of allogeneic hematopoietic cell transplantation (HCT) on post-transplant outcomes between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Japanese nationwide registry data for 6901 patients with AML and 2469 patients with ALL were analyzed. In this study, 2850 (41%), 937 (14%), 62 (1%), and 3052 (44%) AML patients and 1751 (71%), 265 (11%), 23 (1%), and 430 (17%) ALL patients underwent transplantation in first complete remission (CR1), second CR (CR2), third or subsequent CR (CR3 +), and non-CR, respectively. The probabilities of overall survival at 5 years for patients transplanted in CR1, CR2, CR3 + , and non-CR were 58%, 61%, 41%, and 26% for AML patients and 67%, 45%, 20%, and 21% for ALL patients, respectively. Multivariate analyses revealed that the risks of relapse and overall mortality were similar for AML patients transplanted in CR1 and CR2 (P = 0.672 and P = 0.703), whereas they were higher for ALL patients transplanted in CR2 than for those transplanted in CR1 (P < 0.001 for both). The risks of relapse and overall mortality for those transplanted in CR3 + and non-CR increased in a stepwise manner for both diseases, with the relevance being stronger for ALL than for AML patients. These results suggest a significant difference in the effect of disease status at HCT on post-transplant outcomes in AML and ALL. Further investigation to incorporate measurable residual disease data is warranted.
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http://dx.doi.org/10.1007/s00277-021-04661-2DOI Listing
September 2021

Impact of conditioning intensity and regimen on transplant outcomes in patients with adult T-cell leukemia-lymphoma.

Bone Marrow Transplant 2021 Aug 31. Epub 2021 Aug 31.

Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

In allogeneic hematopoietic cell transplantation (allo-HCT) for adult T-cell leukemia-lymphoma (ATL), the optimal conditioning regimens have not yet been determined. We conducted a Japanese nationwide, retrospective study to investigate this issue. This study included 914 ATL patients who underwent allo-HCT between 1995 and 2015. In patients aged 55 years or younger, there was no statistically significant difference between reduced-intensity conditioning (RIC) regimens and myeloablative conditioning (MAC) regimens regarding risk of relapse (vs. RIC group: MAC group, hazard ratio (HR) 0.76, P = 0.071), non-relapse mortality (vs. RIC group: MAC group, HR 1.38, P = 0.115), or overall mortality (vs. RIC group: MAC group, HR 1.17, P = 0.255). Among RIC regimens, fludarabine plus melphalan-based (Flu/Mel) regimens were associated with a lower risk of relapse (Flu/Mel140 group, HR 0.59, P < 0.001; Flu/Mel80 group, HR 0.79, P = 0.021) than the Flu plus busulfan-based regimen (Flu/Bu2 group). Meanwhile, Flu/Mel140 group had a significantly higher risk of non-relapse mortality (vs. Flu/Bu2 group: HR 1.53, P = 0.025). In conclusion, it is acceptable to select a RIC regimen for younger patients. Moreover, it might be beneficial to select a Flu/Mel-based regimen for patients at high risk of relapse.
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http://dx.doi.org/10.1038/s41409-021-01445-0DOI Listing
August 2021

Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency Patients: a Japanese Retrospective Study.

J Clin Immunol 2021 Aug 27. Epub 2021 Aug 27.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan.

Methods: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).

Results: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01).

Conclusion: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.
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http://dx.doi.org/10.1007/s10875-021-01112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390179PMC
August 2021

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors.

Haematologica 2021 Aug 12. Epub 2021 Aug 12.

CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN; University of Minnesota, MMC 480, Minneapolis, MN 55455.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCTs were reported from 1662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCTs had been performed by 2019 from 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCTs were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCTs are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated is plateauing and cord blood in decline.
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http://dx.doi.org/10.3324/haematol.279189DOI Listing
August 2021

Difference in outcomes following allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia and myelodysplastic syndromes.

Leuk Lymphoma 2021 Aug 4:1-9. Epub 2021 Aug 4.

The Jikei University School of Medicine, Tokyo, Japan.

To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) ( = 3318), AML evolving from myelodysplastic syndromes (MDS) ( = 208), and MDS with excess blasts (MDS-EB) ( = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% ( < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM ( = 0.030) and MDS-EB with a higher risk of relapse ( < 0.001), both leading to lower OS ( = 0.010 and  < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB.
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http://dx.doi.org/10.1080/10428194.2021.1961242DOI Listing
August 2021

Newly proposed threshold and validation of white blood cell count at diagnosis for Philadelphia chromosome-positive acute lymphoblastic leukemia: risk assessment of relapse in patients with negative minimal residual disease at transplantation-a report from the Adult Acute Lymphoblastic Leukemia Working Group of the JSTCT.

Bone Marrow Transplant 2021 Jul 30. Epub 2021 Jul 30.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

White blood cell count (WBC) at diagnosis is the conventional prognostic factor in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Nevertheless, little is known about the impact of WBC at diagnosis considering the minimal residual disease (MRD) status at allogeneic hematopoietic cell transplantation (HCT). We evaluated adult patients with Ph ALL who achieved negative-MRD and received HCT in first complete remission between 2006 and 2018. The entire cohort was temporally divided into derivation (n = 258) and validation cohorts (n  =  366). Using a threshold of 15,000/μL, which was determined by a receiver operating characteristic curve analysis in the derivation cohort, high WBC was associated with an increased risk of hematological relapse in both the derivation cohort (25.3% vs. 11.6% at 7 years, P = 0.004) and the validation cohort (16.2% vs. 8.5% at 3 years, P = 0.025). In multivariate analyses, high WBC was a strong predictor of hematological relapse in the derivation cohort (HR, 2.52, 95%CI 1.32-4.80, P = 0.005) and in the validation cohort (HR, 2.32, 95%CI, 1.18-4.55; P = 0.015). In conclusion, WBC at diagnosis with a new threshold of 15,000/μL should contribute to better risk stratification in patients with negative-MRD at HCT.
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http://dx.doi.org/10.1038/s41409-021-01422-7DOI Listing
July 2021

Optimal treatment for Philadelphia-negative acute lymphoblastic leukemia in first remission in the era of high-intensity chemotherapy.

Int J Hematol 2021 Nov 30;114(5):608-619. Epub 2021 Jul 30.

Department of Healthcare Administration, Nagoya University, Nagoya, Japan.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16-24 years and 25-65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.
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http://dx.doi.org/10.1007/s12185-021-03198-4DOI Listing
November 2021

Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission.

Bone Marrow Transplant 2021 Jul 16. Epub 2021 Jul 16.

Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P < 0.001), treatment failure (HR, 0.66; P = 0.004), and overall mortality (HR, 0.72; P = 0.037) among patients with t(8;21). However, pretransplant MRD negativity was not associated with relapse (HR, 0.73; P = 0.420), treatment failure (HR, 0.64; P = 0.063), or overall mortality (HR, 0.69; P = 0.149) among patients with inv(16). In subgroup analysis, pretransplant MRD status significantly affected relapse and LFS only in patients with t(8;21) undergoing allogeneic HCT during CR2. In conclusion, our data demonstrate the different prognostic values of pretransplant MRD for CBF-AML, highlighting the need to develop effective therapeutic strategies for such MRD-positive patients.
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http://dx.doi.org/10.1038/s41409-021-01409-4DOI Listing
July 2021

Cord blood index predicts engraftment and early non-relapse mortality in adult patients with single-unit cord blood transplantation.

Bone Marrow Transplant 2021 Jul 15. Epub 2021 Jul 15.

Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.

How to select optimal cord blood (CB) remains an important clinical question. We developed and validated an index of CB engraftment, the cord blood index (CBI), which uses three weighted variables representing cell doses and HLA mismatches. We modeled the neutrophil engraftment time with competing events by random survival forests for competing risks as a function of the predictors: total nucleated cells, CD34, colony-forming units for granulocytes/macrophages, and the number of HLA mismatches at the antigen and allele levels. The CBI defined three groups that had different neutrophil engraftment rates at day 30 (High, 83.7% [95% CI, 79.2-88.1%]; Intermediate, 77.0% [95% CI, 73.7-80.2%]; Low, 68.4% [95% CI, 63.6-73.2%]), platelet engraftment rates at day 60 (High, 70.4% [95% CI, 64.9-75.9%]; Intermediate, 62.3% [95% CI, 58.5-66.0%]; Low, 49.3% [95% CI, 44.2-54.5%]), and non-relapse mortality at day 100 (High, 14.1% [95% CI, 9.9-18.3%]; Intermediate, 16.4% [95% CI, 13.5-19.3%]; Low, 21.3% [95% CI, 17.1-25.5%]). This novel approach is clinically beneficial and can be adopted immediately because it uses easily obtained pre-freeze data of CB.
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http://dx.doi.org/10.1038/s41409-021-01406-7DOI Listing
July 2021

NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.

Nat Commun 2021 07 7;12(1):4181. Epub 2021 Jul 7.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.
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http://dx.doi.org/10.1038/s41467-021-24509-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263746PMC
July 2021

Residual disease is a strong prognostic marker in patients with acute lymphoblastic leukaemia with chemotherapy-refractory or relapsed disease prior to allogeneic stem cell transplantation.

Br J Haematol 2021 Jul 22;194(2):403-413. Epub 2021 Jun 22.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is one of the curative treatment options for acute lymphoblastic leukaemia (ALL). However, the outcomes in patients transplanted without complete remission (non-CR) have not yet been fully reported, and detailed analyses are required to identify subgroups in which optimal prognosis is expected and to optimize pre-transplant therapeutic strategies. Hence, we performed a multicentred retrospective cohort study including a total of 663 adult ALL patients transplanted at non-CR status; the median bone marrow (BM) blast counts at HSCT was 13·2%, and 203 patients (30·6%) were treated at primary induction failure status. The overall survival (OS) was 31·1% at two years, and the multivariate analyses identified five prognostic risk factors, including older age (≥50 years), increased BM blasts (≥10%), poor performance status, high haematopoietic cell transplantation (HCT)-comorbidity index, and relapsed disease status, among which BM blast was the most significantly related. A predictive scoring system composed of these risk factors clearly stratified OS (15·6-59·5% at two years). In conclusion, this is the first large-scale study to analyze the correlation of patient characteristics with post-transplant prognosis in ALL transplanted at non-CR status. The importance of blast control before HSCT should be focused on for better patient prognosis.
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http://dx.doi.org/10.1111/bjh.17646DOI Listing
July 2021

Differential Effect of Graft-versus-Host Disease on Survival in Acute Leukemia according to Donor Type.

Clin Cancer Res 2021 Sep 22;27(17):4825-4835. Epub 2021 Jun 22.

Division of Hematology, National Defense Medical College, Tokorozawa, Japan.

Purpose: The anti-leukemic activity of allogeneic hematopoietic cell transplantation (HCT) depends on both the intensity of conditioning regimen and the strength of the graft-versus-leukemia (GVL) effect. However, it is unclear whether the sensitivity of the GVL effects differs between donor type and graft source.

Experimental Design: We retrospectively evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on transplant outcomes for adults with acute leukemia ( = 6,548) between 2007 and 2017 using a Japanese database. In all analyses, we separately evaluated three distinct cohorts based on donor type [(8/8 allele-matched sibling donor, 8/8 allele-matched unrelated donor, and unrelated single-cord blood (UCB)].

Results: The multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, showed a reductive effect of grade I-II acute GVHD on treatment failure (defined as 1-leukemia-free survival; < 0.001), overall mortality (OM; < 0.001), relapse ( < 0.001), and non-relapse mortality (NRM; < 0.001) in patients receiving from UCB. A reductive effect of limited chronic GVHD on treatment failure ( < 0.001), OM ( < 0.001), and NRM ( < 0.001) was also shown in patients receiving from UCB. However, these effects were not always shown in patients receiving from other donors. The beneficial effects of mild acute and chronic GVHD after UCB transplantation on treatment failure were noted relatively in subgroups of patients with acute myelogenous leukemia and a non-remission status.

Conclusions: These data suggested that the development of mild GVHD could improve survival after UCB transplantation for acute leukemia.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4856DOI Listing
September 2021

Personalized prediction of overall survival in patients with AML in non-complete remission undergoing allo-HCT.

Cancer Med 2021 07 16;10(13):4250-4268. Epub 2021 Jun 16.

Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT.
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http://dx.doi.org/10.1002/cam4.3920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267144PMC
July 2021
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