Associations between acute and chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). While various risk factors for chronic GVHD have been reported, limited data is available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry dataset. The landmark point was set at day 100 after allo-HCT and patients who died or relapsed before the landmark point were excluded. In total, 14618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and umbilical cord blood (UCB) were analyzed. In the BM/PB cohort, the risk of chronic GVHD requiring systemic steroids increased with each increase within grade 0-II acute GVHD (Grade 0 vs. I: HR, 1.32, 95% CI, 1.19-1.46, P < 0.001; Grade I vs. II: HR, 1.41, 95% CI, 1.28-1.56, P < 0.001), but the risk was similar between grade II and III-IV acute GVHD (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk of severe chronic GVHD increased with each increment in the grade of acute GVHD, even between Grades II and III-IV acute GVHD (Grade II vs. III-IV: HR, 1.70; 95% CI, 1.12-2.58; P = 0.025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk of chronic GVHD and its severity, which might be useful for the development of risk-adopted pre-emptive strategies for chronic GVHD.

Real-World Outcomes of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation in Japan: Retrospective Analysis of the Transplant Registry Unified Management Program Registry.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was received related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT.

Trends in allogeneic hematopoietic cell transplantation survival using population-based descriptive epidemiology method: analysis of national transplant registry data.

Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers.

Donor Types and Outcomes of Transplantation in Myelofibrosis: A CIBMTR Study.

We aim to evaluate impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using CIBMTR registry data for HCTs done between 2013 and 2019. In all 1597 undergoing HCT for myelofibrosis, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study eligible, 1032 patients who received peripheral blood grafts for chronic phase myelofibrosis, 38% recipients of haploidentical-HCT were of non-White/Caucasian ethnicity. Matched sibling donor (MSD)-HCTs were independently associated with superior overall survival (OS) in the first 3 months [reference MSD, haploidentical HR 5.80 (95% CI 2.52-13.35), matched unrelated HR 4.50 (95% CI 2.24-9.03), and mismatched unrelated HR 5.13 (95% CI 1.44-18.31), P<0.001]. This difference in OS aligns with lower graft failure with MSD [haploidentical HR 6.11 (95%CI 2.98-12.54), matched unrelated HR 2.33 (95%CI 1.20-4.51), mismatched unrelated HR 1.82 (95%CI 0.58-5.72). There was no significant difference in OS among haploidentical, matched unrelated, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months post-HCT, relapse, disease-free survival or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. While MSDs remain a superior donor option due to improved engraftment, there is no significant difference in HCT outcomes from haploidentical and matched unrelated donors. These results establish haploidentical-HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

An open-label study of belumosudil, a selective ROCK2 inhibitor, as second or subsequent line of therapy for steroid-dependent/steroid-resistant chronic GVHD.

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.

Flow cytometric profiles with CD7 and CADM1 in CD4+ T cells are promising indicators for prognosis of aggressive ATL.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)-infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1-uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1-infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7-) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1-infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.

Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial.

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

ASTCT Committee on Practice Guidelines Survey on Evaluation and Management of Relapsed/Refractory Multiple Myeloma after Failure of Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.

Severity of Chronic Graft-versus-Host Disease and Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Adults with Hematologic Malignancy.

The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects.

[Adenovirus disease after hematopoietic cell transplantation].

Adenovirus disease can cause disseminated disease or lethal organ damage in patients undergoing hematopoietic cell transplantation (HCT). Renourinary infection is the most common in Japan. The 1-year cumulative incidences of adenovirus disease in children and adults were 0.15% and 0.49%, respectively, after autologous HCT, and 1.52% and 2.99%, respectively, after allogeneic HCT. The annual incidence remained above 100 cases. Viremia or disseminated disease after autologous and allogeneic HCT occurs in 6% and 19%, respectively, in patients with adenovirus disease. Age ≥50 years and lymphoma are associated with adenovirus disease after autologous HCT. Patient age ≥50 years, male patients, adult T-cell leukemia/lymphoma, lymphoma, HCT-specific comorbidity index ≥3, HLA-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, grades II-IV acute graft-versus-host disease (GVHD), and extensive chronic GVHD are associated with adenovirus disease after allogeneic HCT. No regulatory authority has approved an antiviral agent for treating adenovirus disease after HCT. More than half of the patients received only supportive care in Japan. The increased risk of mortality following developing adenovirus disease, even with a single-site infection, after both autologous and allogeneic HCT suggests an urgent unmet need for the development of safe and effective drugs.

Improved Long-Term Net Survival after Allogeneic Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies over Two Decades.

Allogeneic (allo-) hematopoietic cell transplantation (HCT) has evolved as a curative therapy for hematologic malignancies and diseases, with practice changes over the past 2 decades. This study aimed to evaluate the change in 5-year net survival (NS) of allo-HCT recipients in a population-based cohort over the past 2 decades, which allows the estimation of a more HCT-specific long-term survival rate by considering background mortality changes. This study included 42,064 patients with hematologic malignancies who underwent their first allo-HCT in Japan between 2000 and 2018 and were reported to the Transplant Registry Unified Management Program. We compared the 5-year NS after allo-HCT in 4 consecutive HCT periods (2000 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2018). The 5-year NS of the latest period was estimated using the period analysis method. Adjusted excess hazard ratios (EHRs) for 5-year NS over the HCT period were analyzed using an EHR model. In addition to the analysis of all hematologic malignancies, adjusted 5-year NS for each major hematologic malignancy, including acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, adult T cell leukemia/lymphoma, chronic myeloid leukemia (CML), and malignant lymphoma, was analyzed. The probability of adjusted 5-year NS after HCT improved significantly over time: 35% in 2000 to 2004, 39% in 2005 to 2008, 45% in 2009 to 2012, and 49% in 2013 to 2018. The adjusted EHRs were .90 (95% confidence interval [CI], .86 to .93) in the 2005 to 2008 period, .77 (95% CI, .74 to .80) in the 2009 to 2012 period, and .65 (95% CI, .63 to .68) in the 2013 to 2018 period, with the 2000 to 2004 period as the reference. The 5-year NS improved among all hematologic malignancies, with a significant improvement in CML and ALL. The changes in 5-year NS from the 2000 to 2004 period to the 2013 to 2018 period ranged from 46% to 66% in CML and from 41% to 59% in ALL. In addition to the large improvement of 1-year NS, smaller but continued improvement in NS between 1 and 5 years after transplantation was observed. NS at 5 years conditional on being alive at 1 year increased from 64% in 2000 to 2004 to 73% in 2013 to 2018. Even after subtracting the background mortality in the general population, we found a significant improvement in long-term allo-HCT-specific survival rates for patients with hematologic malignancies over the past 2 decades in Japan.

Updated Indications for Immune Effector Cell Therapy: 2023 Guidelines from the American Society for Transplantation and Cellular Therapy.

The American Society for Transplantation and Cellular Therapy (ASTCT) published its guidelines on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) and immune effector cell therapy (IECT) in 2020. Since then, we have witnessed rapid advancements in the field of IECT, resulting in several new chimeric antigen receptor T cell (CAR-T) products and disease indications being approved by the US Food and Drug Administration (FDA). To keep abreast of these practice changes, the ASTCT Committee on Practice Guidelines commissioned a focused update covering CAR-T therapy indications. Here we present updated ASTCT recommendations on indications for CAR-T therapy. Only FDA-approved indications for CAR-T were recommended and categorized as "standard of care," where the indication is well defined and supported by evidence. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

EDTA-induced pseudothrombocytopenia in hematopoietic stem cell donor.

We herein report a case of peripheral blood stem cell transplantation (PBSCT) involving a donor with EDTA-induced pseudothrombocytopenia (PTCP). The apheresis product was inspected for 24 h and there was no platelet clumping or thrombocytopenia. In the first 14 months after PBSCT, there has been no transfer of PTCP symptoms.

Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia.

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n = 1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction = .038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

Romidepsin-induced durable remission for relapsed nodal peripheral T-cell lymphoma with T follicular helper phenotype after allogeneic hematopoietic cell transplantation.

Patients with recurrent peripheral T-cell lymphoma (PTCL) after allogeneic hematopoietic cell transplantation (HCT) have dismal outcomes. Nodal PTCL with the T follicular helper phenotype (PTCL-TFH) is uniquely sensitive to histone deacetylase inhibitors compared to non-TFH phenotypes. We report the case of a 19-year-old man who experienced recurrence of PTCL-TFH shortly after allogeneic HCT and subsequently achieved durable remission with romidepsin. Before HCT, the patient had refractory disease after CHOP and ESHAP chemotherapies but achieved a partial response after two cycles of romidepsin as salvage treatment. HLA-haploidentical peripheral blood stem cell transplantation was performed using conditioning with fludarabine 180 mg/sqm, melphalan 80 mg/sqm, and total body irradiation 2 Gy, and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide. One month after HCT, disease progression was observed in the lung. Romidepsin was readministered every 2 weeks at a reduced dose of 12 mg/sqm. After two cycles of romidepsin, the patient achieved a complete metabolic response without severe GVHD or other non-hematological toxicities. Romidepsin was discontinued after seven treatment cycles due to prolonged lymphopenia. The patient remains in complete remission 30 months after the last dose of romidepsin. Our experience suggests that romidepsin could be safely administered soon after allogeneic transplantation.

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation: a report of three cases.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.

Chronic Graft-versus-host Disease-associated Membranous Nephropathy Following Bone Marrow Transplantation, Successfully Treated with Rituximab.

A 67-year-old woman who had undergone bone marrow transplantation 2 years previously for acute myeloid leukemia (AML) developed complications of chronic graft-versus-host disease (cGVHD). She thereafter also developed nephrotic syndrome, and membranous nephropathy (MN) was diagnosed by a renal biopsy. Although the causative antigens of the MN were not detected, immunofluorescence staining showed codominant deposition of immunoglobulins G2 and G3, a finding indicating secondary MN, thereby suggesting an association between MN and cGVHD. Rituximab treatment was initiated, and her nephrotic syndrome gradually improved without relapse of AML. Our present case suggests that rituximab is a safe and effective therapeutic option for cGVHD-associated MN.