Continuous and differential improvement in worldwide access to hematopoietic cell transplantation: activity has doubled in a decade with a notable increase in unrelated and non-identical related donors.

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-Governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (six WHO regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT number increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/ten million population was observed for autologous HCT (r=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation (r=0.51) was detected from related donors. The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms.

In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS and single lineage dysplasia displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.

Using Artificial Intelligence to Interpret Clinical Flow Cytometry Datasets for Automated Disease Diagnosis and/or Monitoring.

Flow cytometry (FC) is routinely used for hematological disease diagnosis and monitoring. Advancement in this technology allows us to measure an increasing number of markers simultaneously, generating complex high-dimensional datasets. However, current analytic software and methods rely on experienced analysts to perform labor-intensive manual inspection and interpretation on a series of 2-dimensional plots via a complex, sequential gating process. With an aggravating shortage of professionals and growing demands, it is very challenging to provide the FC analysis results in a fast, accurate, and reproducible way. Artificial intelligence has been widely used in many sectors to develop automated detection or classification tools. Here we describe a type of machine learning method for developing automated disease classification and residual disease monitoring on clinical flow datasets.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Pooled Analysis of Pralatrexate Single-Agent Studies in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma.

Patients with relapsed or refractory (r/r) mature NK and T-cell lymphoma (MTCL) have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in r/r PTCL, we performed a pooled analysis of data from four similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (59 years median age; 67.0% male) in the study population, 48.9% had peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median 9.1-month duration of response, 4.6-month progression-free survival, and 16.3-month overall survival. The most common treatment-related all grade adverse events were stomatitis, thrombocytopenia, white blood cell count decreased, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy versus 2 or ≥ 4 prior lines; PTCL NOS or ALCL versus transformed mycosis fungoides; chemotherapy and transplant before pralatrexate versus chemotherapy alone or chemotherapy with other non-transplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with r/r PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic patterns associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.

Recommendations for the treatment and management of adult B-Cell acute lymphoblastic leukemia in Asia-Pacific: Outcomes from a pilot initiative.

The outcomes of adult B-cell acute lymphoblastic leukemia (ALL) remain poor. Recent advancements in the field of leukemia research show potential for improved patient care. However, the adoption of research findings into clinical practice is fraught with practice- and country-specific challenges. The continued addition of new findings warrants critical evaluation for the feasibility of incorporation into clinical practice. A uniform set of evidence-based guidelines can favorably assist physicians in making optimal clinical decisions. Such a resource may also serve as a reference point for strategic planning of initiatives aimed at addressing critical barriers in the optimal management of B-cell ALL. This initiative was undertaken to seek a collaborative perspective and understand the existing challenges. Concordance-based recommendations were outlined through a systematic discussion on various aspects of treatment and management of adult B-cell ALL. The outcomes and experiences gained from this exercise will serve as a foundation for future efforts encompassing the more granular aspects of the management of B-cell ALL across the Asia-Pacific region.

Report on hematopoietic cell transplantations performed in 2018/2019 focusing on the trends of selection of stem cell sources in the Asia-Pacific region: APBMT Activity Survey.

The number of hematopoietic stem cell transplantations (HCTs) is increasing annually worldwide, and the Asia-Pacific (AP) region is no exception. We report on the absolute number of HCTs in 2018 and 2019 and the trends in graft selection and disease indication in the past few decades. In 2018, 24,292 HCTs were performed in the AP region, of which 8,754 (36.0%) were autologous and 15,538 (64.0%) were allogeneic. Among the allogeneic HCTs, 10,552 (67.9%) of the recipients were related to their donors, whereas 4,986 (32.1%) were unrelated. In 2019, 27,583 HCTs were reported, of which 17,613 (63.9%) were allogeneic and 9,970 (36.1%) were autologous. Although, in 2010, there was a nearly equal number of related and unrelated HCTs, the difference has shown an annual increase, with more than double (2.05) the number of related than unrelated HCTs in 2019. Recent trends in the AP region show that peripheral blood has overwhelmingly surpassed the bone marrow as a graft source for both related and unrelated HCTs, with the haploidentical donor type being preferred; however, their trends in each country/region were quite different among countries/regions. In 2019, the main conditions requiring HCT were acute myelogenous leukemia (n=6,629 [24.0%]), plasma cell disorders (PCD) (n=4,935 [17.9%]), malignant lymphoma (ML) (n=4,106 [14.9%]), acute lymphoblastic leukemia (AML) (n=3,777 [13.7%]), myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm (n=1,913 [6.9%]), severe aplastic anemia (n=1,671 [6.1%]), and hemoglobinopathy (n=910 [3.3%]). PCD and ML were the main indications for autologous HCT, and the number of PCD cases has grown more prominent than the corresponding of ML. The increased number of allogeneic transplants for hemoglobinopathy remains prominent, as well as that of AML and acute lymphocytic leukemia for the past 5 years. There was a significant regional variation in the number of facilities performing HCTs, ranging from one in Mongolia and Nepal to 313 in Japan, and differing regional densities varying from 0.1 in Indonesia and Pakistan to 24.7 in Japan. The total transplant density per 10 million population in each country/region also differed (0.2 in Indonesia and 627 in New Zealand). This annual Activity Survey aims to help all participating countries/regions understand the changes in HCT, serve as an asset in promoting HCT activities in the AP region, and be used as a reference for comparison with other registries from Europe and the United States.

Allogeneic hematopoietic stem cell transplantation for B-cell lymphoma in Taiwan.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered for patients with high-risk B-cell lymphoma and relapsed or refractory disease. This study aimed to analyze the long-term follow-up data of patients who underwent allo-HSCT in Taiwan. This was a retrospective observational study using data from the Taiwan Society of Blood and Marrow Transplantation database. A total of 105 patients who underwent allo-HSCT because of high-risk, relapsed, or refractory disease between 2010 and 2019 were included. Forty-five percent of the patients previously underwent autologous stem cell transplantation (ASCT). The median follow-up duration was 18.6 months. The probability of 3-year progression-free survival and overall survival (OS) was 34.5% and 37%, respectively. The probability of 1-year non-relapse mortality was 31.4%, and the major cause was infection (75.8%). The multivariable analysis showed that not in remission at the time of transplantation and the absence of graft-versus-host disease (GVHD) were factors associated with inferior OS. The probability of 3-year OS in patients with diffuse large B-cell lymphoma who underwent allo-HSCT and allo-HSCT after ASCT was 40.2% and 25.2%, respectively. Allo-HSCT could be a salvage therapeutic option for relapsed or refractory B-cell lymphoma. Complete remission at the time of allo-HSCT and the presence of GVHD are independent variables for overall survival.

Lysosomal-targeted doxorubicin delivery using RBC-derived vesicles to overcome drug-resistant cancer through mitochondrial-dependent cell death.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.

Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study.

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47-5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59-6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

Asia-Pacific Leukemia Consortium: An innovative and collaborative initiative to improve care of leukemia and related diseases in the Asia-Pacific region.

The burden of leukemia and related diseases is rapidly growing in Asia. Currently, there is a paucity of regional collaborative groups/initiatives that focus exclusively on the management of leukemia in the Asia-Pacific (APAC) region. The Asia-Pacific Leukemia Consortium (APLC) was established on the 8 September 2021 to understand the status quo, unmet needs, and ways to improve the management of leukemia and related diseases in the APAC region. The APLC working group set up a group of experts from various countries (Singapore, Malaysia, Thailand, Hong Kong, Japan, South Korea, Taiwan, China, and Australia) to discuss on the status of: (i) clinical trials; (ii) disease registry database; (iii) genetic and tissue repository; (iv) patient advocacy and care; and (v) disease prevention and education in the APAC region. Low levels of awareness about leukemia amongst the public, lack of financial support, and limited access to newly approved therapies were identified as barriers to the implementation of effective leukemia management in low- or mid-income Asian countries. Patients often enroll in clinical trials to gain access to novel/approved therapies. The APLC group aims to address the growing threat of leukemia through a collaborative approach to advance disease prevention, research, clinical trials, and education.

Validation of the prognostic significance of the 2022 European LeukemiaNet risk stratification system in intensive chemotherapy treated aged 18 to 65 years patients with de novo acute myeloid leukemia.

The European LeukemiaNet (ELN) recently proposed a revised recommendation for the diagnosis and management of acute myeloid leukemia (AML) in adults, recognized as ELN-2022. However, validation in a large real-world cohort remains lacking. In this study, we aimed to validate the prognostic relevance of the ELN-2022 in a cohort of 809 de novo, non-M3, younger (ages 18-65 years) AML patients receiving standard chemotherapy. The risk categories of 106 (13.1%) patients were reclassified from that determined using ELN-2017 to that determined using ELN-2022. The ELN-2022 effectively helped distinguish patients as favorable, intermediate, and adverse risk groups in terms of remission rates and survival. Among patients who achieved first complete remission (CR1), allogeneic transplantation was beneficial for those in the intermediate risk group, but not for those in the favorable or adverse risk groups. We further refined the ELN-2022 system by re-categorizing AML patients with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 with KIThigh , JAK2 or FLT3-ITDhigh mutations into the intermediate risk subset, AML patients with t(7;11)(p15;p15)/NUP98::HOXA9 and AML patients with co-mutated DNMT3A and FLT3-ITD into the adverse risk subsets, and AML patients with complex or monosomal karyotypes, inv (3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2,MECOM(EVI1) or TP53 mutation into the very adverse risk subset. The refined ELN-2022 system performed effectively to distinguish patients as favorable, intermediate, adverse, and very adverse risk groups. In conclusion, the ELN-2022 helped distinguish younger, intensively treated patients into three groups with distinct outcomes; the proposed refinement of ELN-2022 may further improve risk stratification among AML patients. Prospective validation of the new predictive model is necessary.

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML.

A set of myelodysplasia-related (MDS-R) gene mutations are incorporated into the 2022 European LeukemiaNet risk classification as adverse genetic factors for acute myeloid leukemia (AML) based on their poor prognostic impact on older patients. The impact of these mutations on younger patients (age < 60 years) remains elusive. In the study of 1213 patients with de novo non-M3 AML, we identified MDS-R mutations in 32.7% of the total cohort, 44.9% of older patients and 23.4% of younger patients. The patients with MDS-R mutations had a significantly lower complete remission rate in both younger and older age groups. With a median follow-up of 9.2 years, the MDS-R group experienced shorter overall survival (P = 0.034 for older and 0.035 for younger patients) and event-free survival (P = 0.004 for older and 0.042 for younger patients). Furthermore, patients with MDS-R mutations more frequently harbored measurable residual disease that was detectable using next generation sequencing at morphological CR than those without MDS-R mutations. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) might ameliorate the negative impact of MDS-R mutations. In summary, AML patients with MDS-R mutations have significantly poorer outcomes regardless of age. More intensive treatment, such as allo-HSCT and/or novel therapies, is warranted for AML patients with MDS-R mutations.

Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study.

PURPOSE: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

An Analysis of the Worldwide Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) has an aggressive course and a historically dismal prognosis. For many patients, hematopoietic stem cell transplantation (HSCT) represents the best option for cure, but access, utilization, and health inequities on a global scale remain poorly elucidated. We wanted to describe patterns of global HSCT use in AML for a better understanding of global access, practices, and unmet needs internationally. Estimates of AML incident cases in 2016 were obtained from the Global Burden of Disease 2019 study. HSCT activities were collected from 2009 to 2016 by the Worldwide Network for Blood and Marrow Transplantation through its member organizations. The primary endpoint was global and regional use (number of HSCT) and utilization of HSCT (number of HSCT/number of incident cases) for AML. Secondary outcomes included trends from 2009 to 2016 in donor type, stem cell source, and remission status at time of HSCT. Global AML incidence has steadily increased, from 102,000 (95% uncertainty interval: 90,200-108,000) in 2009 to 118,000 (104,000-126,000) in 2016 (16.2%). Over the same period, a 54.9% increase from 9659 to 14,965 HSCT/yr was observed globally, driven by an increase in allogeneic (64.9%) with a reduction in autologous (-34.9%) HSCT. Although the highest numbers of HSCT continue to be performed in high-resource regions, the largest increases were seen in resource-constrained regions (94.6% in Africa/East Mediterranean Region [AFR/EMR]; 34.7% in America-Nord Region [AMR-N]). HSCT utilization was skewed toward high-resource regions (in 2016: AMR-N 18.4%, Europe [EUR] 17.9%, South-East Asia/Western Pacific Region [SEAR/WPR] 11.7%, America-South Region [AMR-S] 4.5%, and AFR/EMR 2.8%). For patients <70 years of age, this difference in utilization was widened; AMR-N had the highest allogeneic utilization rate, increasing from 2009 to 2016 (30.6% to 39.9%) with continued low utilization observed in AFR/EMR (1.7% to 2.9%) and AMR-S (3.5% to 5.4%). Across all regions, total HSCT for AML in first complete remission (CR1) increased (from 44.1% to 59.0%). Patterns of donor stem cell source from related versus unrelated donors varied widely by geographic region. SEAR/WPR had a 130.2% increase in related donors from 2009 to 2016, and >95% HSCT donors in AFR/EMR were related; in comparison, AMR-N and EUR have a predilection for unrelated HSCT. Globally, the allogeneic HSCT stem cell source was predominantly peripheral blood (69.7% of total HSCT in 2009 increased to 78.6% in 2016). Autologous HSCT decreased in all regions from 2009 to 2016 except in SEAR/WPR (18.9%). HSCT remains a central curative treatment modality in AML. Allogeneic HSCT for AML is rising globally, but there are marked variations in regional utilization and practices, including types of graft source. Resource-constrained regions have the largest growth in HSCT use, but utilization rates remain low, with a predilection for familial-related donor sources and are typically offered in CR1. Further studies are necessary to elucidate the reasons, including economic factors, to understand and address these health inequalities and improve discrepancies in use of HSCT as a potentially curative treatment globally.

A Coarse-to-Fine Pathology Patch Selection for Improving Gene Mutation Prediction in Acute Myeloid Leukemia.

Identifying gene mutation is essential to prognosis and therapeutic decisions for acute myeloid leukemia (AML) but the current gene analysis is inefficient and non-scalable. Pathological images are readily accessible and can be effectively modeled using deep learning. This work aims at predicting gene mutation directly by modeling bone marrow smear images. Traditionally, bone marrow smear slides are cropped into patches with manual segmentation for patch-level modeling. Slide-level modeling, such as multi-instance learning, could aggregate patches for holistic modeling, though suffer from excessive redundancy. In this study, we propose a discriminative multi-instance approach to select useful patches in a coarse-to-fine process. Specifically, we preprocess a slide into patches by using a trained pre-selector network. Then, we rule out low quality patches in the coarse selection with known prior knowledge, and refine the model using gene-discriminative patches in the fine selection. We evaluate the framework for CEBPA, FLT3, and NPM1 gene mutation prediction and obtain 71.67%, 56.26%, and 56.34% F1-score. Further analysis show the effect of different selection criteria on prediction gene mutations using pathological images.

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study.

Iptacopan (LNP023) is a novel, oral selective inhibitor of complement factor B under clinical development for paroxysmal nocturnal hemoglobinuria (PNH). In this ongoing open-label phase 2 study, PNH patients with active hemolysis were randomized to receive single-agent iptacopan twice daily at a dose of either 25 mg for 4 weeks followed by 100 mg for up to 2 years (cohort 1) or 50 mg for 4 weeks followed by 200 mg for up to 2 years (cohort 2). At the time of interim analysis, of 13 PNH patients enrolled, all 12 evaluable for efficacy achieved the primary endpoint of reduction in serum lactate dehydrogenase (LDH) levels by ≥60% by week 12 compared with baseline; mean LDH levels dropped rapidly and durably, namely by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Most patients achieved a clinically meaningful improvement in hemoglobin (Hb) levels, and all but 1 patient remained transfusion-free up to week 12. Other markers of hemolysis, including bilirubin, reticulocytes, and haptoglobin, showed consistent improvements. No thromboembolic events were reported, and iptacopan was well tolerated, with no severe or serious adverse events reported until the data cutoff. In addition to the previously reported beneficial effect of iptacopan add-on therapy to eculizumab, this study showed that iptacopan monotherapy in treatment-naïve PNH patients resulted in normalization of hemolytic markers and rapid transfusion-free improvement of Hb levels in most patients. This trial was registered at www.clinicaltrials.gov as #NCT03896152.

A Chunking-for-Pooling Strategy for Cytometric Representation Learning for Automatic Hematologic Malignancy Classification.

Differentiating types of hematologic malignancies is vital to determine therapeutic strategies for the newly diagnosed patients. Flow cytometry (FC) can be used as diagnostic indicator by measuring the multi-parameter fluorescent markers on thousands of antibody-bound cells, but the manual interpretation of large scale flow cytometry data has long been a time-consuming and complicated task for hematologists and laboratory professionals. Past studies have led to the development of representation learning algorithms to perform sample-level automatic classification. In this work, we propose a chunking-for-pooling strategy to include large-scale FC data into a supervised deep representation learning procedure for automatic hematologic malignancy classification. The use of discriminatively-trained representation learning strategy and the fixed-size chunking and pooling design are key components of this framework. It improves the discriminative power of the FC sample-level embedding and simultaneously addresses the robustness issue due to an inevitable use of down-sampling in conventional distribution based approaches for deriving FC representation. We evaluated our framework on two datasets. Our framework outperformed other baseline methods and achieved 92.3% unweighted average recall (UAR) for four-class recognition on the UPMC dataset and 85.0% UAR for five-class recognition on the hema.to dataset. We further compared the robustness of our proposed framework with that of the traditional downsampling approach. Analysis of the effects of the chunk size and the error cases revealed further insights about different hematologic malignancy characteristics in the FC data.

Stem cell transplant for mantle cell lymphoma in Taiwan.

Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization.