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.

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.

Validation of the molecular international prognostic scoring system in patients with myelodysplastic syndromes defined by international consensus classification.

Myelodysplastic syndromes (MDS) have varied prognoses and require a risk-adapted treatment strategy for treatment optimization. Recently, a molecular prognostic model (Molecular International Prognostic Scoring System [IPSS-M]) that combines clinical parameters, cytogenetic abnormalities, and mutation topography was proposed. This study validated the IPSS-M in 649 patients with primary MDS (based on the 2022 International Consensus Classification [ICC]) and compared its prognostic power to those of the IPSS and revised IPSS (IPSS-R). Overall, 42.5% of the patients were reclassified and 29.3% were up-staged from the IPSS-R. After the reclassification, 16.9% of the patients may receive different treatment strategies. The IPSS-M had greater discriminative potential than the IPSS-R and IPSS. Patients with high, or very high-risk IPSS-M might benefit from allogeneic hematopoietic stem cell transplantation. IPSS-M, age, ferritin level, and the 2022 ICC categorization predicted outcomes independently. After analyzing demographic and genetic features, complementary genetic analyses, including KMT2A-PTD, were suggested for accurate IPSS-M categorization of patients with ASXL1, TET2, STAG2, RUNX1, SF3B1, SRSF2, DNMT3A, U2AF1, and BCOR mutations and those classified as MDS, not otherwise specified with single lineage dysplasia/multi-lineage dysplasia based on the 2022 ICC. This study confirmed that the IPSS-M can better risk-stratified MDS patients for optimized therapeutic decision-making.

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.

Clinico-genetic and prognostic analyses of 716 patients with primary myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia based on the 2022 International Consensus Classification.

The 2022 International Consensus Classification (ICC) recategorized myeloid neoplasms based on recent advances in the understanding of the biology of hematologic malignancies, in which myelodysplastic syndrome (MDS) with blasts of 10%-19% is classified as MDS/acute myeloid leukemia (AML), MDS with mutated SF3B1, irrespective of the number of ring sideroblasts, as MDS-SF3B1, and those with multi-hit TP53 mutations as MDS with mutated TP53. In the analysis of 716 patients with MDS diagnosed according to the 2016 WHO classification, we found that 75.3% of patients remained in the MDS group based on the ICC, while 24.7% of patients were reclassified to the MDS/AML group after the exclusion of 15 patients who were classified to the AML group. Patients with MDS/AML showed a distinct mutational landscape and had poorer outcomes, compared to those with MDS. In the MDS group, patients with MDS-SF3B1 had higher frequencies of DNMT3A and TET2 mutations than those with MDS, not otherwise specified, with single lineage dysplasia or multilineage dysplasia. Patients with mutated TP53 were associated with dismal outcomes, irrespective of the blast percentage. In conclusion, this study showed that the ICC facilitates efficient segregation and risk-stratification of MDS which can help guide the treatment choice of patients with the disease.

Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes. In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.

Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

NOVEL-1st: an observational study to assess the safety and efficacy of nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in Taiwan.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.

Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

Hepatitis B surface antigen positivity is associated with progression of disease within 24 months in follicular lymphoma.

PURPOSE: Studies have reported a positive association between hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and follicular lymphoma (FL). Nevertheless, clinical information concerning chronic HBV infection in FL is sparse. METHODS: This retrospective cohort study investigated the prognostic impact of HBsAg in immunocompetent patients with FL treated with frontline rituximab-containing chemoimmunotherapy in an HBV-endemic area between 2006 and 2016. RESULTS: Among the 149 analyzed patients, 32 (21.5%) were HBsAg-positive. HBsAg positivity was positively associated with symptomatic splenomegaly, significant serous effusions, and peritreatment hepatic dysfunction. HBsAg-positive patients had a trend of lower complete remission rate (59.4% vs. 76.9%, P = 0.07), significantly poorer overall survival (hazard ratio for death, 2.68; 95% confidence interval, 1.21-5.92), and shorter progression-free survival than had HBsAg-negative patients. Multivariate analysis revealed that HBsAg is an independent adverse prognostic factor for overall survival. Intriguingly, HBsAg-positive patients had a higher incidence of progression of disease within 24 months (POD24) than had HBsAg-negative patients (cumulative incidence rate, 25.8% vs. 12.4%, P = 0.045). CONCLUSION: This study revealed that patients with FL and chronic HBV infection represent a distinct subgroup with a markedly poor prognosis. HBsAg was positively associated with POD24 and might serve as a new prognostic predictor of the survival of FL patients in endemic regions for HBV infection.

Busulfan-containing conditioning regimens in allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia: A Taiwan observational study.

BACKGROUND: Allogeneic stem cell transplantation (allo-HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL). AIM: This study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)-based or total body irradiation (TBI)-based regimen in a Chinese population. METHODS: We enrolled 224 adult patients with ALL who received allo-HSCT at National Taiwan University Hospital between 1997 and 2016. RESULTS: The median age at transplantation was 33 years. Before allo-HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy-based conditioning, either myeloablative (MA) or reduced-intensity stem cell transplantation (RIST), and 83 patients received a TBI-based regimen (MA-TBI). Patients receiving the MA-Bu regimen had longer relapse-free survival (RFS) than those receiving the MA-TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA-Bu vs. MA-TBI vs. RIST-Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment-related mortality (TRM), or incidences of grade 3-4 acute graft-versus-host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA-Bu and MA-TBI groups regarding the incidence of grade 3-4 acute GvHD, grade 2-4, and all-grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo-HSCT was the only risk factor impacting RFS and OS. CONCLUSION: In summary, patients receiving Bu/Cy-based or TBI-based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu-based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long-term outcomes.

Bone marrow plasma level of decorin may be associated with improved treatment outcomes in a subset of multiple myeloma patients.

BACKGROUND/PURPOSE: Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. METHODS: We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. RESULTS: Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN <9.76 ng/mL) groups. Patients in the H-DCN group had more advanced-stage disease, including more osteolysis terms of higher levels of C-terminal telopeptides of type I collagen (0.69 ± 0.55 vs. 0.49 ± 0.36 ng/mL; P = 0.028), than those in the L-DCN group. Decorin levels correlated positively with hepatocyte growth factor (HGF) levels in BM plasma samples from NDMM patients (Pearson correlation coefficient, 0.226; P < 0.001). Patients with low HGF (<0.79 ng/mL) but high decorin levels (≥12.95 ng/mL) had a higher treatment response rate (90.5% vs. 54.5%, respectively; P = 0.015) and improved overall survival (not reached vs. 53 months; P = 0.0148) than those with lower decorin levels (<12.95 ng/mL). Multivariate analysis confirmed that a high decorin level was an independent predictive factor for treatment response and survival in patients with low HGF levels. CONCLUSION: Our findings suggest that decorin may exert protective effects in this subset of MM patients.

Clinical implications of sequential MRD monitoring by NGS at 2 time points after chemotherapy in patients with AML.

Next-generation sequencing (NGS) has been applied to measurable/minimal residual disease (MRD) monitoring after induction chemotherapy in patients with acute myeloid leukemia (AML), but the optimal time point for the test remains unclear. In this study, we aimed to investigate the clinical significance of NGS MRD at 2 different time points. We performed targeted NGS of 54 genes in bone marrow cells serially obtained at diagnosis, first complete remission (first time point), and after the first consolidation chemotherapy (second time point) from 335 de novo AML patients. Excluding DNMT3A, TET2, and ASXL1 mutations, which are commonly present in individuals with clonal hematopoiesis of indeterminate potential, MRD could be detected in 46.4% of patients at the first time point (MRD1st), and 28.9% at the second time point (MRD2nd). The patients with detectable NGS MRD at either time point had a significantly higher cumulative incidence of relapse and shorter relapse-free survival and overall survival. In multivariate analysis, MRD1st and MRD2nd were both independent poor prognostic factors. However, the patients with positive MRD1st but negative MRD2nd had a similar good prognosis as those with negative MRD at both time points. The incorporation of multiparameter flow cytometry and NGS MRD revealed that the presence of NGS MRD predicted poorer prognosis among the patients without detectable MRD by multiparameter flow cytometry at the second time point but not the first time point. In conclusion, the presence of NGS MRD, especially after the first consolidation therapy, can help predict the clinical outcome of AML patients.

Comparison of clinicopathological features and treatment outcomes in aggressive primary intestinal B- and T/NK-cell lymphomas.

BACKGROUND: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). METHODS: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. RESULTS: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P < 0.001) and lower complete response rate to first-line chemotherapy regimens (22% vs. 69%, P = 0.009) than aB-PILs. Patients with aB-PILs had a better 5-year event-free survival rate (55.8% vs. 13.9%, P = 0.026) and a 5-year OS rate (74.3% vs. 29.6%, P = 0.036) than those with T/NK-cell lymphomas. Multivariate analysis identified that female gender and stage III/IV were unfavorable prognostic factors. Among the 54 patients with diffuse large B-cell lymphoma (DLBCL), those with International Prognostic Index (IPI) scores of 0-2 had a better 5-year OS rate than those with scores of 3-5 (84.2% vs. 46.8%, P = 0.002). IPI scores of 3-5 (P = 0.026) and tumors located in the large intestine (P = 0.015) were poor prognostic factors based on the multivariate analysis. CONCLUSION: The prognosis of T/NK-PILs was less favorable than that of aB-PILs. Female gender, stage III/IV disease, DLBCL with IPI scores of 3-5, or tumors in the large intestine were poor prognostic factors.

A Knowledge-Reserved Distillation with Complementary Transfer for Automated FC-based Classification Across Hematological Malignancies.

Acute leukemia often comes with life-threatening prognosis outcome and remains a critical clinical issue today. The implementation of measurable residual disease (MRD) using flow cytometry (FC) is highly effective but the interpretation is time-consuming and suffers from physician idiosyncrasy. Recent machine learning algorithms have been proposed to automatically classify acute leukemia samples with and without MRD to address this clinical need. However, most prior works either validate only on a small data cohort or focus on one specific type of leukemia which lacks generalization. In this work, we propose a transfer learning approach in performing automatic MRD classification that takes advantage of a large scale acute myeloid leukemia (AML) database to facilitate better learning on a small cohort of acute lymphoblastic leukemia (ALL). Specifically, we develop a knowledge-reserved distilled AML pre-trained network with ALL complementary learning to enhance the ALL MRD classification. Our framework achieves 84.5% averaged AUC which shows its transferability across acute leukemia, and our further analysis reveals that younger and elder ALL patient samples benefit more from using the pre-trained AML model.

Correlative analysis of overall survival with clinical characteristics in 127 patients with mantle cell lymphoma: a multi-institutional cohort in Taiwan.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma often with extranodal involvement at diagnosis, and yet how this feature correlates with survival awaits elucidation. To address this issue, a correlative analysis between clinical features of 127 MCL patients and their overall survival (OS) was conducted. In this cohort, the median age at MCL diagnosis was 62 years and 81% were males. Eighty-four percent of patients were Ann Arbor stage 4, and 15% were blastoid variants. In patients with gastrointestinal MCL, approximately 40% had gastric involvement. In treatment, CHOP-based induction chemotherapy was given to 61.1% of patients. One-third of patients undertook autologous stem cell transplant (SCT), and 4.7% had allogeneic SCT. The median OS was 82 months and well-stratified in MIPI risk groups. In the multivariate analysis for OS, blastoid variants and gastric involvement were both independent risk factors whereas auto-SCT had a protective effect. Overall, this study corroborated with the current understandings and international therapeutic standards for MCL. Auto-SCT associated with a better OS while allo-SCT remained an option for blastoid variants and those who failed Auto-SCT. Interestingly, patients with gastric involvement tended to have worse survival, a finding that spawns more studies to investigate the mechanism.

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).

Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax.

Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4 months and the median overall survival (OS) was 6.6 months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.