Reduced toxicity (FluBu3) versus myeloablative (BuCy) conditioning in acute myeloid leukemia patients who received first allogeneic hematopoietic stem cell transplantation in measurable residual disease-negative CR1.

In the present study, reduced toxicity (FluBu3) and myeloablative (BuCy) conditioning were compared in patients with AML who received first allogeneic HSCT in MRD-negative CR1. The study included 124 adult patients who underwent HSCT from an HLA-matched (8/8) sibling, unrelated, or 1-locus mismatched (7/8) unrelated donor (MMUD). The median age was 45 years and intermediate cytogenetics comprised majority (71.8%). The 2-year OS, RFS, CIR and NRM for BuCy (n = 78, 62.9%) and FluBu3 (n = 46, 37.1%) groups were 78.3% and 84.5% (p = 0.358), 78.0% and 76.3% (p = 0.806), 7.7% and 21.5% (p = 0.074) and 14.3% and 2.2% (p = 0.032), respectively. At the time of data cut-off, relapse and NRM were the main causes of HSCT failure in each of the FluBu3 and BuCy arms. Among patients, 75% of relapsed FluBu3 patients had high-risk features of either poor cytogenetics or FLT3-ITD mutation compared with 16.7% of BuCy patients. The majority of NRM in the BuCy group was due to GVHD (73%), half of whom received MMUD transplantation. To conclude, the FluBu3 reduced toxicity conditioning showed comparable post-transplant OS and RFS to BuCy and was associated with significantly reduced NRM that was offset by a trend towards higher risk of relapse even in MRD-negative CR1 population.

Comparisons of efficacy between frontline treatment with bortezomib-melphalan-prednisone and lenalidomide-dexamethasone for transplant-ineligible multiple myeloma: a multicenter real-world based registry report, CAREMM-2102 study.

BACKGROUND: Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) remain the standard treatments for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). This study aimed to compare real-world benefits between the two regimens. We also were interested in exploring efficacy according to subsequent therapy following VMP or Rd. METHODS: A total of 559 NDMM patients treated with VMP (n = 443, 79.2%) or Rd (n = 116, 20.8%) was recruited retrospectively from a multicenter database. RESULTS: Rd provided more benefits than VMP-overall response rate: 92.2 vs. 81.8%, p = 0.018; median progression-free survival (PFS): 20.0 vs. 14.5 months, p <0.001; second PFS (PFS2): 43.9 vs. 36.9 months, p = 0.012; overall survival (OS): 100.1 vs. 85.0 months, p = 0.017. Multivariable analysis revealed significant benefits of Rd over VMP, with hazard ratios of 0.722, 0.627, and 0.586 for PFS, PFS2, and OS, respectively. In propensity score-matched cohorts with matched VMP (n = 201) and Rd (n = 67) arms to balance baseline characteristics, Rd still showed significantly better outcomes for PFS, PFS2, and OS than VMP. Following VMP failure, triplet therapy showed significant benefits for response and PFS2; after Rd failure, PFS2 with carfilzomib-dexamethasone was significantly better than bortezomib-based doublet treatment. CONCLUSION: These real-world findings may assist with better selection between VMP and Rd as well as subsequent therapy for NDMM.

Prognostic value of low muscle mass at the 12th thoracic vertebral level in multiple myeloma treated with transplantation: CAREMM-2101 study.

PURPOSE: Autologous hematopoietic stem cell transplantation (ASCT) has been introduced as a standard treatment for newly diagnosed multiple myeloma (NDMM) following novel agent-based induction chemotherapy. This study investigated whether pre-ASCT low muscle mass evaluated using the paraspinal muscle index (PMI) at the 12th thoracic vertebra (T12) level is a reliable prognostic marker in NDMM after chemotherapy. METHODS: A multi-center registry database was retrospectively analyzed. Between 2009 and 2020, 190 patients with chest computed tomography images underwent frontline ASCT following induction therapy. The PMI was defined as the value of the paraspinal muscle area at the T12 level divided by the square of the patient's height. The cut-off value indicating a low muscle mass was sex-specific, using the lowest quintiles. RESULTS: Of the 190 patients, 38 (20%) were in the low muscle mass group. The low muscle mass group had a lower 4-year overall survival (OS) rate than the non-low muscle mass group (68.5% vs. 81.2%; P = 0.074). The median progression-free survival (PFS) in the low muscle mass group was significantly shorter compared with the non-low muscle mass group (23.3 months vs. 29.2 months; P = 0.029). The cumulative incidence of transplant-related mortality (TRM) was significantly higher in the low muscle mass group than in the non-low muscle mass group (4-year probability of TRM incidence, 10.6% vs. 0.7%; P < 0.001). In contrast, no significant difference in the cumulative incidence of disease progression was found between the two groups. Multivariate analysis revealed that low muscle mass was associated with significant negative outcomes for OS [(hazard ratio (HR): 2.14; P = 0.047], PFS (HR: 1.78; P = 0.012), and TRM (HR: 12.05; P = 0.025). CONCLUSION: Paraspinal muscle mass may have a prognostic role in NDMM patients who undergo ASCT. Patients with low paraspinal muscle mass have lower survival outcomes compared to non-low muscle mass group.

ML-based sequential analysis to assist selection between VMP and RD for newly diagnosed multiple myeloma.

Optimal first-line treatment that enables deeper and longer remission is crucially important for newly diagnosed multiple myeloma (NDMM). In this study, we developed the machine learning (ML) models predicting overall survival (OS) or response of the transplant-ineligible NDMM patients when treated by one of the two regimens-bortezomib plus melphalan plus prednisone (VMP) or lenalidomide plus dexamethasone (RD). Demographic and clinical characteristics obtained during diagnosis were used to train the ML models, which enabled treatment-specific risk stratification. Survival was superior when the patients were treated with the regimen to which they were low risk. The largest difference in OS was observed in the VMP-low risk & RD-high risk group, who recorded a hazard ratio of 0.15 (95% CI: 0.04-0.55) when treated with VMP vs. RD regimen. Retrospective analysis showed that the use of the ML models might have helped to improve the survival and/or response of up to 202 (39%) patients among the entire cohort (N = 514). In this manner, we believe that the ML models trained on clinical data available at diagnosis can assist the individualized selection of optimal first-line treatment for transplant-ineligible NDMM patients.

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study.

Background: The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone; VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone; D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd. Methods: Newly diagnosed MM patients aged ＞18 years who underwent induction therapy followed by autologous stem cell transplantation (ASCT) between November 2020 and December 2021 were identified. Finally, patients with VRd (N=37) and those with D-VTd (N=43) were enrolled. Results: After induction, 10.8% of the VRd group showed stringent complete remission (sCR), 21.6% showed complete response (CR), 35.1% showed very good partial response (VGPR), and 32.4% showed partial response (PR). Of the D-VTd group, 9.3% showed sCR, 34.9% CR, 48.8% VGPR, and 4.2% PR (VGPR or better: 67.6% in VRd vs. 93% in D-VTd, P=0.004). After ASCT, 68.6% of the VRd group showed CR or sCR, while 90.5% of the D-VTd group showed CR or sCR (P=0.016). VRd was associated with an increased incidence of skin rash (P=0.044). Other than rashes, there were no significant differences in terms of adverse events between the two groups. Conclusion: Our study supports the use of a front-line quadruplet induction regimen containing a CD38 monoclonal antibody for transplant-eligible patients with newly diagnosed MM.

Response and Dynamics of Renal Function in Transplantation-Eligible Multiple Myeloma Patients Treated with a Novel Agent: The CAREMM-2201 Study.

Newly diagnosed multiple myeloma (NDMM) frequently results in renal impairment (RI), and its natural course has not been fully elucidated in the era of novel agents. We aimed to identify the dynamics of renal function after autologous stem cell transplantation (ASCT) following induction treatment using a novel agent in transplantation-eligible NDMM patients with RI (estimated glomerular filtration rate [eGFR] ≤50 mL/min/1.73 m2) at diagnosis. The factors associated with achieving a renal response based on the term renal benefit regardless of baseline eGFR were investigated as well. In a multicenter registry database including 1795 patients with plasma cell disorder, 140 transplantation-eligible NDMM patients who developed RI at the time of initiation of treatment for NDMM were identified. They received protocol-based treatment (PBT) consisting of induction treatment using proteasome inhibitors and/or immunomodulatory drugs followed by ASCT. MM and renal responses were evaluated using the International Myeloma Working Group response criteria. To evaluate the standardized improvement of renal function irrespective of baseline eGFR, renal benefit was defined as a sustained (for at least 3 months) increase in eGFR >15 mL/min/1.73 m2. The mean patient age was 54.7 ± 7.4 years. With a mean baseline eGFR of 24.8 ± 13.9, the renal complete response (renalCR) and renal benefit rates were 49.3% and 67.9%, respectively. In a multivariable analysis, the 3 factors significantly associated with reduced likelihood of achieving both renalCR and renal benefit were age ≥55 years, light chain type NDMM, and failure to improve eGFR by 5 mL/min/1.73 m2 with supportive care when measured 3 days prior to induction therapy and at the initiation of chemotherapy. Hypertension and advanced eGFR also were associated with poor renalCR achievement. The mean eGFR improved until the time of ASCT and then decreased gradually over time. The mean eGFR improved significantly until 4 months post-PBT compared with each eGFR at previous time points, but this significant improvement disappeared by 5 months post-PBT. In a subgroup of patients who developed RI after undergoing ASCT (n = 55), the eGFR increased temporarily at 1 month post-ASCT; however, this improvement reverted to baseline at 2 months post-ASCT. Among another subgroup of 27 patients who were dialysis-dependent at the time of initial treatment, 18 (66.7%) were no longer dialysis-dependent after a median of 60 days. The best renal response was acquired early during the PBT period, and ASCT did not have a robust impact on the renal outcome. Patients who failed to achieve a renal benefit should be provided with the best supportive care for chronic kidney disease, and this simplified criterion for evaluating the renal response needs to be validated in larger studies before it can be recommended. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are divided in three major groups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 WHO classification incorporates also prefibrotic PMF (pre-PMF) and overt PMF. This study aimed to discriminate the clinical features, genetic alterations, and outcomes in patients with prefibrotic, overt PMF, and secondary MF (SMF). This study included 229 patients with diagnosed myelofibrosis (MF). Among 229 patients, 67 (29%), 122 (53%), and 40 (18%) were confirmed as SMF, overt PMF, and pre-PMF, respectively. The JAK2 V617F mutation was differentially distributed in SMF and PMF, contradictory to CALR and MPL mutations. Regarding nondriver mutations, the occurrence of ASXL1 mutations differed between PMF and SMF or pre-PMF. The three-year overall survival was 91.5%, 85.3%, and 94.8% in SMF, overt PMF, and pre-PMF groups. Various scoring systems could discriminate the overall survival in PMF but not in SMF and pre-PMF. Still, clinical features including anemia and thrombocytopenia were poor prognostic factors throughout the myelofibrosis, whereas mutations contributed differently. Molecular grouping by wild-type SF3B1 and SRSF2/RUNX1/U2AF1/ASXL1/TP53 mutations showed inferior progression-free survival (PFS) in PMF, SMF, and pre-PMF. We determined the clinical and genetic features related to poor prognosis in myelofibrosis.

Treatment for relapsed acute promyelocytic leukemia: what is the best post-remission treatment?

Background: Arsenic trioxide (ATO) is the standard treatment for relapsed acute promyelocytic leukemia (APL). However, consensus on post-remission therapies is still lacking. Methods: We evaluated 52 patients who experienced relapse following initial treatment of APL between 2000 and 2019 at Catholic Hematology Hospital. Among them, 41 patients received reinduction treatment, 30 with ATO-based regimen, whereas 11 with conventional intensive chemotherapy (IC). Results: The ATO reinduction group showed a significantly higher second molecular complete remission (mCR2) rate, superior neutrophil and platelet recovery, and a lower infection rate than the IC reinduction group. No significant differences were observed in survival outcomes after post-remission treatment among the ATO-based (N=19), autologous (N=12), and allogeneic (N=6) hematopoietic stem cell transplantation (HSCT) groups. In the ATO-based and autologous HSCT groups, among patients with mCR2 after ATO reinduction, nine and five patients experienced a second relapse, respectively (50.7% vs. 41.7%, P=0.878). Among these patients, seven received salvage allogeneic HSCT; six remained alive. The other seven patients received ATO without HSCT. Five died from disease progression, and two survived and have been in mCR2 since. Conclusion: Post-remission treatment outcomes of patients with relapsed APL were not significantly different, regardless of the treatment option, suggesting the feasibility of ATO-based treatment without HSCT in mCR2. Allogeneic HSCT may be an effective salvage treatment modality for patients with a second relapse. Owing to a few cases of relapsed APL, multicenter prospective studies may help elucidate the efficacy of each post-remission treatment.

Depth of Response to Intensive Chemotherapy Has Significant Prognostic Value among Acute Myeloid Leukemia (AML) Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation with Intermediate or Adverse Risk at Diagnosis Compared to At-Risk Group According to European Leukemia Net 2017 Risk Stratification.

We evaluated the prognostic efficiency of the European Leukemia Net (ELN) 2017 criteria on the post-transplant outcomes of 174 patients with intermediate (INT; n = 108, 62%) or adverse (ADV) risk (n = 66, 38%) of acute myeloid leukemia; these patients had received the first allogeneic hematopoietic stem-cell transplantation (HSCT) at remission. After a median follow-up period of 18 months, the 2 year OS, RFS, and CIR after HSCT were estimated to be 58.6% vs. 64.4% (p = 0.299), 50.5% vs. 53.7% (p = 0.533), and 26.9% vs. 36.9% (p = 0.060) in the INT and ADV risk groups, respectively. Compared to the ELN 2017 stratification, pre-HSCT WT1 levels (cutoff: 250 copies/104 ABL) more effectively segregated the post-HSCT outcomes of INT risk patients compared to ADV risk patients regarding their 2 year OS (64.2% vs. 51.5%, p = 0.099), RFS (59.4% vs. 32.4%, p = 0.003), and CIR (18.9% vs. 60.0% p < 0.001). Indeed, high WT1 levels were more prominent in INT risk patients than in ADV risk patients. Notably, FLT3-ITD had the greatest impact on post-HSCT outcomes among all the ELN 2017 criteria components; patients in the FLT3-ITD mutant subgroups exhibited the worst outcomes regardless of their allelic ratios or NPM1 status compared to the pre-HSCT WT1 level of other INT and ADV risk patients.

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML).

Background: Evidence that a venetoclax (VEN)-combined regimen is effective in relapsed/refractory acute myeloid leukemia (R/R AML) is emerging. However, it is unknown how VEN-combined low intensity treatment compares to intensive chemotherapy (IC) in medically fit patients with R/R AML. Methods: We compared AML patients who received IC (n = 89) to those who received a VEN in combination with hypomethylating agents or low dose cytarabine (VEN combination) (n = 54) as their first- or second-line salvage after failing anthracycline-containing intensive chemotherapy. Results: The median age was 49 years, and significantly more patients in the VEN combination group were in their second salvage and had received prior stem cell transplantation (SCT). Overall response rates including CR, CRi, and MLFS were comparable (44.0% for IC vs. 59.3% for VEN combination, p = 0.081), but VEN combination group compared to IC group tended to show lower treatment related mortality. The rate of bridging to SCT was the same (68.5%), but the percentage of SCT at blast clearance was significantly higher in the VEN-combined group (62.3% vs. 86.5%, p = 0.010). After median follow-up periods of 22.5 (IC) and 11.3 months (VEN combination), the median overall survival was 8.9 (95% CI, 5.4-12.4) and 12.4 months (95% CI, 9.5-15.2) (p = 0.724), respectively. Conclusion: VEN combination provides a comparable anti-leukemic response and survival to salvage IC, and provide a bridge to SCT with better disease control in medically-fit patients with R/R AML.

Geriatric assessment predicts nonfatal toxicities and survival for intensively treated older adults with AML.

Given that there are only a few prospective studies with conflicting results, we investigated the prognostic value of multiparameter geriatric assessment (GA) domains on tolerance and outcomes after intensive chemotherapy in older adults with acute myeloid leukemia (AML). In all, 105 newly diagnosed patients with AML who were older than age 60 years and who received intensive chemotherapy consisting of cytarabine and idarubicin were enrolled prospectively. Pretreatment GA included evaluations for social and nutritional support, cognition, depression, distress, and physical function. The median age was 64 years (range, 60-75 years), and 93% had an Eastern Cooperative Oncology Group performance score <2. Between 32.4% and 69.5% of patients met the criteria for impairment for each domain of GA. Physical impairment by the Short Physical Performance Battery (SPPB) and cognitive dysfunction by the Mini-Mental State Examination in the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Assessment Packet (MMSE-KC) were significantly associated with nonfatal toxicities, including grade 3 to 4 infections (SPPB, P = .024; MMSE-KC, P = .044), acute renal failure (SPPB, P = .013), and/or prolonged hospitalization (≥40 days) during induction chemotherapy (MMSE-KC, P = .005). Reduced physical function by SPPB and depressive symptoms by the Korean version of the short form of geriatric depression scales (SGDS-K) were significantly associated with inferior survival (SPPB, P = .027; SGDS-K, P = .048). Gait speed and sit-and-stand speed were the most powerful measurements for predicting survival outcomes. Notably, the addition of SPPB and SGDS-K, gait speed and SGDS-K, or sit-and-stand speed and SGDS-K significantly improved the power of existing survival prediction models. In conclusion, GA improved risk stratification for treatment decisions and may inform interventions to improve outcomes for older adults with AML. This study was registered at the Clinical Research Information Service as #KCT0002172.

Differential effects of donor lymphocyte infusion upon treatment response and GVHD according to relapse level and donor sources in patients with myelodysplastic syndrome.

INTRODUCTION: Donor lymphocyte infusion (DLI) is one of the effective options for post-transplant disease control of myelodysplastic syndrome (MDS). Its success or failure depends on the induction of antitumor immune reactions, durability of clinical responses, and severity of unwanted toxicities mainly from graft-versus-host disease (GVHD). METHODS: By analyzing 61 patients receiving DLI for post-transplant MDS relapse, we assessed treatment outcomes and affecting factors, especially focusing on the level of relapse (hematological, molecular, and imminent relapse). RESULTS: The response rate (42.1%, 36.4%, 72.7%), and overall survival (OS) at 2 years (27.8%, 45.5%, 70.1%) were different for each relapse level with imminent relapse group showing the most promising results. For OS, response to DLI or pre-DLI chemotherapy, and time to relapse were independent prognostic factors. Meanwhile, post-DLI GVHD and time to relapse were independently predictive for DLI response; post-DLI GVHD was predictive for DLI response, but not for OS, suggesting a potential detrimental impact of GVHD on survival. The incidence of GVHD and GVHD-related deaths were 37.7% and 10.0%, respectively, and CD3+ cell doses triggering GVHD tended to be lower in cases with haploidentical donor or imminent relapse. CONCLUSION: Despite being limited by small number of cases and its retrospective nature, this study again demonstrated the therapeutic effects of DLI in relapsed MDS, and that earlier detection and intervention at lower level relapse might possibly be associated with better results. Furthermore, we propose that tailored cell dosing schedule based on relapse level and donor source may be helpful in minimizing fatal GVHD.

Low-dose thymoglobulin for prevention of chronic graft-versus-host disease in transplantation from an HLA-matched sibling donor.

Despite the proven efficacy of anti-T-cell or antithymocyte globulin (ATG) for chronic graft-versus-host disease (GVHD) prevention in transplantation from an unrelated donor, dosing protocols and the effects of ATG on relapse and infection remain controversial. In the setting of transplantation from an HLA-matched sibling (MSD-T), few randomized studies have been conducted. We conducted a prospective, single-center, open-label, randomized study of low-dose thymoglobulin (2.5 mg/kg) for chronic GVHD prevention. A total of 120 patients with acute leukemia were randomly assigned in a 1:1 ratio. After a median follow-up of 27 months, the cumulative incidence of chronic GVHD in the ATG and non-ATG groups was 25.0% and 65.4% (p < 0.001), respectively. The ATG group had an increased relapse rate compared with the non-ATG-group (20.0% vs. 9.3%; p = 0.055), with risks that differed according to cytogenetic subgroup (high-risk, 29.6% vs. 9.3%, p = 0.042; non-high-risk, 12.2% vs. 9.2%, p = 0.596). Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group (46.7% vs. 19.4%; p = 0.070), and the difference was significant in a cytogenetic non-high-risk subgroup (45.5% vs. 0%; p = 0.038). No differences were observed in other survival outcomes. Improved physical components in quality-of-life scores were observed in the ATG group at 12 months after transplantation. A higher rate of Epstein-Barr virus reactivation was observed in the ATG group (21.8% vs. 5.1%; p = 0.013), whereas no between-group differences for other complications. In conclusion, the low-dose thymoglobulin effectively prevented chronic GVHD in MSD-T, resulting in improvement in quality-of-life and cGRFS, whereas the necessity of caution for high-risk acute leukemia.

Comparable Outcomes After Alternative and Matched Sibling Donor Hematopoietic Stem Cell Transplantation and the Role of Molecular Measurable Residual Disease for Acute Myeloid Leukemia in Elderly Patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective postremission therapy conferring the chance of cure for acute myeloid leukemia (AML), including elderly patients. Although the number of transplantations for elderly patients with AML (eAML) is increasing owing to greater availability of various graft sources together with the adoption of advanced supportive care and reduced-intensity conditioning (RIC) regimen, there are relatively limited data on the impact of donor type in eAML compared to younger patients. In addition, few studies have evaluated the role of pretransplantation measurable residual disease (MRD) in the elderly population. Given the lack of prospective comparative study, we retrospectively compared transplantation outcomes of elderly patient with AML receiving allo-HSCT from matched sibling donor (MSD-HSCT), matched unrelated donor (MUD-HSCT) or haploidentical related donor (Haplo-HSCT), or autologous HSCT (Auto-HSCT). A total of 154 patients with a median age of 63 years (range 60-74) underwent MSD-HSCT (n = 41), MUD-HSCT (n = 36), Haplo-HSCT (n = 55), or Auto-HSCT (n = 22) for AML. RIC regimens were used in the majority of patients. In Haplo-HSCT, T-cell-replete peripheral blood stem cells with unique RIC regimens using anti-thymocyte globulin (ATG)-based GVHD prophylaxis was used. In the analysis, adjustment for MRD status at the time of transplantation was performed. MRD was measured by the quantitative molecular assays of the targets, including RUNX1-RUNX1T1, CBFB-MYH11, and NPM1, or WT1 in the absence of abnormalities in the aforementioned targets. At a median follow-up of 48 months, survival rates were similar between different donor types, whereas nonrelapse mortality (NRM) was lower in MUD-HSCT compared to MSD-HSCT (P = .002). MSD-HSCT, in which the majority of patients received a conditioning regimen not including ATG, showed more frequent severe chronic graft-versus-host disease (cGVHD). The major causes of non-relapse deaths in MSD-HSCT were related to cGVHD (71%), whereas infectious complications were mainly related to NRM in Haplo-HSCT (50%) or Auto-HSCT (100%). In the MUD-HSCT, GVHD (57%) and infection (43%) contributed similarly to non-relapse death. Cytomegalovirus infection was more frequent in Haplo-HSCT. In multivariate models, pre-transplant MRD-positivity was an independent risk factor for relapse (P = .001), whereas older age (P = .002) and the hematopoietic cell transplantation-comorbidity index (P = .009) were useful in predicting NRM. The current study demonstrated comparable outcomes after alternative and matched sibling donor HSCT in eAML aged 60 years or older, and the results also suggest the necessity for more sophisticated strategies to reduce NRM or relapse according to each donor type. The usefulness of molecular MRD assays demonstrated herein will facilitate trials for MRD-driven decision-making or risk-adaptive approaches in eAML.

Prognostic values of D816V KIT mutation and peri-transplant CBFB-MYH11 MRD monitoring on acute myeloid leukemia with CBFB-MYH11.

Given the controversies in the prognostic value of KIT mutations and optimal thresholds and time points of MRD monitoring for AML with CBFB-MYH11, we retrospectively evaluated 88 patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT, n = 60) or autologous HSCT (Auto-HSCT, n = 28). The D816V KIT mutation was significantly associated with post-transplant relapse, contrasting with other types of mutations in KIT. Pre- and post-transplant (3 months after transplant) CBFB-MYH11 MRD assessments were useful in predicting post-transplant relapse and poor survival. The optimal threshold was determined as a 2 log reduction at both time points. In multivariate analysis, the D816V KIT mutation and CBFB-MYH11 MRD assessments were independently associated with post-transplant relapse and survival. Stratification by D816V KIT and pre-transplant CBFB-MYH11 MRD status further distinguished the risk of relapse and survival. Auto-HSCT was superior to Allo-HSCT in MRD negative patients without D816V KIT, while Allo-HSCT trended to be superior to Auto-HSCT in patients with MRD positivity or the D816V KIT mutation. In conclusion, this study demonstrated the differentiated prognostic value of the D816V KIT mutation in AML with CBFB-MYH11 and clarified optimal time points and thresholds for CBFB-MYH11 MRD monitoring in the setting of HSCT.

Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1-RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1-RUNX1T1.

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1-RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1-RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1-RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

The clinical, laboratory, and radiologic improvement due to siltuximab treatment in idiopathic multicentric Castleman's disease.

BACKGROUND/AIMS: Idiopathic multicentric Castleman disease (iMCD) comprises approximately 30% of all cases of Castleman disease. It is characterized by constitutional symptoms, enlarged lymph nodes at multiple anatomical sites, and laboratory test abnormalities, which are primarily related to the overproduction of interleukin 6 (IL-6). Siltuximab is a human-mouse chimeric immunoglobulin G1κ monoclonal antibody against human IL-6. In view of the limited treatment options for iMCD, this study aimed to evaluate the efficacy and safety of siltuximab in the management of this condition. METHODS: In this real-world retrospective study, we administered siltuximab to 15 patients with iMCD who previously received conventional chemotherapy and/or steroid pulse therapy. The median time to a durable symptomatic response was 22 days (range, 17 to 56). The serum hemoglobin and albumin levels and erythrocyte sedimentation rates significantly normalized after the first 3 months of siltuximab treatment. Lymph node involution, assessed using imaging, was relatively gradual, demonstrating a complete or partial response at 6 months. RESULTS: On an average, the improvements in clinical, laboratory, and radiologic parameters of iMCD in responders were observed after one, three, and eight cycles of siltuximab treatment, respectively. Siltuximab demonstrated a favorable safety profile, and prolonged treatment was well-tolerated. CONCLUSION: Despite the small sample size of the present study, the results are encouraging and demonstrate the potential of siltuximab as the first-line treatment of iMCD. Further large multicenter studies are needed to evaluate the clinical outcomes and adverse events associated with siltuximab.

Haploidentical vs matched unrelated donor transplantation for acute myeloid leukemia in remission: A prospective comparative study.

Despite comparable outcomes of haploidentical transplants (Haplo-HSCT) with HLA-matched unrelated transplants (MUD-HSCT) in retrospective comparisons, few studies have prospectively compared Haplo-HSCT with MUD-HSCT in AML. Here, we prospectively compared the outcomes of Haplo-HSCT with MUD-HSCT for AML in remission (n = 110) to prove non-inferiority of overall survival in Haplo-HSCT. Both groups were well balanced in factors related to biological features of AML and measurable residual disease (MRD) status by Wilms' tumor gene 1 (WT1) assay. A unique, reduced-toxicity preparative regimen was used for Haplo-HSCT, whereas mostly-myeloablative regimen was for MUD-HSCT. Both groups showed similar patterns of neutrophil and platelet recovery, whereas delayed T-cell reconstitution in Haplo-HSCT was found compared with MUD-HSCT. No significant differences were found in acute or chronic graft-vs-host-disease (GVHD) and post-transplant infectious events with an exception of EBV or CMV infection, which occurred more frequently in Haplo-HSCT. After a median follow-up of 47 months, no significant differences in overall survival (65% vs 54%, P = .146), disease-free survival (67% vs 53%, P = .142), relapse (20% vs 21%, P = .858), non-relapse mortality (14% vs 26%, P = .103), or GVHD-free/relapse-free survival (54% vs 41%, P = .138) were observed for Haplo-HSCT vs MUD-HSCT. In multivariate analysis, WT1 expression before transplantation independently predicted relapse, resulting in inferior survival. Separate analysis of unenrolled patients (n = 110) who were excluded or refused to participate in this study showed consistent results with enrolled patients. This prospective study demonstrated the non-inferiority of Haplo-HSCT to MUD-HSCT for AML in remission, and validated the role of WT1 quantification as an MRD marker (ClinicalTrial.gov identifier: NCT01751997).

Impact of Epstein-Barr Virus on Peripheral T-Cell Lymphoma Not Otherwise Specified and Angioimmunoblastic T-Cell Lymphoma.

PURPOSE: The significance of Epstein-Barr virus (EBV) infections for the prognosis of patients with peripheral T-cell lymphomas (PTCLs), specifically angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS), remains unclear. The Epstein-Barr encoding region can be used to detect EBV in tissue sections by in situ hybridization (ISH) and by polymerase chain reaction (PCR) assays of peripheral blood samples from patients with PTCLs. This study compared the outcomes patients with AITL or PTCL-NOS for whom the presence of EBV infection was assessed by these two methods. PATIENTS AND METHODS: This was a retrospective study of patients newly diagnosed with AITL or PTCL-NOS. All patients were selected from a single transplantation center. EBV-positive lymphomas were detected at the time of diagnosis in tissue sections by ISH or in the blood by PCR. RESULTS: Out of a cohort of 140 patients with histologically confirmed AITL or PTCL-NOS, 105 were EBV-positive. The 3-year overall survival of patients with EBV-positive TCL was 43.3% compared to 68.6% in patients with EBV-negative TCL (p = .01). Patients who were treated with autologous or allogeneic hematopoietic stem cell transplantation (n = 28 and n = 11, respectively) or chemotherapy alone (n = 66) had 3-year survival rates of 67.0%, 62.3%, and 30.2%, respectively (p <.02). Patients with EBV-positive TCL had a better prognosis after treatment with hematopoietic stem cell transplantation compared to chemotherapy alone, but no difference was seen among patients with EBV-negative TCL. CONCLUSIONS: EBV infection was shown to negatively affect the clinical outcomes of patients with TCL. Stem cell transplantation has been found to be an effective treatment for EBV-associated lymphomas. Further investigations are warranted to determine the optimal treatment for these patients.

Early Interim Chemotherapy Response Evaluation by F-18 FDG PET/CT in Diffuse Large B Cell Lymphoma.

Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) after one cycle of standard chemotherapy in patients with diffuse large B cell lymphoma (DLBCL) was assessed. Prospectively enrolled 51 patients had four PET/CT studies using the same protocol and system: at baseline and after one, three, and six cycles of chemotherapy (PET0, PET1, PET3, PET6). The PET1 and PET6 Deauville five-point score (D5PS) agreed in 60.8%, while PET3 and PET6 D5PS agreed in 90.2%. The absolute and percent changes of peak standard uptake value corrected for lean body mass (SULpeak) compared to baseline were significantly different between PET1 and PET3 (p = 0.001, p < 0.001) and PET1 and PET6 (p = 0.002, p = 0.001), but not between PET3 and PET6 (p = 0.276, p = 0.181). The absolute SULpeak from PET1 predicted treatment failure with accuracy of 78.4% (area under the curve 0.73, p = 0.023). D5PS, SULpeak, and metabolic tumor volume (MTV) were not statistically different between responders versus non-responders, or the one year disease-free versus relapse groups. D5PS and PERCIST responses showed 100% agreement at end-of-therapy. In conclusion, the responses after three and six cycles of therapy showed high degree of agreement. D5PS or MTV after one cycle of chemotherapy could not predict response or one-year disease-free status, but the SULpeak from PET1 was associated with response to first line therapy in DLBCL. Deauville and PERCIST criteria show high concordance.