Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

3D CNN-based Deep Learning Model-based Explanatory Prognostication in Patients with Multiple Myeloma using Whole-body MRI.

Although magnetic resonance imaging (MRI) data of patients with multiple myeloma (MM) are used to predict prognosis, few reports have applied artificial intelligence (AI) techniques for this purpose. We aimed to analyze whole-body diffusion-weighted MRI data using three-dimensional (3D) convolutional neural networks (CNNs) and Gradient-weighted Class Activation Mapping (Grad-CAM), an explainable AI, to predict prognosis and explore the factors involved in prediction. We retrospectively analyzed the MRI data of a total of 142 patients with MM obtained from two medical centers. We defined the occurrence of progressive disease after MRI evaluation within 12 months as a poor prognosis and constructed a 3D CNN-based deep learning model to predict prognosis. Images from 111 cases were used as the training and internal validation data; images from 31 cases were used as the external validation data. Internal validation of the AI model with stratified 5-fold cross-validation resulted in a significant difference in progression-free survival (PFS) between good and poor prognostic cases (2-year PFS, 91.2% versus [vs.] 61.1%, P = 0.0002). The AI model clearly stratified good and poor prognostic cases in the external validation cohort (2-year PFS, 92.9% vs. 55.6%, P = 0.004), with an area under the receiver operating characteristic curve of 0.804. According to Grad-CAM, the MRI signals of the spleen and bones of the vertebrae and pelvis contributed to prognosis prediction. This study is the first to show that image analysis of whole-body MRI using a 3D CNN without any other clinical data is effective in predicting the prognosis of patients with MM.

GPAM mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia.

Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML-specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34+ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol-3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), rate-limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol-3-phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM-inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM-mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target.

IKZF1plus alterations are not associated with outcomes in Philadelphia-positive acute lymphoblastic leukemia patients enrolled in the FBMTG ALL/MRD2008 trial.

OBJECTIVE: The prognostic significance of IKZF1plus in adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients had remained to be clarified. METHODS: We conducted a prospective, multicenter study, the ALL/MRD2008 trial, and investigated the clinical significance of IKZF1plus . RESULTS: From December 2008 to November 2013, 38 untreated Ph+ ALL patients were enrolled. At the end of the induction, 97.4% of patients (37/38) achieved complete hematological remission, with MRD-negativity of 48.6% (18/37). There were 19 patients with IKZF1plus , 13 with IKZF1 deletion alone (ΔIKZF1) and 4 with no IKZF1 deletions (no ΔIKZF1). The probability of 3-year DFS and OS in these Ph+ ALL patients were 50% (95% confidence interval [CI], 33-65) and 55% (95% CI, 38-69), respectively. There was no significant difference between IKZF1plus , ΔIKZF1, and no ΔIKZF1 in DFS (47%, 54%, 75% [p = .63]) or OS (47%, 62%, NA [p = .39]). CONCLUSIONS: We revealed no relationship between IKZF1plus status and survival outcomes in Ph+ ALL patients treated with imatinib/dasatinib combination chemotherapy. Further investigations are warranted to clarify the prognostic significance of IKZF1plus in adult Ph+ ALL patients.

Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan.

BACKGROUND: In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan. METHODS: Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1-28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1-10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed. RESULTS: Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61-84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome. CONCLUSIONS: The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events.

[Maintenance therapy after allogeneic hematopoietic stem cell transplantation].

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.

Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan.

Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.

Disrupted tongue microbiota and detection of nonindigenous bacteria on the day of allogeneic hematopoietic stem cell transplantation.

Disruption of the intestinal microbiota caused by intensive chemotherapy, irradiation and antibiotics can result in development of severe gut graft-versus-host disease and infectious complications, leading to poorer outcomes among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the oral cavity is also densely colonized by indigenous microorganisms, the bacterial composition in allo-HSCT recipients remains unclear. We determined the tongue microbiota composition of 45 patients with hematological disorders on the day of transplantation and compared them to 164 community-dwelling adults. The V1-V2 regions of the 16S rRNA gene sequences demonstrated that the allo-HSCT recipients had less diverse and distinct microbiota from that of community-dwelling adults. The full-length 16S rRNA gene sequences identified 146 bacterial taxa in the microbiota of allo-HSCT recipients, of which 34 bacterial taxa did not correspond to bacteria primarily inhabiting the oral cavity deposited in the expanded Human Oral Microbiome Database. Notably, the detection of Staphylococcus haemolyticus and/or Ralstonia pickettii was significantly associated with a higher risk of mortality during the follow-up period. These results demonstrate that the oral cavity of allo-HSCT recipients is colonized by a disrupted microbiota on the day of transplantation and suggest that detection of specific nonindigenous taxa could be a predictor of transplant outcome.

A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells.

In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa-/- mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.

Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia.

Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.

Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil.

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation.

We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT.

Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia.

BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.

Safety and Efficacy of Blinatumomab in Japanese Adult and Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Final Results from an Expansion Cohort.

INTRODUCTION: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Globally recommended blinatumomab doses were administered to adult (9-28 µg/day) and pediatric (5-15 µg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. RESULTS: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response. CONCLUSION: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy.

BACKGROUND: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. METHODS: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle. RESULTS: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. CONCLUSIONS: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study.

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.

Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia.

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II-IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P < 0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P = 0.016), but not in UD recipients (HR 1.1, P = 0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants.

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy.

BACKGROUND: In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27). METHODS: VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1-28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1-10). The primary endpoint was median overall survival. RESULTS: In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each). CONCLUSIONS: Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy.