Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

Subcutaneous epcoritamab monotherapy in Japanese adults with relapsed/refractory diffuse large B-cell lymphoma.

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1-3, every 2 weeks during cycles 4-9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1-2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA.

Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3-53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06-0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05-0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.

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.

Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.

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.

Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial.

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.

Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.

BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial.

BACKGROUND: In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. METHODS: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. RESULTS: Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. CONCLUSIONS: Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014.

Daratumumab plus bortezomib, melphalan, and prednisone in East Asian patients with non-transplant multiple myeloma: subanalysis of the randomized phase 3 ALCYONE trial.

In the ALCYONE trial, daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) reduced the risk of disease progression or death by 50% versus bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible newly diagnosed multiple myeloma. Here, we report a subanalysis of East Asian patients from ALCYONE. After a median follow-up of 17.1 and 15.9 months for Japanese (n = 50) and Korean (n = 41) patients, respectively, median progression-free survival for D-VMP versus VMP was not reached (NR) versus 20.7 months in Japanese patients and NR versus 14.0 months in Korean patients. The overall response rate for D-VMP versus VMP was 96% versus 92% in Japanese patients and 91% versus 61% in Korean patients. Using next-generation sequencing, minimal residual disease negativity at 10-5 sensitivity for D-VMP versus VMP was 33% versus 8% among Japanese patients and 17% versus 0% among Korean patients. Rates of any grade and grade 3/4 pneumonia were consistent with the rates observed for the global safety population. Similar efficacy and safety findings were observed in the combined Japanese and Korean subgroup and ≥ 75 years of age subgroup. In conclusion, D-VMP was safe and efficacious in East Asian patients, consistent with the global ALCYONE population.

Prospective evaluation of minimal residual disease monitoring to predict prognosis of adult patients with Ph-negative acute lymphoblastic leukemia.

OBJECTIVE: We investigated whether minimal residual disease (MRD) status in adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) is useful for decision on clinical indications for allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL. RESULTS: Among 103 adult ALL patients enrolled, 59 were Ph-negative, and MRD status was assessed in 51 patients. The probability of 3-year overall survival (OS) and disease-free survival (DFS) was 69% (95%CI 54-80) and 50% (95%CI 36-63), respectively. Patients who were MRD-negative after induction therapy (n = 15) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 30; 73% vs 41%, P = 0.018). Patients who were MRD-positive after induction but became MRD-negative after consolidation chemotherapy C in the first course (n = 11) showed a significantly worse 3-year DFS compared with patients who were MRD-negative after induction chemotherapy A in the first course (45% vs 73%, P = 0.025). CONCLUSIONS: These results indicate that DFS of about 70% can be expected in MRD-negative patients after induction therapy, and the patients did not benefit from HSCT in 1CR. This study was registered with the UMIN Clinical Trials Registry (UMIN-CTR), number UMIN000001519.

Treatment-associated outcomes of patients with primary ocular adnexal MALT lymphoma after accurate diagnosis.

BACKGROUND: Differentiation between primary ocular adnexal mucosa-associated lymphoid tissue (POA-MALT) lymphoma and reactive lymphoid hyperplasias sometimes may be difficult. We have examined the treatment-associated mortality of POA-MALT lymphoma after confirmed diagnosis and evaluated their proper treatments. PATIENTS AND METHODS: From 1991 through 2016, cases of POA-MALT lymphoma were retrospectively analyzed based on their pathological and molecular/immunological diagnoses. RESULTS: A total of 78 cases with POA-MALT lymphoma with a median age of 66 years were analyzed over median/mean observations of 6.4/7.1 years. Forty-four patients (56%) were diagnosed with IgH gene clonality and 10 patients (13%) were diagnosed with flow cytometric analysis in addition to the pathological decision. The rest (24 patients, 31%) were diagnosed employing pathological decisions of hemato-pathologists and clinical decisions. All patients, except cases of watchful waiting, achieved complete remission. After initial treatment, 68 patients (87%) presented disease-free during the observation period. As treatment, a radiotherapy-based strategy was followed with 15 patients (19%, group A). Immuno-chemotherapy was administered to 24 patients (31%, B). Surgical extraction only was selected for 36 patients (46%, C). Watchful waiting was selected with three patients (4%). Recurrence after the initial treatment was found in one patient (7%) out of A, in three patients (13%) out of B, and in six patients (17%) out of C, respectively. Progression-free survivals at 5 and 10 years were 100 and 100% in A, 95 and 75% in B, and 88 and 81% in C, respectively. The recurrence rates between the patients who were diagnosed with only pathological decision (n = 24) and the patients who were diagnosed with molecular and immunological procedures (n = 54) did not show any statistical differences. CONCLUSION: Our results indicate that radiotherapy-based treatment strategies for patients with POA-MALT lymphoma show a low rate of recurrence and may improve their prognosis even after the accurate diagnosis. However, contamination of the cases with reactive (polyclonal) lymphoid hyperplasia into those with MALT lymphoma should be carefully removed to avoid unnecessary treatment for malignancies that do not exist.

Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol.

BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide after Busulfan-Containing Reduced-Intensity Conditioning.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT.

Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate-associated large B lymphoproliferative disorders.

AIMS: To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD). METHODS AND RESULTS: Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01). CONCLUSIONS: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.

A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

[Effect of bortezomib-based induction therapy on the peripheral blood stem cell harvest in multiple myeloma].

A high dose of melphalan followed by autologous stem cell transplantation (ASCT) is considered as the standard therapy for multiple myeloma. For induction therapy, 78 patients received conventional regimens (control group) and 32 patients received bortezomib-containing regimens (bortezomib group). We retrospectively compared the yield of harvested CD34+ cells between the two groups. In order to mobilize CD34+ cells, 83% of the control group and 63% of the bortezomib group received a high dose of cyclophosphamide followed by G-CSF, and 12% of the control group received a high dose of etoposide instead of cyclophosphamide. Furthermore, 5% of the control group and 38% of the bortezomib group received G-CSF alone for CD34+ cell mobilization. Overall, the yield of CD34+ cells was higher in the control group than in the bortezomib group (7.4 vs. 5.2×10(6)/kg, P=0.004). Regarding the patients mobilized by a high dose of cyclophosphamide followed by G-CSF, the rate of achieving CD34+ cells >2.0×10(6) cells/kg was similar. Bortezomib did not significantly affect the successful collection of at least CD34+ cells > 2.0×10(6) cells/kg after mobilization with a high dose of cyclophosphamide followed by G-CSF.

Impact of a third dose of anti-SARS-CoV-2 vaccine in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10-40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.

[Acute lung injury in a patient with concurrent diffuse large B-cell lymphoma and myelodysplastic syndrome].

A 67-year-old man developed a diffuse large B-cell lymphoma, and was simultaneously diagnosed as myelodysplastic syndrome(refractory cytopenia with multilineage dysplasia). Acute lung injury was complicated after the 6th course of rituximab injection, but was recovered by steroid pulse therapy. At that moment, marked leucocytosis was prominent due to the disease progression of myelodysplastic syndrome. Two months later, he relapsed into lymphoma systematically. During salvage chemotherapy without rituximab, the patient deteriorated into lethal respiratory failure. Autopsy findings revealed the diffuse alveolar damage with microscopic evidence of an adenovirus infection. His bone marrow showed the transformation of myelodysplastic syndrome into acute myeloid leukemia. The coincidence of myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. We should be cautious when acute lung injury occurs during such a condition.