Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Isatuximab Plus Carfilzomib and Dexamethasone in East Asian Patients With Relapsed Multiple Myeloma: Updated IKEMA Subgroup Analysis.

BACKGROUND: The Phase 3 IKEMA study (NCT03275285) demonstrated isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in patients with relapsed multiple myeloma (MM) compared with Kd. A post-hoc analysis of East Asian patients in IKEMA evaluated the efficacy and safety of Isa-Kd versus Kd in this population and was previously published. PATIENTS AND METHODS: Patients with relapsed MM who had received 1 to 3 prior lines of therapy were randomized 3:2 to receive Isa-Kd or Kd. The primary endpoint was PFS, and key secondary endpoints included rate of very good partial response or better (≥VGPR), complete response (CR) rate, and minimal residual disease (MRD) negativity. Of the IKEMA overall population, 46 patients were of East Asian descent. This is an updated analysis of the efficacy and safety of Isa-Kd in East Asian patients, including data through 14 January 2022. RESULTS: Isa-Kd continued to demonstrate improved efficacy and safety versus Kd in East Asian patients with relapsed MM, with improved PFS, rate of ≥VGPR, CR rate, and MRD negativity, that was consistent with the overall IKEMA population. The rate of Grade ≥3 treatment-emergent adverse events was also consistent with the prior analysis and overall IKEMA population. CONCLUSION: Based on the results of this analysis, Isa-Kd is a novel treatment option for East Asian patients with relapsed MM.

EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress.

Extramedullary disease (EMD) is known to be associated with chemoresistance and poor prognosis in multiple myeloma (MM); however, the mechanisms of its development are not fully understood. Elucidating the mechanism of EMD development and its therapeutic targeting would greatly contribute to further improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44, especially long-stretch variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) in vitro and in murine models via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Treatment of HA-injected mice with anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD from transplanted MM cells and significantly prolonged the survival of recipients by overcoming PI resistance. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the prediction, prevention, and treatment of EMD in patients with MM.

Anti-CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Isatuximab plus carfilzomib and dexamethasone in East Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

In the phase 3 IKEMA study (NCT03275285), isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in relapsed multiple myeloma (MM), compared with Kd. This IKEMA subgroup analysis evaluated efficacy and safety of Isa-Kd versus Kd among East Asian patients. Eligible patients had 1-3 prior lines of therapy and were stratified by number of prior lines and revised International Staging System. The primary endpoint was PFS. Key secondary endpoints included overall response, very good partial response or better (≥VGPR), minimal residual disease (MRD) negativity, and complete response (CR) rate. Forty-six East Asian patients (19 Japanese, 27 South Korean) were randomized to Isa-Kd (n = 25) or Kd (n = 21). Isa-Kd improved PFS (HR 0.64; 95% CI 0.23-1.76), ≥VGPR (80.0% vs 52.4%), MRD negativity rate (44.0% vs 9.5%), and CR (44.0% vs 23.8%). The rate of grade ≥ 3 treatment-emergent adverse events (TEAEs) was 79% for Isa-Kd versus 55% for Kd. The rate of serious TEAEs was 46% versus 50%, and the rate of TEAEs leading to treatment discontinuation was 4% versus 10%. Overall, Isa-Kd improved efficacy and safety versus Kd in East Asian patients with relapsed MM, consistent with the overall IKEMA population.

Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis.

BACKGROUND: In the pivotal phase III, randomized, multicenter ICARIA-MM study (NCT02990338), isatuximab plus pomalidomide and dexamethasone (Isa-Pd) improved progression-free survival and overall response rate versus pomalidomide and dexamethasone (Pd) in the overall population of patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: In this predefined subgroup analysis, efficacy, and safety between East Asian patients and the overall population were assessed. RESULTS: In total, 36 East Asian patients were included (Japanese, n = 13; Korean, n = 9; Taiwanese, n = 14). At a median follow-up of 11.6 months, median progression-free survival was not reached (95% confidence interval [CI] 5.80-not calculable) in the Isa-Pd arm and was 7.9 months (95% CI 2.90-not calculable) in the Pd arm. The hazard ratio for the between-group difference was 0.52 (95% CI 0.19-1.39), which was similar to the overall population (hazard ratio, 0.60; 95% CI 0.44-0.82). No new safety signals were observed, except that a higher proportion of patients in the East Asian population experienced Grade ≥ 3 neutropenia compared with the overall population. CONCLUSION: These results confirm the efficacy of Isa-Pd in East Asian patients with relapsed/refractory multiple myeloma, and the related safety data are consistent with those observed in the overall population and are manageable.

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients.

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.

Correction to: Plerixafor for mobilization and collection of haematopoietic stem cells for autologous transplantation in Japanese patients with non-Hodgkin lymphoma: a randomized phase 2 study.

The affiliation of the last author, Kenshi Suzuki has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

Plerixafor for mobilization and collection of haematopoietic stem cells for autologous transplantation in Japanese patients with non-Hodgkin lymphoma: a randomized phase 2 study.

The present study (ClinicalTrials.gov Identifier: NCT02221492) was conducted to assess the efficacy and safety of plerixafor for the mobilization and collection of haematopoietic stem cells (HSCs) for autologous transplantation in Japanese non-Hodgkin lymphoma (NHL) patients. In this randomized phase 2 study, patients received granulocyte-colony stimulating factor (G-CSF, filgrastim) 400 µg/m²/day for up to 8 days. Starting on the evening of day 4, patients received, for up to 4 days, either plerixafor (240 µg/kg/day) in the G-CSF+ plerixafor arm (GP arm) or G-CSF alone arm (G arm). On day 5, daily apheresis started and was continued for up to 4 days, or until ≥ 5 × 106 CD34+ cells/kg was collected. A total of 32 patients were randomized to either the GP or G arm. In the GP arm, 9/16 patients (56.3%) achieved collection of ≥ 5 × 106 CD34+ cells/kg in ≤ 4 days of apheresis, while 1/16 patient (6.3%) achieved this target in the G arm. The most common treatment-emergent adverse events in the GP arm were back pain (56.3%), platelet count decreased (25.0%), headache, diarrhoea, and nausea (18.8% each). We found that plerixafor was well tolerated and effective for the mobilization and collection of peripheral HSCs for autologous transplantation in Japanese NHL patients.

The Efficacy of Reduced-dose Dasatinib as a Subsequent Therapy in Patients with Chronic Myeloid Leukemia in the Chronic Phase: The LD-CML Study of the Kanto CML Study Group.

Objective The aim of this study was to prospectively investigate the efficacy and safety profiles of low-dose dasatinib therapy (50 mg once daily). Methods Patients with chronic myeloid leukemia in the chronic phase (CML-CP) who were being treated with low-dose imatinib (≤200 mg/day), but were resistant to this agent were enrolled in the current study (referred to as the LD-CML study). Results There subjects included 9 patients (4 men and 5 women); all were treated with dasatinib at a dose of 50 mg once daily. Among 8 patients who had not experienced major molecular response (MMR; BCR-ABL1 transcript ≤0.1% according to International Scale [IS]) at study enrollment, 5 attained MMR by 12 months. In particular, 3 of 9 patients demonstrated a deep molecular response (DMR; IS ≤0.0069%) by 18 months. Five patients developed lymphocytosis accompanied by cytotoxic lymphocyte predominance. There was no mortality or disease progression, and all continue to receive dasatinib therapy at 18 months with only 2 patients requiring dose reduction. Toxicities were mild-to-moderate, and pleural effusion was observed in 1 patient (grade 1). Conclusion Low-dose dasatinib can attain MMR and DMR without severe toxicity in patients with CML-CP who are unable to achieve MMR with low-dose imatinib. Switching to low-dose dasatinib should therefore be considered for patients in this setting, especially if they are otherwise considering a cessation of treatment.

Case report of subcutaneous panniculitis-like T-cell lymphoma complicated by eyelid swelling.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare, highly malignant, extranodal lymphoma that preferentially infiltrates into subcutaneous adipose tissue. No case of SPTCL with the earliest symptoms occurring in the eye region has been reported. We report a case of SPTCL complicated by eyelid swelling. CASE PRESENTATION: A 19-year-old Japanese man presented with worsening left eyelid swelling. The patient's best-corrected visual acuity (BCVA) was 0.8, left intraocular pressure was 36 mm Hg, and he had prominent mucosal hyperemia and edema. His left eye had light reflex attenuation and a positive relative afferent pupillary defect, but no abnormality in the visual field or central flicker value. Magnetic resonance imaging showed left orbital adipose tissue inflammation. The blood examination was normal. He was hospitalized for an intensive examination and treatment for possible cellulitis, orbital panniculitis, and inflammatory pseudotumor. Systemic antibiotics were initiated. The following day, he underwent a sub-Tenon's injection of triamcinolone. Left eyelid swelling gradually improved. He was discharged on the ninth day and followed up with oral prednisolone. Two months later, he visited our department because of a high fever and slight right eyelid swelling. Ocular hypertension was detected. A blood examination revealed pancytopenia. Computed tomography showed fluid retention, hydrothorax, and abdominal dropsy. Magnetic resonance imaging revealed right orbital panniculitis. Because of suspected hemodyscrasia, he was referred to the hematology department of another hospital where he was diagnosed with SPTCL. CONCLUSIONS: The possibility of SPTCL, with attention to recurrence and systemic symptoms, should be considered in young patients with sudden eyelid swelling.

Corynebacterium jeikeium bacteraemia and pulmonary infiltrates in a patient with acute myelogenous leukaemia.

The authors used vancomycin (VCM) to treat Corynebacterium jeikeium bacteraemia and pulmonary infiltrates in a patient with acute myelogenous leukaemia. Pulmonary infiltrates are found in about one-third of patients with haematological pathologies accompanying C jeikeium bacteraemia. Although linezolid and daptomycin are antimicrobial alternatives for treating Corynebacterium infections, the authors believe that VCM is the best choice for immediate treatment success and to prevent pulmonary infiltrates from developing in the presence of bloodstream infection with Corynebacteria in patients with haematological malignancies.

Diffuse large B-cell lymphoma complicated with autoimmune thrombocytopenia.

A patient was diagnosed with autoimmune thrombocytopenia and concurrent diffuse large B-cell lymphoma (DLBCL). Both autoimmune thrombocytopenia and DLBCL were successfully treated using chemotherapy, while steroid therapy, rituximab monotherapy, and high-dose parenteral glucocorticoid therapy combined with high-dose intravenous immunoglobulin failed to improve thrombocytopenia. A greater understanding of the pathogenesis and treatment options can only be definitively clarified by analyses of settings such as the present case, as autoimmune thrombocytopenia is uncommon in patients with malignant lymphoma and the etiology and optimal treatment remain unclear.