Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

BACKGROUND: Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). METHODS: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. RESULTS: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). CONCLUSION: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Expression, mutation, and methylation of cereblon-pathway genes at pre- and post-lenalidomide treatment in multiple myeloma.

Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.

High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma: Data From the Japan Society for Hematopoietic Cell Transplantation Registry.

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

OBJECTIVES: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). METHODS: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m ) were the post-treatment factors investigated to predict the molecular response. RESULTS: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. CONCLUSIONS: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.

Outcome From a Randomized Controlled Clinical Trial　- Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT).

BACKGROUND: The clinical usefulness of peripheral blood (PB) mononuclear cell (MNC) transplantation in patients with peripheral arterial disease (PAD), especially in those with mild-to-moderate severity, has not been fully clarified.Methods and Results:A randomized clinical trial was conducted to evaluate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMNC transplantation in patients with PAD (Fontaine stage II-IV and Rutherford category 1-5) caused by arteriosclerosis obliterans or Buerger's disease. The primary endpoint was progression-free survival (PFS). In total, 107 subjects were enrolled. At baseline, Fontaine stage was II/III in 82 patients and IV in 21, and 54 patients were on hemodialysis. A total of 50 patients had intramuscular transplantation of PBMNC combined with standard of care (SOC) (cell therapy group), and 53 received SOC only (control group). PFS tended to be improved in the cell therapy group than in the control group (P=0.07). PFS in Fontaine stage II/III subgroup was significantly better in the cell therapy group than in the control group. Cell therapy-related adverse events were transient and not serious. CONCLUSIONS: In this first randomized, large-scale clinical trial of G-CSF-mobilized PBMNC transplantation, the cell therapy was tolerated by a variety of PAD patients. The PBMNC therapy was significantly effective for inhibiting disease progression in mild-to-moderate PAD.

A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.

Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial.

OBJECTIVES: In cases of hematological malignancy, patients with persistent fever and neutropenia receive antifungal empirical therapy to prevent and treat invasive fungal infections. The clinical efficacy and safety of micafungin and voriconazole were compared. METHODS: In this randomized, cooperative group, open-label trial, we assessed and compared the efficacy and safety of micafungin and voriconazole as an empirical antifungal therapy in febrile neutropenic patients with hematological malignancy. Patients were classified according to invasive fungal infection risk. RESULTS: There were no significant differences in clinical efficacy between the two treatments, evaluated based on (i) successful treatment of baseline fungal infection (no evaluation), (ii) absence of breakthrough fungal infection (P = 0.106), (iii) survival for ≥7 days after study completion (P = 0.335), (iv) premature study discontinuation due to poor efficacy (P = 0.424), and (v) resolution of fever during neutropenia (P = 0.756). Discontinuation due to drug-related adverse events (grades 3-4) occurred less frequently in the micafungin group (P = 0.005). CONCLUSIONS: The clinical efficacy did not differ between micafungin and voriconazole. Micafungin was generally better tolerated than voriconazole when given as an empirical antifungal therapy in patients with persistent fever and neutropenia.

Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia.

PURPOSE: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients. METHODS: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration. RESULTS: Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively). CONCLUSION: These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis.

A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria.

BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). METHODS: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. RESULTS: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. CONCLUSIONS: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.

A single high-resolution HLA mismatch has a similar adverse impact on the outcome of related hematopoietic stem cell transplantation as a single low-resolution HLA mismatch.

The relative importance of the resolution level of HLA typing has not been fully defined for related donor transplantation. To address this question, we retrospectively evaluated patients who underwent a first related hematopoietic stem cell transplantation (HSCT) from 2000 to 2011 from an HLA high-resolution matched (MRD, n = 2,244), high-resolution 1 locus-mismatched (HR-MMRD, n = 116), or low-resolution 1 locus-mismatched related donor (LR-MMRD, n = 396) in the graft-versus-host direction at three loci (HLA A, B, and DRB1) using the database of the Japan Society for Hematopoietic Cell Transplantation. The median age was 40 years (0-74). The median follow-up duration of surviving patients was 950 days. Although the cumulative incidences of grade III-IV acute graft-versus-host disease (GVHD) in the HR-MMRD and LR-MMRD groups were significantly higher than those in the MRD group (HR-MMRD 19.8%, LR-MMRD 20.4%, and MRD 9.5%), there was no statistically significant difference between the HR-MMRD and LR-MMRD groups (P = 0.65). Although both HR-MMRD and LR-MMRD were significantly associated with an increased risk of non-relapse mortality and a worse overall survival, there was no statistically significant difference between the HR-MMRD and LR-MMRD groups. In conclusion, LR-MM and HR-MM have a similar adverse impact on the outcome in related HSCT.

Asciminib in Patients With CML-CP Previously Treated With ≥ 2 Tyrosine Kinase Inhibitors: 96-Week Results From the Japanese Subgroup Analysis of the ASCEMBL Study.

Asciminib is a first-in-class BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket (STAMP). It is approved worldwide and in Japan for chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to previous tyrosine kinase inhibitor (TKI) therapy. In the Phase 3 ASCEMBL study, patients with CML-CP who received ≥ 2 prior ATP-competitive TKIs were randomized (2:1) to asciminib 40 mg twice-daily or bosutinib 500 mg once-daily. Here, we report the 96-week results of the subgroup analysis of Japanese patients (asciminib, n = 13; bosutinib, n = 3) in the ASCEMBL study. The MMR rate at Week 96 was 46.2% in asciminib-treated patients, increasing from Weeks 24 and 48. Patients who achieved MMR at Week 24 remained in MMR up to the Week 96 cutoff. While a high proportion of patients treated with asciminib remained on treatment at cutoff, none randomized to bosutinib were on treatment at Week 96. Despite the longer duration of exposure to asciminib, its safety and tolerability continued to be favorable with no new or worsening safety findings. Overall, the efficacy and safety outcomes in the Japanese subgroup were comparable with the ASCEMBL global study population, which supports the use of asciminib in Japanese patients with previously treated CML-CP.

Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study.

Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS ] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut-off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09-61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.

Quantification of Epstein-Barr virus DNA is helpful for evaluation of chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) presents with chronic or recurrent infectious mononucleosis-like symptoms, such as low-grade fever, liver dysfunction, lymphadenopathy, and hepatosplenomegaly. Immunological methods are useful for the diagnosis of viral infections. However, CAEBV patients do not necessarily have high titers of Epstein-Barr virus (EBV)-specific antibodies. Hosts that are immunocompromised after hematopoietic stem cell transplantations sometimes suffer from systemic EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and EBV-positive lymphoma. Patients with EBV-associated diseases are often diagnosed by analyses of bone marrow. Cytomegalovirus (CMV) can cause serious pneumonia or retinitis in immunocompromised hosts. In order to noninvasively understand the clinical status of patients with EBV-associated diseases, we conducted real-time polymerase chain reaction (PCR) methods in their peripheral blood in order to quantify EBV and CMV DNA levels, which reflect viral activity. Here, we describe a 30-year-old Japanese female patient with CAEBV. The patient had repeated fever, fatigue, and liver dysfunction. The histopathological results of liver biopsies were positive for EBV-encoded RNA-1. Acute hepatitis was associated with the EBV infection. The whole-blood EBV DNA levels were high and above 1.0 × 107 copies/mL. After immunosuppressive and antiviral therapies, EBV DNA levels lowered. However, she had to receive bone marrow transplantation because of her EBV-HLH. As the number of lymphocytes increased in the post-transplantation period, EBV DNA levels gradually increased again. The simultaneous detection of CMV DNA was more sensitive than the CMV antigenemia test that is often used to diagnose CMV infections. Unfortunately, the patient died due to a fungal infection. Observing EBV DNA levels closely with real-time quantitative PCR methods is helpful for evaluating the changes in the clinical course.

A phase II randomized study evaluating azacitidine versus conventional care regimens in newly diagnosed elderly Japanese patients with unfavorable acute myeloid leukemia.

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.

Monitoring twenty-six chronic myeloid leukemia patients by BCR-ABL mRNA level in bone marrow:a single hospital experience.

Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.

A high CD34+ cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors.

To elucidate the impact of infused CD34+ cell doses on transplant outcome, we retrospectively analyzed 851 adult patients who received peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-matched related donors. The patients were divided into high- and low-CD34 groups at the cutoff value of 4.5 × 106/kg. Overall, the high CD34 group showed early neutrophil and platelet recovery. Stratification of disease risks demonstrated that among the patients with low-risk diseases, the high-CD34 group showed better disease-free survival (DFS) (64.9% vs. 55.5%, P = 0.0415) than did the low-CD34 group, without any increase in graft-versus-host disease (GVHD). Meanwhile, a higher CD34+ cell dose had no impacts on the outcomes of patients with high-risk diseases. Multivariate analyses for the patients with low-risk diseases revealed that a high CD34+ cell dose (hazard ratio [HR] 0.72, P = 0.048) and development of grade III-to-IV acute GVHD (HR 1.64, P = 0.018) were significantly associated with DFS. An excessive dose of CD34+ cells (>8.0 × 106/kg) led to an increase in acute GVHD. By stratification of disease risk, a CD34+ cell dose between 4.5 and 8.0 × 106/kg can be suggested for patients with low-risk diseases who undergo PBSCT from HLA-matched related donors.

Elotuzumab plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma: a randomized, open-label, phase 2 study in Japan.

Novel therapies are needed for patients with newly diagnosed multiple myeloma (NDMM). Elotuzumab plus lenalidomide and dexamethasone (ELd) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2 study in Japan evaluated ELd vs lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation. Elotuzumab infusion was accelerated to 5 mL/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 h. The primary endpoint was overall response rate (ORR) in the ELd arm. Secondary endpoints were the difference in ORR between treatments, and progression-free survival (PFS). Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld). In the ELd arm, ORR was 88% [70% confidence interval (CI) 80-93]. The estimated difference in ORR between treatments was 13% (95% CI - 4, 30) in favor of ELd. Progression-free survival data were immature. Safety was consistent with previous findings of ELd in Japanese patients with RRMM. No infusion reactions occurred at the maximum rate of 5 mL/min, which was used in 89% of elotuzumab infusions. ELd may be an effective, well-tolerated frontline treatment for patients with NDMM ineligible for stem cell transplantation.

Efficacy and safety of obinutuzumab in patients with previously untreated follicular lymphoma: a subgroup analysis of patients enrolled in Japan in the randomized phase III GALLIUM trial.

GALLIUM is a global phase III study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with obinutuzumab plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). In this single-country subgroup analysis, we explored patterns of efficacy and safety in patients enrolled in the GALLIUM study in Japan (Japanese subgroup). Patients were randomized to open-label induction treatment with G-chemo or R-chemo. Responders received maintenance monotherapy with their randomized antibody for up to 2 years. The primary endpoint was investigator-assessed PFS. Overall, 123 patients with FL were randomized in the Japanese subgroup (G-chemo, n = 65; R-chemo, n = 58). The majority of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (82.9 vs 33.1% in the global GALLIUM FL population). PFS at 3 years was 89.9% (G-chemo) vs. 74.7% (R-chemo); hazard ratio 0.42; 95% confidence interval 0.15, 1.15; P = 0.08. Higher rates of grade 3-5 adverse events (96.9 vs. 89.7%) and serious adverse events (35.4 vs. 22.4%) were observed with G-chemo vs R-chemo, respectively. Neutropenia was frequent in the Japanese subgroup (92.3% G-chemo; 79.3% R-chemo). Overall, the results in the Japanese subgroup were consistent with those in the global GALLIUM population.

[Long-term complete remission after single therapy with gemtuzumab ozogamicin for refractory AML in an elderly patient].

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, that is rapidly internalized after binding to CD33. This is followed by intracellular release of calicheamicin, which induces double-stranded DNA breaks, cell cycle arrest, and apoptosis. So GO is a more selective agent for acute myeloid leukemia (AML), because the CD33 antigen is expressed on AML, while it is not expressed on normal hematopoietic stem cells and nonhematopoietic tissues. However, some studies indicated that this agent showed resistance to refractory AML cells via various mechanisms, and that there were no potent effects. In this study, we report a 76-year-old female with recurrent AML who responded to single therapy with GO, achieving complete remission for more than 1 year after the start of administration, although additional remission induction was impossible. The response to GO can be stratified with reference to the response to conventional chemotherapy.