Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

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.

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.

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.

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings.

BACKGROUND: Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities. METHODS: In this phase 1/2 study (NCT02265731), Japanese patients (≥60 years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400 mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 per 28-day cycle until disease progression or unacceptable toxicity. RESULTS: As of 10 December 2019, six patients were enrolled (median age: 75 years; untreated: n = 5; relapsed/refractory: n = 1); median treatment duration: 10.3 months (range, 0.7-29.4). Most common grade ≥ 3 adverse events were lymphopaenia and febrile neutropaenia (n = 4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n = 3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0 month (range, 0.8-5.5); median overall survival: 15.7 months (95% confidence interval: 6.2, not reached). CONCLUSIONS: Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

[Clinical statistics of recurrent acute low-tone senseorineural hearing loss].

Recently, acute low-tone senseorineural hearing loss (ALHL) has become common, and its good prognosis is known well. On the other hand, several reports have suggested that ALHL is frequently associated with Meniere's disease. We retrospectively examined the clinical course of 357 cases that were diagnosed and treated as ALHL at our hospitals. Forty-four of these cases that showed high-tone hearing loss in association with age-related changes were classified as atypical cases. The clinical futures of 49 "poor prognosis cases", who experienced recurrent hearing loss and/or profound hearing loss, are reported. Eight of the 49 cases who experienced recurrences had progressive hearing loss upto middle or high tones. Seventeen cases complained of vertiginous sensation, and 8 of these cases experienced recurrent attacks of vertigo and were diagnosed as having Meniere's disease. The former seventeen cases accounted for 34.7% of the "poor prognosis cases", and the latter eight accounted for 16.3% of these cases. Our results suggest that the hearing loss is more frequently associated with Meniere's disease in cases who experience recurrent hearing loss. Thus, cases initially diagnosed as ALHL may include some cases of progressive hearing loss and Meniere's disease. Even in cases in which hearing improvement is obtained, careful clinical observation is necessary, especially in older patients with bilateral affliction and atypical presentation. ALHL has been generally considered to have a good prognosis, however our examination revealed a relatively high frequency of recurrences, progressive hearing loss and complication by vertigo. We recommend, based on this evidence, that careful explanation of this disease is necessary at time of initial informed consent.

An analytical system for determining delta17O in CO2 using continuous flow-isotope ratio MS.

We developed a simple measurement system for delta17O in nanomole quantities of CO2 using continuous flow isotope ratio mass spectrometry (CF-IRMS). The analytical system consisted of a sample injection system, a helium-purged CO2 purification line, a capillary GC, a combustion unit, and CF-IRMS. A unique feature of the system is that we use molecular CO2 to determine the isotopic compositions including delta17O. The delta17O of CO2 in a sample is calculated from the mass ratios of both 45/44 and 46/44 of two different kinds of CO2, which have been purified quantitatively from different aliquots of a sample. While one aliquot (rCO2) flows into IRMS directly, the other (eCO2) flows through a CuO unit (900 degrees C) prior to injection into IRMS, to exchange oxygen atoms in the sample CO2 molecules with those in CuO for which we can assume Delta17O = 0. In our system, we introduce both rCO2 and eCO2 alternately to IRMS repeatedly by using an automatic multianalytical system to improve analytical precision statistically. The standard deviation of 0.35 per thousand for Delta17O can be realized using as little as 8.7 nmol CO2 in a approximately 3-h analysis. Based on this system, we have quantified delta17O in the stratospheric CO2 over Japan.

[Bilaterality in acute low-tone sensorineural hearing loss].

Bilaterality in acute low-tone sensorineural hearing loss (ALHL) is more generally recognized than that in idiopathic sudden sensorineural hearing loss. Subjects were 274 patients diagnosed with ALHL based on criteria of a study group of the Ministry of Health, Labor and Welfare of Japan, i.e., total of 3 low tone hearing of 70dB or more and, a total of 3 high-tone hearing of 60dB or less, and treated at the departments of otolaryngology at Yamanashi University and Suwa Central Hospital. ALHL involving bilateral ears symptoms and/or bilateral hearing impairment conforming to diagnostic criteria was selected and summarized. Clinical ear symptoms, clinical test results, and hearing levels (total 3 low tone hearing, 1kHz, and total of 3 high-tone hearing) were statistically analyzed. We also reviewed Japanese clinical reports of ALHL that include bilateral cases. In 32 cases (11.7%) of 274 cases, both ear symptoms and hearing impairment were bilateral. In 22 (8.0%) of the 274, bilateral ear symptoms were present, but showed unilateral hearing loss conforming to diagnostic criteria. Another 22 (8.0%) out the 274 reported unilateral ear symptoms, but hearing tests indicated bilateral ALHL. A total of 76 cases (27.7%) of the 274 had bilaterality in either ear symptoms or hearing loss. Our review indicated that 9.0% (162 of 1803) ALHL patients were bilaterally affected, possibly indicating that AIHL includes a larger number of bilateral cases than currently assumed, if the opposite side were given a especially detailed clinical interview. Statistical analysis (Mann Whitney test, P<0.01) of hearing of unilateral cases indicated that 3 low tone hearing was more affected than 3 high-tone hearing, even on the normal side. These results indicate that ALHL tends to be bilateral, possibly due to the mechanism of pathogenesis, and also that the mechanism may include both local and general conditions. This more closely resembles Meniere's disease than idiopathic sudden sensorineural hearing loss. Both sides of bilateral cases were not usually the same in hearing patterns, glycerol test results, or prognosis. A statistically significant difference (Mann Whitney test, P<0.01) in total of 3 low tone hearing was seen between worse and better sides in bilateral cases. The degree of disease on both sides in bilateral cases thus was not always the same. Bilateral cases may result from both the influence of general conditions such as fatigue, stress, and lack of sleep and local conditions such as pathogenesis of endolymphatic hydrops that may cause differences in both ears. No clear difference was seen in clinical symptoms, hearing levels, and clinical examination, e.g., Schellong and glyceol tests, between unilateral and bilateral cases. Bilateral cases had a poorer prognosis (lower complete recovery ratio; chi2 test P<0.01) than unilateral cases. Our results indicated that cautious evaluation of opposite ear is necessary in diagnosis, treatment, and prognostication of ALHL.

Carbon dioxide laser vaporization of the inferior turbinate for allergic rhinitis: short-term results.

Carbon dioxide laser vaporization of the turbinate has recently become accepted as a common treatment for allergic rhinitis. Usually, only a single procedure is applied to minimize trauma. However, repeated procedures on separate days are often required to achieve an adequate effect. Therefore, we attempted a new method of vaporization and evaluated the outcome, and also tried to determine which patients have good indications for laser treatment. To widely and deeply vaporize the inferior turbinate, we repeated the procedure 3 times in 1 session after removing the carbon coating from the previous vaporization under nasal endoscopic observation. After the procedure, most patients experienced complete nasal obstruction for 2 or 3 days, but there was no intraoperative or postoperative bleeding or severe pain. All patients obtained improvement of their chief complaints and were satisfied 2 months after the operation. In particular, 60% of the patients were completely relieved of refractory nasal obstruction. Most patients were more satisfied with the effects than are those treated by the usual methods. Completely successful cases (improvement in all symptoms and complete satisfaction obtained) were selected and were compared with other cases. Favorable prognostic factors are more severe complaints, longer symptomatic periods, stronger allergic reactions, and worse nasal resistance and its greater improvement with administration of decongestant nasal drops. This method may be especially accepted by patients with severe complaints, in particular nasal obstruction, who do not experience enough relief with conservative therapies or have enough time to make frequent visits to an outpatient clinic over a period of several weeks.

Clinical study of acute low-tone sensorineural hearing loss: survey and analysis of glycerol test and orthostatic test.

Fifty patients (14 men and 36 women ranging in age from 16 to 66 years) with acute low-tone sensorineural hearing loss (ALHL) were retrospectively analyzed in this study. The glycerol test and the orthostatic test were performed. On the glycerol test, 43.8% of 16 ears of the 14 men and 33.3% of 39 ears of the 36 women with ALHL had a positive result. On the orthostatic test, 42.9% of the 14 men and 52.7% of the 36 women with ALHL had a positive result. In addition, 28.6% of the 14 men and 33.3% of the 36 women had hypotension with a systolic blood pressure of 100 mm Hg or less. Our results suggest that endolymphatic hydrops as shown by the glycerol test and an underlying autonomic imbalance and/or insufficient blood circulation as shown by the orthostatic test may be important factors in the causation of ALHL.