A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m², rituximab 375 mg/m² (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.     

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma

BackgroundTazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin‐type lymphoma (B‐NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity.MethodsTazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28‐day/cycle manner. Tazemetostat dose‐limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations.ResultsAs of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B‐cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59‐85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment‐related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment‐related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment.ConclusionsTazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B‐NHL.     

The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma

The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft‐versus‐host disease did not affect progression‐free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge. Am. J. Hematol. 90:132–138, 2015. © 2014 Wiley Periodicals, Inc.     

Sporadic late‐onset nemaline myopathy as a rare cause of slowly progressive muscle weakness with young adult onset

Introduction: Sporadic late‐onset nemaline myopathy (SLONM) is a rare intractable acquired myopathy characterized by progressive muscle weakness and atrophy, usually with middle to late adult onset. Autologous peripheral blood stem cell transplantation (auto‐PBSCT) has been reported to be a promising treatment for SLONM. Methods: In this study we performed clinical characterization, muscle histopathological analysis, and muscle power monitoring after auto‐PBSCT in a 27‐year‐old HIV‐negative man with monoclonal gammopathy. Results: He showed improved muscle strength after treatment with high‐dose melphalan and auto‐PBSCT. Conclusions: Considering the recent reports of successful treatment of SLONM, early and correct diagnosis of this condition in association with monoclonal gammopathy is important. SLONM should be added to the list of diseases to consider in the differential diagnosis of progressive muscle weakness with young adult onset. Muscle Nerve 51 :772–774, 2015     

High-grade cytomegalovirus antigenemia after hematopoietic stem cell transplantation

Clinical impact of high-grade (HG) cytomegalovirus (CMV) antigenemia after hematopoietic stem cell transplantation has not been clarified. Therefore, in order to investigate the risk factors and outcome for HG-CMV antigenemia, we retrospectively analyzed the records of 154 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2002 at the University of Tokyo Hospital. Among 107 patients who developed positive CMV antigenemia at any level, 74 received risk-adapted preemptive therapy with ganciclovir (GCV), and 17 of these developed HG-antigenemia defined as > or = 50 positive cells per two slides. The use of systemic corticosteroids at > or = 0.5 mg/kg/day at the initiation of GCV was identified as an independent significant risk factor for HG-antigenemia. Seven of the 17 HG-antigenemia patients developed CMV disease, with a cumulative incidence of 49.5%, which was significantly higher than that in the low-grade antigenemia patients (4%, P<0.001). However, overall survival was almost equivalent in the two groups. In conclusion, the development of HG-antigenemia appeared to depend on the profound immune suppression of the recipient. Although CMV disease frequently developed in HG-antigenemia patients, antiviral therapy could prevent a fatal outcome.     

Cardiac-related sympathetic nerve activity during circulation with only the left ventricular assist device.

Circulatory maintenance with a left ventricular assist device (LVAD) alone during cardiac arrest until heart transplantation has been evaluated. To assess the effect on the autonomic nervous system, the sympathetic neurogram was analyzed by power spectrum and coherence function. LVAD were inserted between the left atrium and the descending aorta in seven adult mongrel dogs and ventricular fibrillation was induced electrically. Renal sympathetic nerve activity (RSNA) was detected by bipolar electrodes attached to the left renal sympathetic nerve. Values of squared coherence between the arterial pulse wave and RSNA were calculated. Under the condition of circulatory maintenance with only LVAD, coherence at the cardiac rhythm frequency was decreased, and coherence at the LVAD pumping rhythm frequency was increased. These results indicate that the arterial pulse wave observed during maintenance of the circulation with only LVAD contributed to the sympathetic neurogram.     

DNA analysis cervical and vaginal cancer cells during radiotherapy by rapid high-resolution cytometry

The DNA content of the nuclei of cancer cells of 12 cases of cervical cancer and 2 cases of vaginal cancer, treated with radiotherapy, were studied in 50 specimens. Specimens were taken from each case before radiotherapy and at the totals of 1,000 rad, 2,000 rad, 3,000 rad and 4,500 rad (or 5,000 rad). All specimens were stained by the Papanicolaou method and were analyzed by rapid high-resolution cytometry. Total optical density, mean nuclear area and the 5N-exceeding rate (5NER) increased gradually following irradiation. Cancer cells disappeared in good response cases before 3,000 rad. Eight smears with a 5NER under 100 at the dose of 3,000 rad or more seemed to be poor response cases. Low 5NER and low mean nuclear areas were observed in both patients who died with persistent disease after radiotherapy, as well as in one case treated with chemotherapy for persistent disease after radiotherapy.     

Properties of the HCO 3 − -stimulated Mg2+-ATPase activity in red cell membranes

The HCO-3-stimulated Mg2+ -ATPase activity in red cell ghost fragments was investigated. Increasing the HCO-3 concentration in the incubation medium resulted in increased ATPase activity. NaHCO3 appeared to be more effective than KHCO3 in this regard. The ATPase activities were slightly stimulated by increases in ionic strength and utilized ITP almost as readily as ATP. A Mg/ATP ratio of 1.0 and a pH of 7.6 yielded maximum activity. These properties are of interest since the present enzyme is the only unquestionable instance where a HCO-3 ATPase is located in the surface membrane of a cell.