Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study.

BACKGROUND: Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL. METHODS: Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375). FINDINGS: 86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown). INTERPRETATION: Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial. FUNDING: Bristol-Myers Squibb. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Phase 2 results of idecabtagene vicleucel (ide-cel, bb2121) in Japanese patients with relapsed and refractory multiple myeloma.

BACKGROUND: In the phase 2 KarMMa trial, patients with relapsed/refractory multiple myeloma (RRMM) achieved deep and durable responses with idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy. Here we report a sub-analysis of the Japanese cohort of KarMMa. METHODS: Adult patients with RRMM who had received  ≥ 3 prior treatment regimens, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, and had disease refractory to last treatment received ide-cel at a target dose of 450 × 106 CAR positive T cells. RESULTS: Nine patients were treated with ide-cel. The overall response rate was 89% (median follow-up, 12.9 months). The best overall response was stringent complete response in 5 patients (56%), very good partial response in 3 (33%), and stable disease in 1. Median duration of response was not reached. All patients experienced grade ≤ 2 cytokine release syndrome and one patient experienced grade 2 neurotoxicity, but all resolved. Two patients died, one each from plasma cell myeloma and general health deterioration. CONCLUSION: Ide-cel yielded deep, durable responses with a tolerable and predictable safety profile in Japanese patients with RRMM. These results are similar to those of the non-Japanese population in KarMMa.

Pomalidomide, dexamethasone, and daratumumab in Japanese patients with relapsed or refractory multiple myeloma after lenalidomide-based treatment.

In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile.

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.

OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.

Bone marrow graft-versus-host disease: evaluation of its clinical impact on disrupted hematopoiesis after allogeneic hematopoietic stem cell transplantation.

Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = .0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = .012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P = .0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.

Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies.

Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies who receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the incidence and treatment outcomes of proven and probable IFI in 22 institutions between 2006 and 2008 following the recent European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) consensus criteria. We analyzed 2,821 patients with hematological malignancies, including 597 who had undergone HSCT; these included patients with acute leukemia (n = 697), myelodysplastic syndrome (n = 284), lymphoma (n = 1465), or multiple myeloma (n = 375). IFIs were diagnosed in 38 (1.3%) patients (18 proven and 20 probable), including 20 patients who underwent HSCT and 18 who received chemotherapy alone; these included patients with aspergillosis (n = 23), candidiasis (n = 6), mucormycosis (n = 6), trichosporonosis (n = 2), and geotrichosis (n = 1). The incidence of IFI was 5.4 % in allogeneic HSCT patients, 0.4 % in autologous HSCT patients, and 0.8 % in patients receiving chemotherapy alone. Eighteen patients with aspergillosis were diagnosed with probable pulmonary IFI as determined by computed tomography scan and positive galactomannan assay. Overall, antifungal targeted therapies resulted in successful outcomes in 60.0 % of patients. IFI-attributable mortality rate was higher in HSCT patients than in those receiving chemotherapy alone, but the difference was not statistically significant.

Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation.

GOAL OF WORK: Little is known about the effects of professional oral health care (POHC) on the outcome of hematopoietic stem cell transplantation (HSCT). We evaluated the effects of POHC given by dentists and dental hygienists on the development of oral mucositis and febrile neutropenia (FN) after allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: We retrospectively studied 140 adult patients who had received allogeneic BMT, with or without POHC, in our hospital consecutively between February 2002 and December 2009. Oral mucositis was evaluated according to the World Health Organization scale. MAIN RESULTS: The incidence of oral mucositis was 66.7% (52/78) in the patients who had received POHC, compared to 93.5% (58/62) in the non-POHC group (P < 0.001). The incidence of FN and the maximal level of CRP were also significantly lower in the POHC group. Multivariate analysis revealed that the POHC was significantly associated with the incidence of oral mucositis (odds ratio, 7.58; 95%CI, 2.45-23.34; P < 0.001). CONCLUSIONS: We concluded that POHC reduced the incidences of oral mucositis and FN by upgrading the overall oral hygiene during HSCT.

A comparison of oral mucositis in allogeneic hematopoietic stem cell transplantation between conventional and reduced-intensity regimens.

Severe oral mucositis developed in allogeneic hematopoietic stem cell transplantation (HSCT) accompanies intolerable pain and risk for systemic bacteremia infection. Conventional stem cell transplantation (CST) and reduced-intensity regimens for allogeneic HSCT (RIST) may differently affect the occurrence and severity of oral mucositis. Here, we comparatively examined oral mucositis in patients undergoing CST and that in RIST patients to search for measures to alleviate oral mucositis. We retrospectively analyzed the data of 130 consecutive patients undergoing HSCT (conventional, 60; RIST, 70). Oral mucositis was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. We also investigated the risk factors for severe oral mucositis in each regimen. The incidence of oral mucositis was not significantly different between RIST and CST patients. The use of opioid analgesics to control pain due to oral mucositis was significantly less in patients undergoing RIST compared with those receiving CST. The risk factors for severe oral mucositis, determined by univariate and multivariate analyses, were "younger age (<40)" in CST and "longer duration of neutropenia (≥ 14 days)" in RIST. Although the incidences of oral mucositis were almost the same, the need for opioid analgesics and the risk factors for severe oral mucositis differed between CST and RIST patients.

Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia.

The prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) for refractory acute lymphoblastic leukemia (ALL) is very poor. To improve survival rates, we attempted to intensify the conditioning regimen with daunorubicin, vincristine, prednisolone, medium-dose etoposide, cyclophosphamide, and total body irradiation (DNR/VCR/PSL plus medium-dose VP/CY/TBI). Four patients in relapse or induction failure of B-precursor ALL without other complications underwent allogeneic HSCT. Initially, chemotherapy comprising DNR 60 mg/m(2) for 3 days, VCR 1.4 mg/m(2) for 1 day, and PSL 60 mg/m(2) for 3 days was administered, which was followed by medium-dose VP/CY/TBI; some modifications were made for individual patients. All patients achieved engraftment and complete remission after HSCT. Regimen-related toxicities were tolerable and no patient died within 100 days. Two patients were alive without disease on days 563 and 1,055. The third patient relapsed on day 951, while the fourth died on day 179 without disease. Our results indicate that intensified myeloablative HSCT should be considered for patients with refractory ALL.

Therapeutic impact of human bone marrow stromal cells expanded by animal serum-free medium for cerebral infarct in rats.

BACKGROUND: The donor cell culture in animal serum-free medium is important for the clinical application of cell transplantation therapy. Recently, human-derived platelet lysate (PL) gained interest as a substitute for fetal calf serum (FCS), but there are no studies that evaluate the validity of human bone marrow stromal cells (hBMSCs) expanded with PL-containing medium for central nervous system disorders. OBJECTIVE: To test the hypothesis that hBMSCs expanded with FCS-free, PL-containing medium can promote functional recovery after cerebral infarct. METHODS: hBMSCs were cultured in the FCS- or PL-containing medium. Cell-growth kinetics were analyzed. The vehicle or hBMSCs was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. RESULTS: There was no significant difference in hBMSC expansion between the 2 groups. Transplantation of hBMSCs expanded with the FCS- or PL-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the 2 groups. CONCLUSION: hBMSCs expanded with PL-containing medium retained their capacity of migration, survival, and differentiation and significantly promoted functional recovery when stereotactically transplanted into the infarct brain. The PL may be a clinically valuable and safe substitute for FCS in expanding hBMSCs to regenerate the infarct brain.

Validity of bone marrow stromal cell expansion by animal serum-free medium for cell transplantation therapy of cerebral infarct in rats-a serial MRI study.

This study was aimed to test the hypothesis that human bone marrow stromal cells (hBMSC) expanded in fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium would retain their capacity of migration, survival, and neural differentiation when transplanted into the infarct brain, using serial in vivo magnetic resonance imaging (MRI). Cell growth kinetic analysis revealed that hBMSC maintain their proliferative activity when cultured either in conventional FCS-containing medium or FCS-free, PL-containing medium. Subsequently, hBMSC were labeled with a superparamagnetic iron oxide agent and were stereotactically transplanted into the ipsilateral striatum of rats at 7 days after permanent middle cerebral artery occlusion. Serial MRI performed over 8 weeks revealed that they retain their migratory capacity towards the cerebral infarct. Moreover, double fluorescence immunohistochemistry also revealed that they preserve their capacity of differentiation into the neural cells in the peri-infarct area. The hBMSC expanded in the FCS-free, PL-containing medium retain their capacity of migration, survival, and differentiation when stereotactically transplanted into the infarct brain. The present findings strongly suggest the clinical utility of PL as a substitute to expand autologous hBMSC for cerebral infarct in the future.

Biological Features of Human Bone Marrow Stromal Cells (hBMSC) Cultured with Animal Protein-Free Medium-Safety and Efficacy of Clinical Use for Neurotransplantation.

The donor cell culture in animal serum-free medium is quite important for the clinical application of cell transplantation therapy. This study was aimed to test the hypothesis that the human bone marrow stromal cells (hBMSC) expanded with fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium retain their biological features favoring central nervous system regeneration. The hBMSC were cultured with 5% PL or 10% FCS. Their phenotypes were analyzed with flow cytometry, and their production of growth factors was quantified with enzyme-linked immunosorbent assay. Their capacity of neural differentiation was verified by immunocytochemistry. There was no significant difference in morphology and cell surface marker between the hBMSC-FCS and hBMSC-PL. Both of them were positive for CD44, CD90, CD105, and CD166 and were negative for CD34, CD45, and CD271. The production of human brain-derived neurotrophic factor, human hepatocyte growth factor, human ß-nerve growth factor, and human platelet-derived growth factor-BB did not differ between the two groups, although the hBMSC-PL produced significantly more amount of TGF-ß1 than the hBMSC-FCS. There was no significant difference in their in vitro differentiation into the neurons and astrocytes between the two groups. The hBMSC expanded with PL-containing medium retain their biological capacity of neural differentiation and neuroprotection. The PL may be a clinically valuable and safe substitute for FCS in expanding the hBMSC for cell therapy.

DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma.

DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression. Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy.

Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients.

Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m(2)), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low-dose total body irradiation (TBI; 4 Gy) (Flu-BU2-TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty-eight patients (58%) were high-risk patients (median age: 56 years). The overall survival rate at 2 years of the high-risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard-risk patients (P = 0.68). The relapse rates at 2 years in the standard-risk and high-risk patients were 16 and 28%, respectively, and day 100 treatment-related mortality rates were 0 and 6%, respectively. The Flu-BU2-TBI regimen for high-risk patients showed therapeutic effects equivalent to those for standard-risk patients and favorable outcomes compared with those of other previous RIC regimens.

Successful treatment of acute myelogenous leukemia with favorable cytogenetics by reduced-intensity stem cell transplantation.

Acute myelogenous leukemia (AML) with favorable cytogenetics responds well to chemotherapy. If the leukemia relapses, allogenic hematopoietic stem transplantation (allo-HSCT) is considered as a treatment option. Since the efficacy of reduced-intensity stem cell transplantation (RIST) for AML with favorable cytogenetics has not been established, we retrospectively analyzed the outcomes of allo-HSCT in AML patients according to cytogenetic risks. The outcome of allo-HSCT for AML patients with favorable cytogenetics seemed to be superior to that for AML patients with intermediate cytogenetics. In AML patients with favorable cytogenetics, the 3-year overall survival (OS) and relapse-free survival (RFS) rates were 88 and 76%, respectively, in the RIST group. Both the 3-year OS and RFS rates were 81% in the conventional stem cell transplantation (CST) group. The outcome of RIST for AML patients with favorable cytogenetics was comparable to that for patients who received CST despite the more advanced age and greater organ dysfunction in RIST group than in CST group. None of the patients died within 90 days after RIST. Moreover, there was no relapse in patients with favorable cytogenetics who were in hematological remission prior to RIST. Thus, RIST for AML patients with favorable cytogenetics in remission is safe and effective.