An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study).

Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.

Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.

[Successful treatment with blinatumomab for refractory B lymphoblastic leukemia complicated with malignant pleural effusion].

A 77-year-old man diagnosed with mixed-phenotype acute leukemia (MPAL (B/Myeloid), NOS) achieved complete remission (CR) after eight courses of hyper-CVAD/MA therapy. However, 6 months later, blasts were observed on peripheral blood smear, and bone marrow aspiration revealed that the disease had relapsed as B lymphoblastic leukemia (ALL). At this time, he had left pleural effusion. He received two courses of inotuzumab ozogamicin (InO) and achieved second hematological CR, but the left pleural effusion worsened over time, suggesting poor disease control. After changing the regimen to blinatumomab, aspiration biopsy cytology showed that the blasts in the pleural fluid disappeared and respiratory distress improved after one course of treatment. Flow cytometry results showed increased populations of CD3-positive T-cells, suggesting that blinatumomab may have migrated into the pleural fluid and exerted an antitumor effect. Although new ALL-specific antibody drugs, such as InO and blinatumomab, are expected to improve prognosis, only few reports have described their tissue migration. The difference between InO and blinatumomab in terms of efficacy of treating malignant pleural effusion remains unclear and should be explored in additional cases.

Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.

BACKGROUND: Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required. OBJECTIVE: We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever. METHODS: Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d). RESULTS: Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07). CONCLUSION: ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.

[Acute myeloid leukemia complicated by pneumonia and vertebral osteomyelitis during induction chemotherapy].

A 76-year-old woman was operated on for rectal cancer in 2011 without chemotherapy and was followed up in the outpatient department. Decrease in white blood cell count was observed from 2013, and she developed anemia in 2015. Bone marrow aspiration was performed, and she was diagnosed with acute myeloid leukemia with myelodysplasia-related changes (AML/MRC). First, remission induction therapy was initiated with idarubicin and cytarabine administration, but pneumonia and vertebral osteomyelitis developed during the neutropenic period. Although the progress of antibiotics aided in the improvement of the recent prognosis of vertebral osteomyelitis compared with the past, poor prognosis with high death rate was still inevitable. Then, consolidation therapy was initiated with azacitidine (AZA) administration, and treatment was carried out for vertebral osteomyelitis with several antibiotics in parallel, which together led to the successful treatment of vertebral osteomyelitis while maintaining a remission state of AML. Because AZA is known to be well-tolerated and neutropenic phase is shorter than intensive chemotherapy in general, it can be an effective treatment option for patients who need both infection control and AML treatment.

Tandem autologous versus autologous/allogeneic transplantation for multiple myeloma: propensity score analysis.

Autologous hematopoietic stem cell transplantation (auto-HCT) is considered a standard therapy for transplant-eligible patients with multiple myeloma, while allogeneic HCT (allo-HCT) is controversial. We retrospectively analyzed 765 patients with myeloma who underwent tandem transplantation between 1998 and 2012 using Japanese registry data. We evaluated the clinical outcomes of tandem auto-HCT (n = 676) and auto/allo-HCT (n = 89). To adjust for a selection bias, we compared overall survival (OS) between the two groups by a propensity score analysis. The probability of OS at six years was 58.5% for the tandem auto-HCT group and 54.4% for the tandem auto/allo-HCT group (p = 0.47). In a matched-pair analysis based on the propensity score, the difference in survival between the two groups was not statistically significant, although the survival curve appeared to reach a plateau beyond five years in the auto/allo group. Further strategies to reduce treatment-related mortality and enhance a graft-versus-myeloma effect are necessary to improve OS.

Mantle cell lymphoma diagnosed by conjunctival salmon-pink lesion biopsy.

Conjunctival lesions are rarely seen in mantle cell lymphoma. Here, we report a patient who developed bilateral conjunctival lesions in the course of chronic lymphocytic leukemia as an initial diagnosis, resulting in the final diagnosis of mantle cell lymphoma by conjunctival biopsy. A 66-year-old man developed conjunctival salmon-pink lesions on both sides in the 1.5-year course of chronic lymphocytic leukemia. He also had irregularly shaped masses with low tissue density in the orbital apex on both sides. Bilateral conjunctival biopsy showed subepithelial infiltration with lymphoid cells, positive for CD20, CD5, and cyclin D1, but negative for CD3, CD10, and CD23. Immunohistochemical restaining of the previous bone marrow biopsy specimen demonstrated lymphoid cells positive for cyclin D1, confirming the diagnosis of mantle cell lymphoma with leukemic presentation. As the case presenting stage IV lymphoma with systemic lymphadenopathy, he underwent 3 courses of combination chemotherapy with fludarabine and cyclophosphamide, and then 6 courses of bendamustine with rituximab, leading to complete remission for the following 3 years. In conclusion, mantle cell lymphoma should be included in the differential diagnosis of conjunctival salmon-pink lesions.

Prediction of number of apheresis procedures necessary in healthy donors to attain minimally required peripheral blood CD34+ cells.

BACKGROUND: Allogeneic peripheral blood stem cell (PBSC) transplantation is widely performed as a curative therapy for hematopoietic malignancies. Donors for PBSC harvest (PBSCH) are usually healthy subjects and undergo granulocyte-colony-stimulating factor treatment and apheresis procedures. A considerable proportion of donors experience poor mobilization, necessitating additional harvesting or marrow collection or remobilization. Although some characteristics have been reported to correlate with poor mobilization, they may not be taken into account in selecting PBSC donors. To protect healthy donors, it is preferable to predict the number of apheresis procedures needed for PBSCH before the procedure is initiated. STUDY DESIGN AND METHODS: A retrospective cohort study of 83 subjects was conducted, using statistical models to predict the probability of obtaining a sufficient number of CD34+ cells (>or=2.0 x 10(6)/kg) in the first to the third apheresis procedures and the probability of failure to obtain sufficient cells within three apheresis sessions. This study explored potential candidate factors in an ordinal probit regression analysis. RESULTS: Significant factors predicting successful PBSCH were donor age, donor sex, and body weight difference between donor and recipient. The predictive model showed good agreement with the observed number of apheresis sessions. Simulation tables are presented with this model. CONCLUSION: The statistical model developed to predict the number of apheresis procedures for PBSCH may be useful for planning PBSCH in clinical practice.

Clinical outcomes of unrelated donor umbilical cord blood transplantation for 30 adults with hematological malignancies.

BACKGROUND: Umbilical cord blood transplantation (CBT) has increasingly been used as a therapeutic option for adult patients for whom allogeneic stem-cell transplantation is not indicated, due to the availability of cord blood. However, myeloablative conditioning regimens are associated with significant mortality, and high relapse rates in reduced-intensity regimens may result in a poor rate of disease-free survival for those with advanced stages of hematological malignancies. Therefore, it remains unknown whether CBT is a truly effective option for such adults with high-risk disease, as well as for those with standard-risk disease. PATIENTS AND METHODS: Thirty adult patients with a median age of 45 years (range: 16-67) with standard or high-risk disease underwent CBT from unrelated donors at Okayama University Hospital between October 2002 and May 2007. Twenty-one patients had diseases classified as high-risk for transplantation. The median number of nucleated cells in infused cord blood was 2.65 x 10(7)/kg (range: 1.73-4.87). RESULTS: Twenty-three patients achieved neutrophil engraftment at a median time of 22 days (range: 13-42) after CBT. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 53.6% . Out of the 30 patients, 11 were alive and disease-free at a median time of 446 days (range: 124-1153) after CBT. The cumulative 1-year overall survival in patients with standard-risk or high-risk disease was 63.5% and 15.4%, respectively (p=0.01). CONCLUSION: Although from a retrospective study, these results suggest that unrelated donor CBT could be safe and effective for adult patients with standard-risk disease who cannot find a suitable HLA-matched volunteer marrow or peripheral blood donor.

Dock2 participates in bone marrow lympho-hematopoiesis.

Dock2 has been shown to be indispensable for chemotaxis of mature lymphocytes as a critical Rac activator. However, the functional expression of Dock2 in immature hematopoietic cells is unclear. In this study, we demonstrate that Dock2 is broadly expressed in bone marrow (BM) hematopoietic compartment, including hematopoietic stem/progenitor cell (HSC/HPC) fraction. Response of Dock2-/- HPCs to CXCL12 in chemotaxis and actin polymerization in vitro was impaired, although alpha4 integrin activation by CXCL12 was not altered. Myelosuppressive stress on HSCs in vivo, such as consecutive 5-FU administration and serial bone marrow transplantation, did not show hematopoietic defect in Dock2-/- mice. Long-term engraftment of transplanted Dock2-/- BM cells was severely impaired in competitive reconstitution. However, this was not intrinsic to HSCs but originated from the defective competition of Dock2-/- lymphoid precursors. These results suggest that Dock2 plays a significant role in BM lymphopoiesis, but is dispensable for HSC engraftment and self-renewal.

Rapid hematopoietic progenitor mobilization by sulfated colominic acid.

Hematopoietic progenitor cells (HPCs) can be mobilized from bone marrow (BM) to the blood by G-CSF. In this process, CXCR4 and CD26 play critical roles. Sulfated colominic acid (SCA) inhibits HIV entry, the step which requires CXCR4 and CD26 as co-receptors. Thus, we hypothesized that SCA would modulate HPC trafficking. We first found that SCA mobilized HPCs rapidly via CD26-independent mechanism. In vitro progenitor migration toward chemokine SDF-1 was significantly enhanced by SCA, and it was completely abrogated by CXCR4 inhibition. This likely originated from the inhibition of CXCR4 down-regulation after interaction with SDF-1. Serum SDF-1 level increased after SCA injection, whereas no change was observed in BM and bone. These results suggest that SCA induces HPC mobilization by modulating CXCR4 function resulting in attraction toward increased SDF-1 in the circulation. Furthermore, we confirmed an additive effect with G-CSF in mobilization. SCA may provide an efficacy in clinical mobilization.

Chronic lymphoproliferative disorder with regulatory T-cell phenotype.

We report a case of T-cell chronic lymphoproliferative disorder (CLPD) that shows neither features of T-cell prolymphocytic leukemia nor disease progression for more than 34 months. Flow cytometric analyses of the lymphocytes revealed high expression of CD4 and CD25. Up-regulation of Foxp3, a master regulatory gene for developmental differentiation of regulatory T cells (Treg), was confirmed at mRNA and protein levels. To our knowledge, this is the first case of extremely indolent CLPD with Treg phenotype.

Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution.

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.