Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Alternating bortezomib-dexamethasone and lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma aged over 75 years.

More than 40% of Japanese patients with multiple myeloma (MM) are over 75 years of age at diagnosis. Regardless of the treatment benefits, complications and relapses obstruct long-term survival. We conducted a phase II, open-label, single-arm, multicenter clinical trial to assess the efficacy and safety of alternating bortezomib-dexamethasone (Bd) and lenalidomide-dexamethasone (Ld) (Bd/Ld) treatment in MM patients aged over 75 years (MARBLE trial). Patients received Bd therapy from days 1 to 35 and Ld therapy from days 36 to 63. For Bd therapy, patients were administered bortezomib 1.3 mg/m2 and oral dexamethasone 20 mg on days 1, 8, 15, and 22. For Ld therapy, they were administered lenalidomide 15 mg from days 36 to 56 and dexamethasone 10 mg on days 36, 43, 50, and 57. They underwent six treatment cycles in total, each consisting of a 63-day regimen. In total, 10 patients were enrolled, with a median age of 81 years. Efficacy was not evaluated because the patients were fewer than planned. The overall response rate was 80.0% and complete response rate 40.0%. Seventy percent of patients completed the study treatment. Progression-free survival and overall survival at 2 years were 40.0% and 80.0%, respectively. Adverse events of grade 3 or higher, including anemia, decreased lymphocyte count, neutropenia, and hypokalemia, were observed in eight patients. Alternating chemotherapy with Bd/Ld might be feasible, but its efficacy should be verified further.

Importance of Compliance With Guidelines for the Prevention of Varicella-Zoster Virus Reactivation in Multiple Myeloma.

BACKGROUND/AIM: The importance of compliance with National Comprehensive Cancer Network (NCCN) guidelines for preventing varicella-zoster virus reactivation (VZVr) in multiple myeloma (MM) in a clinical setting has not been well investigated. PATIENTS AND METHODS: We retrospectively studied the clinical characteristics and outcomes of 118 patients with MM treated with proteasome inhibitors. RESULTS: Thirty-nine episodes of VZVr were observed in 37 patients (VZVr group). The proportion of prophylactic antiviral prescriptions and compliance with antiviral prophylaxis based on the NCCN Clinical Practice guidelines was 76% and 30% in the VZVr group, and 88% and 74% in the non-VZVr group, respectively. Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZVr (p=0.0017). CONCLUSION: It is important that prophylactic antivirals are prescribed for an appropriate duration of time to prevent the reactivation of VZV in compliance with existing guidelines.

[Discordant lymphoma of diffuse large B-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified in a human T-cell leukemia virus type-I carrier].

A 69-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL) negative for Epstein-Barr virus-encoded small nuclear RNA 1 (EBER-1) in October 2011, when he was also diagnosed as having a human T-cell leukemia virus type-I (HTLV-1) carrier. He achieved complete response after six courses of R-CHOP therapy. In February 2015, the patient had high fever and markedly elevated serum lactate dehydrogenase (LDH) level. Bone marrow examination revealed infiltration of CD4-positive T-cell malignancy. Based on the tentative diagnosis of adult T-cell leukemia/lymphoma, modified LSG15 therapy was initiated. His symptoms and serum LDH level quickly improved after the start of treatment. During the treatment, HTLV-1 proviral DNA integration was reported negative, allowing his final diagnosis to be peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Despite discontinuation of chemotherapy in the middle of the second course due to the patient's preference, complete remission was reached. He remains in clinical remission at 28 months after the treatment discontinuation. Discordant lymphoma of DLBCL and PTCL-NOS in HTLV-1 carrier has not been well characterized and will be discussed with a literature review.

Safety and Effectiveness of Ixazomib Dose-escalating Strategy in Ixazomib-Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma.

BACKGROUND/AIM: Gastrointestinal toxicity is common in patients receiving common therapy of ixazomib with lenalidomide and low-dose dexamethasone (IRd) for relapsed/refractory multiple myeloma. Here, we investigated the safety and effectiveness of ixazomib dosing schedules. PATIENTS AND METHODS: We retrospectively evaluated 17 consecutive patients treated with IRd (10 patients on ixazomib dose-escalation strategy (2.3 mg starting dose); seven patients on standard dose). RESULTS: The incidence of grade 3 or more haematological and grade 2 or more non-haematological adverse events was lower in the dose-escalation group than in the standard-dose group, and only that of diarrhoea was significantly lower. The median time to treatment interruption was significantly longer in the dose-escalation group than in the standard-dose group. There was no significant difference in the overall response rate (20% vs. 43%) and disease control rate (70% vs. 86%). CONCLUSION: A dose-escalation strategy to optimise ixazomib dosing may reduce treatment interruption due to adverse events without compromising its antitumor activity.

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.

[Occurrence of acquired factor V inhibitor during antibiotic therapy for a surgical wound infection].

Acquired factor V (FV) inhibitor is a rare disorder. Herein we report a case of an 82-year-old Japanese woman with FV inhibitor exhibiting a pseudo decline in the activities of the multiple coagulation factors. After rectal cancer surgery, she received antibiotic therapy for wound infection. As prothrombin and activated partial thromboplastin time was prolonged, heparin for atrial fibrillation was discontinued without improvement. Coagulation factor activity assays revealed deficiencies in II, V, VII, VIII, IX, X, XI, and XII factor activities; in particular, the FV activity was markedly decreased to <1%. The cross-mixing test findings revealed an inhibitor pattern, and multiple coagulation factor inhibitors were positive. The FV inhibitor level was high at 62 Bethesda U/ml. The patient exhibited no bleeding tendency with the prolonged wound infection without immunosuppressive therapy. The inhibitor disappeared four months after the onset.

First isolation and genetic characterization of pseudocowpox virus from cattle in Japan.

BACKGROUND: Pseudocowpox virus (PCPV) infects cattle worldwide with zoonotic potential but has not been isolated in Japan. Thus, the epidemiological status of PCPV infection in cattle is undetermined. RESULTS: In May 2016, a cattle in a farm in Yamaguchi Prefecture showed white vesicles and hyperemia in the mucosa under the tongue surface, but not on the teats and coronary cushions. A parapoxvirus was isolated from the oral lesion swab and was genetically characterized based on the full-length sequence of B2L gene encoding viral envelope. Phylogenetic analysis showed that the isolated virus was classified into PCPV. CONCLUSION: This case indicates its potential spread in Japan. This is the first report of isolation of PCPV in Japan.

Bridging-to-transplant with Azacitidine for Myelodysplastic Syndrome and Acute Myeloid Leukemia, Reduces the Incidence of Acute Graft-versus-host Disease.

Allogeneic stem cell transplantation (allo-SCT) is the only curative option for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Azacitidine (AZA) has a good toxicity profile compared with intensive chemotherapy and can be considered a pre-transplant regimen in elderly patients and in patients with comorbidities. To investigate the impact of pre-transplant AZA on patient outcome after allo-SCT, we conducted a retrospective analysis of AZA pre-treatment followed by allo-SCT in patients with high-risk MDS and AML. Twenty patients who were divided into two groups according to AZA treatment given prior to allo-SCT (AZA vs non-AZA group, 10 each). Overall survival, event-free survival and incidence of chronic graft-versus-host disease (GVHD) were not significantly different between the two groups. The overall incidence of grade II to IV acute GVHD in the AZA group was significantly lower than that in the non-AZA group (P=0.004). Bridging to transplant with AZA should be considered as an immunomodulator and effective treatment strategy for patients with MDS and AML.

Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice.

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD.

[Relapsed/refractory multiple myeloma with CD138 shedding and formation of extramedullary disease in the common bile duct region presenting as obstructive jaundice].

A 56-year-old man was diagnosed with immunoglobulin (Ig) A-κ multiple myeloma in July 2007. After three courses of vincristine, adriamycin, and dexamethasone (VAD) chemotherapy, autologous peripheral blood stem cell transplantation was performed and achieved a very good partial response. In February 2010, an increase in the M-protein concentration and plasmacytoma in the L3/4 lumbar vertebrae were observed, and radiation treatment was performed. This was followed by administrations of bortezomib, lenalidomide, and thalidomide, none of which achieved a good response. In November 2011, the patient presented with obstructive jaundice, and imaging tests revealed tumorous lesions in the lower bile duct region and bilateral kidneys. Plasmacytoma was diagnosed from biopsy of the right renal mass. Radiotherapy to the common bile duct tumor resulted in jaundice amelioration, but the patient died despite subsequent treatment efforts. Autopsy revealed multiple extramedullary lesions in the abdominal cavity and in the region around the common bile duct. CD138 shedding was observed in the myeloma cells. We include a discussion of the literature on CD138 shedding and 38 reports of obstructive jaundice associated with extramedullary disease.

Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major risk factor for prolonged humoral immunodeficiency and vaccine unresponsiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the underlying mechanisms for this immunodeficiency are poorly understood. In this article, we describe previously overlooked impacts of GVHD on lymph node (LN) stromal cells involved in humoral immune responses. In major- and minor-mismatched mouse allo-HSCT models, recipients with CD8(+) T cell-mediated GVHD suffered severe and irreversible damage to LN structure. These mice were susceptible to pathogenic infection and failed to mount humoral immune responses despite the presence of peripheral T and B cells. These humoral immune defects were associated with the early loss of fibroblastic reticular cells, most notably the CD157(+) cell subset, as well as structural defects in high endothelial venules. The disruption to these LN stromal cells was dependent on alloantigens expressed by nonhematopoietic cells. Blockade of the Fas-FasL pathway prevented damage to CD157(+) fibroblastic reticular cells and ameliorated LN GVHD. However, blockade of CD62L- or CCR7-dependent migration of CD8(+) T cells to the LN was insufficient to prevent stromal cell injury. Overall, our results highlight GVHD-associated loss of functional stromal cells and LN GVHD as a possible explanation for the prolonged susceptibility to infectious disease that is experienced by allo-HSCT patients.

[Rapid improvement of fluid retention with lenalidomide plus low-dose dexamethasone for POEMS syndrome relapsed after autologous peripheral blood stem cell transplantation].

We report a 53-year-old male with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome who relapsed after autologous peripheral stem cell transplantation (ASCT), but responded extremely well to lenalidomide (LEN) plus low dose dexamethasone (Ld) therapy. The patient had been diagnosed with POEMS syndrome in November 2006, and underwent ASCT in February 2007. In July 2011, he developed respiratory distress, generalized edema, and massive bilateral pleural effusion. Plasma vascular endothelial growth factor (VEGF) and M protein were increased, strongly indicating a relapse. Ld therapy was remarkably effective for these symptoms, resulting in complete remission with M-protein becoming undetectable by immunofixation. Since completing 11 courses of therapy with an every 4 weeks regimen, he has remained in clinical remission. The patient's activities of daily living have also markedly improved from total physical incapacity to being able to stand with slight assistance. LEN is associated with a lower incidence of peripheral neuropathy than other new drugs. Although LEN has occasionally been given to patients with POEMS syndrome in recent years, there are still few reports on its use for patients with recurrent disease after ASCT. Our successful management of this patient suggests that Ld therapy is not only relatively safe but also a promising option for POEMS syndrome relapsing after ASCT.

Synthesis of oxovanadium complexes and their apoptosis-inducing activity in leukemia cells.

Vanadium complexes with different ligands were synthesized and evaluated for antiproliferative activity on U937 cells. The alkyl chain length of the ligands affected the antiproliferative activity, and two complexes-3b and 4-exhibited strong activities with IC(50) values of 6.02 and 3.90 µM respectively. Annexin V staining and DNA ladder formation indicated that these complexes induced apoptosis in U937 cells.

Oxovanadium complexes with quinoline and pyridinone ligands: syntheses of the complexes and effect of alkyl chains on their apoptosis-inducing activity in leukemia cells.

Vanadium complexes with quinoline ligands (1b-g) and pyridinone ligands (2b-d) were synthesized, and the effect of the length and shape of alkyl chains on the antiproliferative activity toward U937 cells was studied. For the synthesis of the vanadium complexes, quinoline and pyridinone ligands were prepared and then treated with VOSO(4) or VO(acac)(2). The vanadyl(IV) complexes were characterized by IR, ESR, and UV-vis spectroscopy and elemental analyses. The antiproliferative activity of 1a-g toward U937 cells showed little dependence on the length and shape of the alkyl chain. In contrast, a good correlation was found between the IC(50) values and partition coefficients (logP) values of 2a-c. Among them, 2c showed the highest inhibitory activity, and its IC(50) value was smaller than that of cisplatin. The apoptosis-inducing ability of 2b and 2c was supported by annexin V-propidium iodide staining experiments and agarose gel electrophoresis analysis. Inhibitors of caspase-3, -8, and -9 did not affect the antiproliferative activity of 2c, indicating that the apoptosis induced by 2c was via a caspase-independent pathway.