Successful Pregnancy and Fetal Outcomes Following Brentuximab Vedotin for Early Relapsed Classic Hodgkin Lymphoma After Autologous Stem Cell Transplant.

Brentuximab vedotin (BV), an anti-CD30 antibody with monomethyl auristatin E conjugate, has shown clinical effects against relapsed/refractory classic Hodgkin lymphoma (cHL) and hence is widely used in the clinical setting. We report a special clinical case of successful pregnancy and fetal outcome in a patient with cHL who achieved long-term remission with BV for early relapse after an autologous stem cell transplant (auto-SCT). A 27-year-old woman with advanced cHL achieved complete response (CR) after six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen. Embryos obtained from intracytoplasmic sperm injection were cryopreserved before the initiation of induction chemotherapy. Despite achieving a second CR following intensive salvage chemotherapy, auto-SCT, and radiotherapy, she relapsed again six months after transplantation. BV monotherapy was administered as salvage therapy. She completed 16 cycles of BV and achieved CR. Six months after BV completion, she expressed her desire to bear a child. She achieved pregnancy through third in vitro fertilization and embryo transfer and delivered a healthy baby. BV may provide a potentially curative treatment for patients with cHL relapsed after auto-SCT. Pregnancy should be avoided during BV administration up to a certain period after the end of administration. Fertility preservation is important for adolescent and young adult cancer survivors, and patients should be informed of cancer-related infertility and fertility preservation options prior to the initiation of cancer treatment.

Successful Treatment With Venetoclax Plus Azacytidine Combined With Radiation Therapy and Donor Lymphocyte Infusion in a Patient With Extramedullary Relapse of Acute Myeloid Leukemia After Stem Cell Transplantation.

Extramedullary (EM) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) is rare and causes systemic relapse. Consequently, the prognosis is very poor because limited treatment is feasible in post-transplant patients. The efficacy and safety of venetoclax (VEN), a newly developed oral inhibitor of B-cell leukemia/lymphoma-2, plus azacytidine (AZA) in patients newly diagnosed with AML who are ineligible for intensive chemotherapy have been reported. We report a case in which VEN + AZA salvage treatment following radiation therapy and donor lymphocyte infusion afforded promising results in a patient with AML who showed post-allo-HSCT EM relapse.

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01.

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

Anti-CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Multiple Myeloma with Hyperammonemia Treated with Novel Agents: A Case Series of Three Patients.

Multiple myeloma (MM) is a cancer characterized by the expansion of plasma cells in the bone marrow. Survival times of patients with MM have increased due to the development of novel therapeutic agents. We herein highlight three MM cases that had a poor prognosis despite treatment with novel therapeutic agents. Of note, all patients presented with hyperammonemia that led to a consciousness disorder. The outcome for patients with MM showing high levels of serum ammonia continues to be poor, even with the use of novel therapies. For such patients showing a consciousness disorder, hyperammonemia should be considered as a possible cause.

Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease.

IL-26 is a Th17 cytokine, with its gene being absent in rodents. To characterize the in vivo immunological effects of IL-26 in chronic systemic inflammation, we used human IL26 transgenic (hIL-26Tg) mice and human umbilical cord blood mononuclear cells (hCBMC) in mouse allogeneic-graft-versus-host disease (GVHD) and chronic xenogeneic-GVHD model, respectively. Transfer of bone marrow and spleen T cells from hIL-26Tg mice into B10.BR mice resulted in GVHD progression, with clinical signs of tissue damage in multiple organs. IL-26 markedly increased neutrophil levels both in the GVHD-target tissues and peripheral blood. Expression levels of Th17 cytokines in hIL-26Tg mice-derived donor CD4 T cells were significantly increased, whereas IL-26 did not affect cytotoxic function of donor CD8 T cells. In addition, granulocyte-colony stimulating factor, IL-1ß, and IL-6 levels were particularly enhanced in hIL-26Tg mice. We also developed a humanized neutralizing anti-IL-26 monoclonal antibody (mAb) for therapeutic use, and its administration after onset of chronic xenogeneic-GVHD mitigated weight loss and prolonged survival, with preservation of graft-versus-leukemia effect. Taken together, our data elucidate the in vivo immunological effects of IL-26 in chronic GVHD models and suggest that a humanized anti-IL-26 mAb may be a potential therapeutic agent for the treatment of chronic GVHD.

Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis.

BACKGROUND: In the pivotal phase III, randomized, multicenter ICARIA-MM study (NCT02990338), isatuximab plus pomalidomide and dexamethasone (Isa-Pd) improved progression-free survival and overall response rate versus pomalidomide and dexamethasone (Pd) in the overall population of patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: In this predefined subgroup analysis, efficacy, and safety between East Asian patients and the overall population were assessed. RESULTS: In total, 36 East Asian patients were included (Japanese, n = 13; Korean, n = 9; Taiwanese, n = 14). At a median follow-up of 11.6 months, median progression-free survival was not reached (95% confidence interval [CI] 5.80-not calculable) in the Isa-Pd arm and was 7.9 months (95% CI 2.90-not calculable) in the Pd arm. The hazard ratio for the between-group difference was 0.52 (95% CI 0.19-1.39), which was similar to the overall population (hazard ratio, 0.60; 95% CI 0.44-0.82). No new safety signals were observed, except that a higher proportion of patients in the East Asian population experienced Grade ≥ 3 neutropenia compared with the overall population. CONCLUSION: These results confirm the efficacy of Isa-Pd in East Asian patients with relapsed/refractory multiple myeloma, and the related safety data are consistent with those observed in the overall population and are manageable.

Prospective comparison of 5- and 7-day administration of azacitidine for myelodysplastic syndromes: a JALSG MDS212 trial.

The hypomethylating agent azacitidine (AZA) significantly extends overall survival (OS) in patients with higher risk myelodysplastic syndromes (MDS), when compared with other conventional care regimens, including supportive care and low-dose and intensive chemotherapy. However, the effects of 5- and 7-day treatment schedules of AZA (AZA-5 and AZA-7, respectively) on the OS of MDS patients had not been compared prospectively. We started a phase 3 trial comparing the effects of AZA-7 and AZA-5 on MDS patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T). However, this trial was prematurely terminated because of poor recruitment. Using all data, there was no significant difference in the OS of patients between AZA-7 (92 patients) and AZA-5 (95 patients), with the 2-year OS rates of AZA-7 and AZA-5 at 36.4% and 25.8%, respectively (P = 0.293). Adverse event profiles were similar between the two groups. Interestingly, data of the centrally diagnosed RAEB and RAEB-T cases showed that AZA-7 significantly prolonged the time to leukemia transformation compared with AZA-5 (P = 0.022), confirmed by multivariate analysis. Although this trial could not provide definite evidence, the results support the use of AZA-7 for RAEB and RAEB-T. (UMIN Clinical Trials Registry UMIN000009633).

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer.

Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series.

BACKGROUND: Although spinal cord injury (SCI) is a major cause of disability, current therapeutic options remain limited. Recent progress in cellular therapy with mesenchymal stem cells (MSCs) has provided improved function in animal models of SCI. We investigated the safety and feasibility of intravenous infusion of MSCs for SCI patients and assessed functional status after MSC infusion. METHODS: In this phase 2 study of intravenous infusion of autologous MSCs cultured in auto-serum, a single infusion of MSCs under Good Manufacturing Practice (GMP) production was delivered in 13 SCI patients. In addition to assessing feasibility and safety, neurological function was assessed using the American Spinal Injury Association Impairment Scale (ASIA), International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92). Ability of daily living was assessed using Spinal Cord Independence Measure (SCIM-III). The study protocol was based on advice provided by the Pharmaceuticals and Medical Devices Agency in Japan. The trial was registered with the Japan Medical Association (JMA-IIA00154). RESULTS: No serious adverse events were associated with MSC injection. There was neurologic improvement based on ASIA grade in 12 of the 13 patients at six months post-MSC infusion. Five of six patients classified as ASIA A prior to MSC infusion improved to ASIA B (3/6) or ASIA C (2/6), two ASIA B patients improved to ASIA C (1/2) or ASIA D (1/2), five ASIA C patients improved and reached a functional status of ASIA D (5/5). Notably, improvement from ASIA C to ASIA D was observed one day following MSC infusion for all five patients. Assessment of both ISCSCI-92, SCIM-III also demonstrated functional improvements at six months after MSC infusion, compared to the scores prior to MSC infusion in all patients. CONCLUSION: While we emphasize that this study was unblinded, and does not exclude placebo effects or a contribution of endogenous recovery or observer bias, our observations provide evidence supporting the feasibility, safety and functional improvements of infused MSCs into patients with SCI.

Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer.

Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis, induced by nivolumab plus ipilimumab.

Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study.

OBJECTIVES: Intensive nutritional support during allogeneic hematopoietic stem cell transplantation (allo-HSCT) yields improved clinical outcomes. However, the clinical implications of early enteral nutrition (EN) in allo-HSCT remain unclear. This retrospective study was conducted to determine the significance of early EN in individuals who underwent allo-HSCT, and the association between early nutritional intervention and clinical outcomes, including the status of the intestinal microbiome. METHODS: Thirty-one participants received EN before conditioning. The intestinal microbiota was examined by meta 16S rRNA gene sequencing of fecal samples. RESULTS: The median body mass variation was only -0.35 kg on day 60. The probability of 2-y overall survival was 61.1%. The cumulative incidence of treatment-related mortality was 17.4%, and those of acute graft-versus-host disease were 32.3% (grades II-IV) and 3.2% (grades III-IV). Chronic graft-versus-host disease was observed in four participants. Dysbiosis of the intestines and acute graft-versus-host disease occurred simultaneously, and Enterococcus species were abundant. CONCLUSIONS: Our results suggest that early nutritional support can improve the outcomes for individuals who have undergone allo-HSCT and can maintain homeostasis of their intestinal microbiome. Future prospective clinical trials are required to elucidate the role of EN in allo-HSCT and the association between the intestinal microbiome and EN.

[Diffuse large B cell lymphoma with HIV infection presented with disseminated thromboembolism during antiretroviral therapy].

Patients with HIV are at higher risk of developing thrombosis than the general population. We present a rare case of a 57-year-old Japanese man with HIV infection and a malignant lymphoma. He had fever with unknown origin and cervical lymph node swelling 2 months before his hospital visit. Because he was positive for the HIV antibody, he was referred to our HIV special outpatient section. HIV RNA level was found to be 846,680 copies/ml. Therefore, antiretroviral therapy of DTG/ABC/3TC was initiated. However, the high fever continued for 7 days after treatment initiation; moreover, renal dysfunction was progressive. After admission, antibiotic therapy was initiated, due to which the fever subsided. However, renal dysfunction continued to progress. Fourteen days later, he died due to acute renal failure with hyperkalemia. An autopsy revealed a large mass in the spleen, and histological findings revealed a diffuse large B cell lymphoma (DLBCL). Furthermore, thrombi were detected in the right and left ventricles, right atrium, iliac artery, and renal artery. Pathological findings revealed that the thrombus induced the renal failure. These thrombi contained fibrin with inflammatory cell infiltration but not tumor cells. Patients with HIV and malignant lymphoma are at a higher risk of thrombosis. It is important to consider thrombosis during the treatment of patients with HIV.

Successful Treatment by Surgery and Lenvatinib of a Patient with Adrenal Metastasis of Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is considered an indolent cancer, but some PTC patients do present with distant metastases and treatment strategies for such patients are not well established. Recently, lenvatinib, an inhibitor of multiple tyrosine kinases, has been introduced to treat patients with advanced PTC but carries a risk of serious adverse events such as hemorrhage. Here, we report a PTC patient with a left adrenal metastasis and lenvatinib-induced hemorrhage who underwent successful surgical resection and was subsequently treated with a lower dose of lenvatinib. The patient has now been in a stable state with no adverse events for nearly two years. This case highlights the importance of surgical resection of metastatic PTC and subsequent lenvatinib therapy, even when the tumor is at an advanced stage.

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

[Good's syndrome developing hemophagocytic lymphohistiocytosis following thymectomy].

This report presents the case of a 68-year-old female patient previously diagnosed with thymoma by her local doctor. She was referred to our hospital for surgery, and the thymoma was removed and diagnosed as a World Health Organization (WHO) classification type AB thymoma. After surgery, she experienced general malaise, a loss of appetite, and weight loss, so she visited our hospital in May 2019. A blood test showed hypogammaglobulinemia and low B lymphocytes. A bone marrow examination revealed no morphological abnormalities. Flow cytometric analysis indicated a marked decrease in both the B cell-related surface markers CD19 and CD20 and the T cell-related surface marker CD4, and the CD4/CD8 ratio was also low. She was diagnosed with Good's syndrome, and immunoglobulin replacement therapy was administered. She subsequently developed hemophagocytic lymphohistiocytosis (HLH) due to infection and was treated according to the HLH2004 protocol, but she finally succumbed to multiple organ damage as a result of sepsis. Given that Good's syndrome is associated with both humoral and cellular immune dysfunctions, affected patients tend to develop severe infections and have a poor prognosis. In such cases, early detection, regular immunoglobulin replacement therapy, and infection prevention therapies are important.

Successful brentuximab vedotin monotherapy against late relapse of classical Hodgkin lymphoma 6 years after first remission.

Brentuximab vedotin monotherapy for late-relapse CHL is a promising therapeutic with sustained CR benefit and avoiding potential toxicities caused by aPBSCT/HDT.

Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.