Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study.

PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).

[Methotrexate-related lymphoproliferative disease showing different histological findings at recurrence].

A 55-year old female patient was treated with methotrexate (MTX) and infliximab (IFX) for rheumatoid arthritis (RA). She experienced unknown fever, generalized lymphadenopathy, and liver tumors. Histological examination of the inguinal lymph node and a liver tumor resulted in the pathological diagnosis of classic Hodgkin lymphoma, with many Reed-Sternberg cells with the positivity of Epstein-Barr virus (EBV). She was diagnosed with MTX-related lymphoproliferative disorders (MTX-LPDs). She received chemotherapy after the cessation of MTX and IFX and achieved complete remission. RA showed recurrence after a while, and she was treated with steroids or other drugs. Six years after the chemotherapy, she experienced low-grade fever and anorexia. Whole computed tomography images showed an appendix tumor and enlargement of the surrounding lymph nodes. Appendectomy with the radical lymph nodes dissection was performed. The pathological diagnosis was diffuse large B-cell lymphoma, resulting in the clinical diagnosis of the relapse of MTX-LPD. EBV was negative at this point. The pathological findings of MTX-LPD may change at relapse; thus, biopsy should be considered when the relapse of MTX-LPD is suggested.

Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth.

Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.

[Progressive multifocal leukoencephalopathy during the treatment for mycosis fungoides].

A 58-year-old man was diagnosed with mycosis fungoides (MF) confirmed by skin biopsy for systemic erythema that appeared in 2006 and had been on psoralen plus ultraviolet A (PUVA) therapy and topical steroids. In September 2017, he had diffuse large B-cell lymphoma and received chemotherapy. Since March 2019, tumor stage MF with large cell transformation was observed, and chemotherapy containing brentuximab vedotin (BV) was performed, which yielded a remarkable response. During the preparation for allogeneic hematopoietic stem cell transplantation, bradykinesia, delayed response, and cognitive decline were observed. Head magnetic resonance imaging fluid-attenuated inversion recovery images showed hyperintensity in the deep white matter below the bilateral frontal cortex. The general cerebrospinal fluid test revealed no abnormalities and was below the sensitivity of JC virus (JCV) quantitative PCR. As progressive multifocal leukoencephalopathy (PML) was strongly suspected from clinical symptoms and radiographic signs, ultrasensitive JCV testing was performed. The test result was positive; hence, the patient was diagnosed with PML. Chemotherapy was discontinued, but his central nervous system symptoms worsened, and he died on the 135th day of illness. We considered that PML developed based on the underlying disease and immunodeficiency caused by chemotherapy such as BV.

No clear survival benefit of azacitidine for lower-risk myelodysplastic syndromes: A retrospective study of Nagasaki.

The efficacy of azacitidine (AZA) on survival of lower risk (LR) - myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long-term survival benefit of AZA for patients with LR-MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR-MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis-stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection-related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR-MDS patients.

Treatment with mogamulizumab or lenalidomide for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience.

Mogamulizumab (Mog) and lenalidomide (Len) are new therapeutic candidates for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we retrospectively analyzed 12 patients who received Mog or Len monotherapy for relapsed ATL after allo-HSCT. Eight and three patients received Mog and Len, respectively. The remaining patient received Mog for the first relapse and Len for the third relapse. A complete response was achieved by three and two patients who received Mog and Len, respectively, two and one of whom remained alive with a complete response for more than 20 months. In terms of adverse events, the emergence or progression of graft-versus-host disease was observed in three out of four patients treated with Len and in none of the patients treated with Mog. The development or progression of cytomegalovirus reactivation was detected in four out of eight patients treated with Mog and in none of those treated with Len. The present results suggest that Mog and Len would be promising treatment options for relapsed ATL after allo-HSCT and need to be selected based on adverse event profiles.

[Composite adult T-cell leukemia/lymphoma and Epstein-Barr virus-positive diffuse large B-cell lymphoma].

Human T-cell leukemia virus type I (HTLV-1) infection and adult T-cell leukemia-lymphoma (ATL) have been shown to cause immunodeficiency. However, only a few cases have been reported on the development of Epstein-Barr virus positive-diffuse large B-cell lymphoma (EBV-DLBCL) in HTLV-1 carriers or in patients with ATL. Here we report a case of a female HTLV-1 carrier who developed cytomegalovirus (CMV) retinitis. During the CMV retinitis treatment, she developed a liver tumor. The diagnosis of composite ATL and EBV-DLBCL was made by tumor biopsy. The patient also suffered from pulmonary cryptococcosis and invasive pulmonary aspergillosis at the time of chemotherapy initiation. She had repeated CMV antigenemia and bacterial sepsis during the course of chemotherapy, and she died of bacterial sepsis. HTLV-1 carriers who are complicated with opportunistic infections should be carefully observed not only for ATL development but also for the development of EBV-DLBCL and associated infectious complications.

The outcome and characteristics of patients with relapsed adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation.

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo-HSCT. Some long-term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty-six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43-0.93; P = .02], suggesting the efficacy of a graft-versus-ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22-0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo-HSCT. Further investigations of incorporation of immune-based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.

Diagnostic Utility of Cytomegalovirus Nucleic Acid Testing during Antigenemia-Guided Cytomegalovirus Monitoring after Hematopoietic Stem Cell Transplantation or Liver Transplantation.

Cytomegalovirus (CMV) is an opportunistic pathogen, and careful monitoring of CMV is important for immunocompromised patients. Antigenemia-based CMV monitoring is a standard test used for managing CMV infection in transplant recipients; however, in Japan, there are no reports of CMV monitoring using the standardized test. The utility of a standardized CMV nucleic acid test (NAT) was evaluated during antigenemia-based CMV monitoring after hematopoietic stem cell transplantation (HSCT) or liver transplantation. Blood collection for CMV monitoring was performed under the physician's instructions depending on the condition of the patient, and CMV NAT and antigenemia was evaluated. For HSCT recipients, blood collection only for NAT was additionally performed during the pre-engraftment phase. The results of the NAT were blinded to those evaluating the results. A total of 34 patients were enrolled (11 HSCT recipients and 23 liver transplant recipients). NAT detected the first CMV episode no later than antigenemia in 2 (18.2%) HSCT recipients and 3 (13.0%) liver transplant recipients, earlier than antigenemia in 3 (27.3%) HSCT recipients and 7 (30.4%) liver transplant recipients, and later than antigenemia in 1 (9.1%) HSCT recipient and 1 (4.3%) liver transplant recipient. In 5 HSCT recipients, NAT was positive during the pre-engraftment phase. Among the 468 blood samples which were evaluated by both NAT and antigenemia, 124 (26.7%) were positive in NAT and 51 (10.9%) were positive in antigenemia. The standardized CMV NAT is useful for accurately diagnosing CMV infection and determining appropriate therapeutic interventions for HSCT recipients and liver transplant recipients.

[Gingival squamous cell carcinoma diagnosed on the occasion of osteonecrosis of the jaw in a patient with chronic GVHD].

A 44-year-old male was diagnosed with acute myeloid leukemia with a complex karyotype. He underwent bone marrow transplantation using an HLA 6/6 antigen-matched sibling donor, but developed chronic graft-versus-host disease (cGVHD) with skin erythema and oral and esophageal lichen planus changes. Treatment with a combination of prednisolone and cyclosporine was initiated on day 646 after transplantation, but oral symptoms persisted. The patient developed bilateral osteonecrosis of the lower jaw after extraction of the lower left and right molars on days 2,861 and 3,339, respectively. As the disease gradually progressed, segmental mandibular osteotomy was performed. Biopsy specimens demonstrated proliferation of squamous epithelial carcinoma cells in the bilateral gingiva and lower jaw bone, which confirmed the diagnosis of bilateral gingival squamous cell carcinoma. Thus, gingival squamous cell carcinoma should be considered as a differential diagnosis in post-transplant patients with refractory osteonecrosis of the jaw during the course of cGVHD.

[Ectopic pulmonary calcification after parathyroidectomy in multiple myeloma].

Ectopic soft tissue calcification (ESTC), a rare clinical condition, causes tissue and organ damage. It is associated with chronic renal failure, hyperparathyroidism, and malignant neoplasms, including multiple myeloma, and it is reportedly resistant to treatment. Here, we present the case of a 71-year-old male with multiple myeloma who had rapid ESTC in the lung. He had developed hypoparathyroidism secondary to thyroidectomy. During the course of our observation, he rapidly developed ectopic pulmonary calcification approximately 2 weeks after acquiring an infection. There was no evidence of further progression of multiple myeloma after the onset of ESTC, and treatment with ferric citrate hydrate and precipitated calcium resulted in immediate improvement of his pulmonary signs. We recommend cautious monitoring for patients with multiple myeloma and hypoparathyroidism to detect the onset of ectopic calcification. In addition, low blood phosphorus levels should be effectively treated.

Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki.

The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (<1·5 km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted.

[Durable remission attained with plasmapheresis and intravenous immunoglobulin therapy in a patient with acute exacerbation of GVHD-related myasthenia gravis].

A 17-year-old male underwent a second bone marrow transplantation using a 6/8 allele HLA-matched unrelated donor. On day 100 after transplantation, steroid treatment for chronic graft-versus-host disease (GVHD) was started. On day 766, the patient experienced general fatigue, followed by double vision, ptosis, and dysphagia on day 810. Based on the positivity of the acetylcholine receptor antibody and a waning electromyography pattern, he was diagnosed with GVHD-related myasthenia gravis (MG). On day 861, we initiated plasmapheresis (PE), followed by the administration of intravenous immunoglobulin (IVIg) ; this treatment attenuated the bulbar symptoms of MG. Although the steroid treatment was continued, we restarted the administration of tacrolimus. On day 2,739 after transplantation, we stopped the steroid treatment, and the patient remained in remission for MG following the cessation of the steroid treatment on day 2,897. This case suggests that PE followed by IVIg could be an effective therapeutic alternative for MG associated with GVHD.

Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki.

There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS-R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS-R, and exposure distance. Of those, 31 were exposed at <1.5 km, 35 at 1.5-2.99 km, and 74 at ≥3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS-R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS-R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors.

Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience.

Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT.

Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.

Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKß, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.

[Successful treatment with a combination of lenalidomide and dexamethasone for cryoglobulinemia associated with multiple myeloma].

Cryoglobulinemia (Cg) in multiple myeloma (MM) is rare and no standard treatment has yet been established. Herein, we report a case of MM with Cg, successfully treated with a combination of lenalidomide and dexamethasone. A 76-year-old woman suffering from skin ulcerations, extremity pain and peripheral neuropathy was diagnosed as having IgG-kappa MM with Cg in 1992. She intermittently received conventional chemotherapy, immunosuppressant therapy and plasma exchange. Despite these treatments, Cg-related symptoms eventually became uncontrollable. She was admitted to our hospital in 2012 because of worsening skin symptoms involving both ankles. Plasmapheresis proved ineffective. Improvement of skin ulcerations and numbness was achieved with administration of lenalidomide at 25 mg daily with weekly dexamethasone, which also decreased the cryoglobulin level. The course of this patient suggests that lenalidomide plus dexamethasone is a promising treatment for MM with Cg.

Septic arthritis as breakthrough invasive fusariosis after cord blood transplantation.

A 63-year-old male received a third allogeneic hematopoietic stem cell transplantation with voriconazole prophylaxis for relapsed acute myeloid leukemia. He developed septic arthritis without any typical skin lesions due to fungal infection on day 42. Treatment with liposomal amphotericin B was initiated following surgical debridement; however, he died of progressive fungal infection. Ribosomal DNA sequencing identified Fusarium solani species complex (FSSC) harboring voriconazole resistance. This clinical course indicates that breakthrough invasive fusariosis (azole-resistant FSSC infection) needs to be considered as a pathogen when patients with hematological malignancies develop septic arthritis without typical skin lesions during voriconazole prophylaxis.

Individual HLAs affect survival after allogeneic stem cell transplantation in adult T-cell leukaemia/lymphoma.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for adult T-cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo-HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo-HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA-identical sibling donors or HLA-A, -B, -C or -DRB1 allele-matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA-A, -B and -DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA-B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51-0.90; p = 0.008), whereas HLA-B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19-2.27; p = 0.003). In addition, HLA-B62 was associated with a lower risk of transplant-related mortality (TRM) (HR, 0.52; 95% CI: 0.32-0.85, p = 0.009), whereas HLA-B60 was associated with a higher risk of grades III-IV acute graft-versus-host disease (HR, 2.63; 95% CI: 1.62-4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA-B60-positive patients and the lower risk of TRM in HLA-B62-positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo-HSCT.