Sumito Shingaki

Phase 2 trial of daily, oral epigallocatechin gallate in patients with light-chain amyloidosis

Previous studies have suggested that an increase in mitochondrial reactive oxygen species may cause organ damage in patients with light-chain (AL) amyloidosis; however, this damage can be decreased by antioxidant-agent treatment. Epigallocatechin gallate (EGCG), the major natural catechin in green tea, has potent antioxidant activity. Because EGCG has recently been reported to have a favorable toxicity profile for treating amyloidosis, we sought to examine the clinical efficacy and toxicity of EGCG in patients with AL amyloidosis. Fifty-seven patients were randomly assigned to the EGCG and observation groups and observed for six months. There were no increases in grade 3–5 adverse events and EGCG therapy was well tolerated. Although a decrease in the urinary albumin level was found in the EGCG group in patients with obvious albuminuria after treatment initiation, its antioxidant activity may not be sufficient to clarify the potential effect of EGCG in patients with AL amyloidosis. Because some of the biological markers responsible for organ damage were well correlated to the level of antioxidant potential in patients’ plasma, the status of oxidative stress in the blood may indicate the extent of organ damage in clinical situations.

The clinical significance of decrease in CD138 positive cell ratio in multiple myeloma

CD138 has been considered to be strongly expressed in multiple myeloma cells. However, CD138⁺ cells were decreased in some patients during the course of treatment. To clarify the clinical significance of this finding, we evaluated the correlations of CD138 levels with laboratory data employing flow cytometry. We found that CD138⁺ cells were decreased in 12 patients during treatment and were retained in the remaining 105 patients throughout their clinical courses. For nine (75%) patients in the CD138⁺ cells reduced group, median survival time was 25 months after the reduction in CD138⁺ cells was detected, and all nine died of myeloma. Furthermore, extramedullary lesions and specific cytogenetic abnormalities [del(17p), t(4;14), amplification of c-MYC] were observed in some patients when the number of CD138⁺ cells started to decrease. Interestingly, 2 of 3 patients who survived until the end of observation period showed re-increase in their CD138⁺ levels. Taking these observations together, it is unclear whether reduction of the number of CD138⁺ cells is associated with a poor prognosis and resistance to drugs. However, if treatment does not produce a reincrease in CD138⁺ levels, long term survival might be difficult to achieve.

[Induction treatment with bortezomib-cyclophosphamide-dexamethasone (CyBorD) for newly diagnosed transplant-eligible patients with multiple myeloma].

Twenty-nine transplant eligible newly diagnosed multiple myeloma (NDMM) patients have received Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) as induction treatment in our institute since November 2011. CyBorD is composed of CPA 300 mg/m2 p.o., Bor 1.3 mg/m2 i.v. or s.c., and Dex 40 mg/body p.o. on days 1, 8, 15, and 22. The median number of CyBorD cycles was 4 (range 2-6), except in one patient who progressed during the first cycle. Grade 4 neutropenia was observed in 2 patients, but none experienced grade 2 thrombocytopenia. Grade 3 non-hematologic adverse events were observed in two patients with varicella-zoster virus reactivation. Responses after CyBorD were ≥PR in 72%, ≥VGPR in 52%, ≥CR in 21%, and sCR in 21%. Autologous stem cells were harvested in 27 patients. Seventeen of these 27 patients received high-dose melphalan and autologous stem cell transplantation (ASCT) within 12 months after diagnosis. Patients with ≥CR increased to 59% after ASCT. Our data suggest the efficacy and the feasibility of administering CyBorD to transplant eligible NDMM patients.

Feasibility of myeloablative allogeneic hematopoietic cell transplantation from unrelated donors for patients with relapsed or refractory multiple myeloma

Allogeneic hematopoietic cell transplantation (allo‐HCT) for patients with multiple myeloma (MM) is performed increasingly as salvage therapies, from unrelated donors and, to our surprise, in transplant number despite in the era of novel agents. While the major limitation in the use of allo‐HCT in patients with MM has been the high transplant‐related mortality (TRM), the early data on myeloablative allo‐HCT have proven its curative potential. The purpose of this retrospective case series was to analyze the feasibility of a myeloablative conditioning regimen, incorporating both of 140 mg/m of melphalan and 8 Gy of total body irradiation, followed by allo‐HCT from unrelated donors for patients with relapsed or refractory MM. We identified consecutive patients with relapsed or refractory MM who received first allo‐HCT from unrelated donors after the myeloablative conditioning regimen between April 2013 and July 2015 at the Japanese Red Cross Medical Center and conducted data extraction on the reference date of March 1, 2017. The standardized myeloablative conditioning regimen for myeloma patients receiving allo‐HCT in the institution was the Flu/Mel/TBI regimen. This regimen originally consisted of fractionated total body irradiation (TBI) at 2 Gy twice daily on days ‐9 to ‐8 (total dose, 8 Gy), fludarabine at 25 mg/m once daily on days ‐7 to ‐3 (total dose, 125 mg/m), and melphalan at 140 mg/m once daily on day ‐2. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Japanese Red Cross Medical Center. Informed consent was obtained from all individual participants included in the study. Regimen‐related toxicity (RRT) was graded according to the Bearman criteria. Acute and chronic graft‐versus‐ host disease (GvHD) were graded as described. Responses, lines of therapy, and patient populations were defined as described. We used the Kaplan‐Meier estimates for the probabilities of progression‐ free survival (PFS) and overall survival (OS), and the cumulative incidence estimates for the occurrences of GvHD. All statistical analyses were performed with R software, version 3.2.3. Eight patients were identified (Table 1). The median follow‐up among the survivors was 36.5 months (range, 19‐55 mo) after allo‐HCT. Two patients (patient nos 6 and 7) presented with translocation t(4;14) detected by FISH. Deletion of 17p was not involved any of the patients. The median age at allo‐HCT, the time from diagnosis of

Coexistent adrenal diffuse large B cell lymphoma in a patient with Waldenström's macrogloblinemia/lymphoplasmacytic lymphoma

Dear Editor, The clinical courses of patients with malignant lymphoma are sometimes complicated with the occurrence of another type of lymphoma. Comorbid lymphoma can occur in the form of transformation, composite lymphoma, ormultiple primary lymphomas. Here, we present a patient with Waldenstrom’s macrogloblinemia/lymphoplasmacytic lymphoma (WM/LPL) who was subsequently diagnosed with adrenal diffuse large B cell lymphoma (DLBCL). A 69-year-old Japanese male was referred to our hospital for a work-up of positron emission tomography (PET)-avid bilateral adrenal nodular lesions, incidentally noticed at a yearly health check (Fig. 1a). The image study was not suggestive of neoplastic involvement of other organs, including the lymph nodes and spleen. An increased serum IgM (4184 mg/dl) with a monoclonal component was documented. Bone marrow examination revealed a collection of small lymphoid cells and plasma cells (Fig. 1b). They were immunohistochemically positive for CD20 and kappa and negative for CD5, CD10, CD23, and cyclin D1. CD38 was positive in the plasma cells and negative in the lymphoid cells. TheMIB-1 index was less than 5%.MYD88 L265Pmutation was detected by polymerase chain reaction (PCR) and gene sequence techniques. He was diagnosed with WM/LPL. Although the level of IgM was gradually increasing, he was observed without treatment because of the absence of symptoms related to WM/LPL. The PET finding of adrenal lesions showed no remarkable change 3 months later. He presented with severe general malaise 10 months after the diagnosis of WM/LPL. A blood examination showed surges in the values of lactate dehydrogenase (700 IU/l) and soluble interleukin-2 receptor (11,200 U/ml), and computed tomography (CT) revealed an obvious enlargement of the adrenal lesions (Fig. 1c). Unilateral CT-guided biopsy was performed, and the invasion of large lymphocytes with nuclear debris was documented (Fig. 1d). These lymphocytes were positive for CD20 and MUM1 and negative for CD5, CD10, BCL2, BCL6, and EBER-ISH. The MIB-1 index was approximately 95 %. A split signal of c-myc was not observed by fluorescence in situ hybridization assay. Based on this combination of findings, we diagnosed adrenal DLBCL with probable bilateral involvements. Six cycles of R-CHOP (rituximab, doxorubicin, vincristine, cyclophosphamide, and prednisolone) resulted in a complete response. In order to clarify the clonal relatedness betweenWM/LPL and DLBCL, we carried out an analysis of immunoglobulin heavy chain (IGH) clonality with specimens of bone marrow and adrenal gland using commercially available PCR-based kits (Invivoscribe Technologies, San Diego, CA) [1]. The PCR products underwent direct sequencing and were analyzed by IMGT/V-QUEST [2]. The resultant sequence data showed that WM/LPL cells utilized rearranged the VH4-39 gene whereas DLBCL cells utilized rearranged the VH1-46 gene. There have been just a few reports on the concomitant occurrence of WM/LPL and DLBCL [3]. In such cases, DLBCL can either be clonally related or unrelated to WM/ LPL [4–7]. While the transformation of WM/LPL into DLBCL has been recognized, the coincidence of different * Sumito Shingaki shinpth2@tmd.ac.jp