Yuichi Yahagi

Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study.

In order to investigate better molecular‐target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33‐positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara‐C) (100 mg/m2 × 7 days), combined with either idarubicin (IDR) (10–12 mg/m2 × 3 days) or daunorubicin (DNR) (50 mg/m2 × 3–5 days), and then GO (3–5 mg/m2), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose‐limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33–64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m2 GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non‐hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m2 GO showed DLT. No patients had veno‐occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m2 GO combined with Ara‐C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy. (Cancer Sci 2011; 102: 1358–1365)

A case of primary esophageal mucosa-associated lymphoid tissue lymphoma with a numerical abnormality of 18q21 detected by fluorescence in situ hybridization.

Dear Editor, Mucosa-associated lymphoid tissue (MALT) lymphoma, which was first described in 1983. MALT lymphoma can develop from organs where lymphocytes are normally absent by the acquisition of MALT. The acquired MALT appears in association with chronic inflammation induced by persistent infection or autoimmune disorders such as Helicobacter pylori (H. pylori) infection, Sjogren’s syndrome, or Hashimoto’s disease. Although MALT lymphoma arises from any different organs, esophagus is a rare site of origin in the literature. We report here a primary esophageal MALT lymphoma with a numerical cytogenetic abnormality detected by fluorescence in situ hybridization (FISH). A 70-year-old woman has received endoscopy and submucosal tumors (SMT) were detected incidentally in October 2004. The examination revealed two SMT lesions (0.6×0.4 cm, 2.0×0.8 cm) approximately 26 and 28 cm from the incisor teeth (Fig. 1a). Histological examination of biopsied samples revealed that smallto medium-sized cells resembling marginal zone cells (Fig. 1b). Tumor cells were positive for CD20, CD79a, bcl-2, and negative for CD5, CD10, and cyclin D1. She had no episode of any autoimmune diseases or H. pylori gastritis. Computed tomography demonstrated no evidence of enlarged regional lymph nodes in the neck, chest, or abdomen. No bone marrow involvement was detected. We diagnosed her with primary esophageal MALT lymphoma. Endoscopic mucosal resection was performed in January 2005. Immunophenotypical analysis showed a kappa light chain restriction. FISH analysis was carried out using paraffin-embedded tissue with two differentially labeled probes each placed on upstream and downstream to MALT1, resulting three non-split signals (Fig. 1c). She received additional radiation therapy (30 Gy) after endoscopic mucosal resection. The patient is alive without any symptoms or recurrence of MALT lymphoma. MALT lymphoma exemplifies the close relationship between chronic inflammation and lymphomagenesis. It is well known that the most frequent primary involved site is the gastrointestinal tract. The lymphoma cells are preceded by the acquisition of MALT as a result of H. pylori infection. Eradication of H. pylori can result in regression of the lymphoma in 75% cases. However, additional genetic environmental or other factors should play a role, since most patients with H. pylori gastritis do not develop lymphoma. Recently cytogenetic data on MALT lymphoma has been accumulated. The t(11;18)(q21;q21) results in a Ann Hematol (2009) 88:703–704 DOI 10.1007/s00277-008-0653-y

Intensified Daunorubicin in Induction Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Postremission Therapy (Double-7 Protocol) for Adult Acute Myeloid Leukemia

To investigate whether an intensified dose of daunorubicin (DNR) in induction therapy and autologous peripheral blood stem cell transplantation (PBSCT) in the postremission period are effective treatments, we used a Double-7 protocol to treat adult patients with de novo acute myeloid leukemia (excluding M0 and M3). Induction therapy consisted of 40 mg/m2 of DNR intravenous drip infusion for 7 days and 200 mg/m2 of ara-C by continuous infusion for 7 days (7 + 7 DC regimen). Patients who achieved complete remission (CR) were given high-dose chemotherapy with autologous PBSCT in postremission therapy. Of the 22 assessable patients, 16 attained CR (73%). Disease-free survival (DFS) and overall survival (OS) at 3 years were 61.2% and 48.1%, respectively. Nine of the CR patients underwent PBSCT without therapy-related mortality. Patients in a favorable cytogenetic group (n = 7) attained 100% CR and long-term survival (71.4% DFS and 85.7% OS at 3 years). Thus, intensified DNR administration of 280 mg/m2 (40 mg/m2 per day for 7 days) in induction therapy for adult patients younger than 60 years of age might be optimal or at least comparable with the new anthracyclines such as idarubicin. In addition, autologous PBSCT in postremission therapy might improve DFS and OS, at least for patients in a favorable cytogenetic group, such as those with a t(8;21) abnormality.Int J Hematol. 2002; 76: 436-445.

Rapid progression and unusual premortal diagnosis of mucormycosis in patients with hematologic malignancies: analysis of eight patients

Mucormycosis is a rare but emerging group of life-threatening opportunistic mycoses. We described experience of eight patients who developed mucormycosis. These patients had developed hematologic malignancies, and none achieved complete remission. Six of the eight patients presented with neutropenia, five received corticosteroid, and four had concomitant hyperglycemia. The most frequent physical finding was fever, and five patients complained of facial pain, headache, or chest pain. Four patients presented with concomitant bacterial infection, pulmonary aspergillosis, or intestinal candidiasis. Premortal diagnosis of mucormycosis was made in only one patient. Postmortem biopsy or autopsy was the diagnostic tool for the other patients. Although patients who were treated with amphotericin B survived longer than those treated with micafungin or voriconazole, all patients died due to the progression of mucormycosis. Estimated median survival was 23 days. Premortal diagnosis was rarely achieved as biopsy of infected tissues was the only diagnostic tool, and four patients who revealed dual infection were diagnosed with aspergillosis or bacterial infections. In patients with a high risk of mucormycosis presenting with pain and uncontrollable fever, mucormycosis should be included in the differential diagnosis. High dosages of liposomal amphotericin B should be given and surgical debridement should be performed promptly in cases highly suggestive of mucormycosis.

Epstein-Barr Virus-associated Lymphoproliferative Disorder with Encephalitis Following Anti-thymocyte Globulin for Aplastic Anemia Resolved with Rituximab Therapy: A Case Report and Literature Review

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.

Clinical significance of cancer-related fatigue in multiple myeloma patients

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.

Clinical significance of granule‐containing myeloma cells in patients with newly diagnosed multiple myeloma

The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to investigate the clinical significance of granule‐containing myeloma cells in patients with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed the records of 122 patients diagnosed with NDMM between January 2007 and December 2013. Granule‐containing myeloma cells were defined as myeloma cells that exhibited three or more granules in their cytoplasm by May‐Giemsa staining. The patients were classified into two groups, the granule‐containing myeloma (GM) and nongranule‐containing myeloma (non‐GM) groups, depending on the proportion of myeloma cells that contained granules (cut‐off value: 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM group displayed significantly higher CD56 and CD49e expression than those in the non‐GM group (t‐test, P = 0.027 and 0.042). None of the patient characteristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall response rates of the two groups were similar. During the median follow‐up period of 33.9 months, the overall survival (OS) in the GM group was similar to that in the non‐GM group; 4‐year OS of the GM and non‐GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule‐containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival.