Nobuaki Dobashi

Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia: Results From a Randomized Controlled Trial

PURPOSE The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. PATIENTS AND METHODS Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. RESULTS A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. CONCLUSION In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m2 given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that Cmax and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy.

Role of daunorubicin in the induction therapy for adult acute myeloid leukemia

PURPOSE To evaluate the relationship of total-dose of daunorubicin (DNR) to the induction therapy and treatment outcome, we have administered individualized doses of DNR during induction treatment to patients with acute myelogenous leukemia (AML). PATIENTS AND METHODS Ninety-two previously untreated adult patients with AML who entered our hospital were analyzed for the dose of DNR required to achieve complete remission (CR), the CR rate, disease-free survival (DFS), and overall survival (OS). Induction therapy consisted of DNR 40 mg/m2 daily intravenously from day 1 until the marrow was hypoplastic, cytarabine (Ara-C), prednisolone (PRD), and/or 6-thioguanine (6-TG). RESULTS Eighty-three of 92 patients with adult AML were assessable for this study. Sixty-three (76%) patients achieved CR. Fifty-two of 63 CR patients achieved the CR in the first course of induction therapy, and 11 patients required the second course of induction therapy. The 5-year and 10-year DFS rates were 31.2% and 5-year and 10-year OS rates were 45.1% and 42.3%, respectively. The median total dose of DNR in the induction therapy was 280 mg/m2 (120 to 480 mg/m2). DNR dose did not influence the response to therapy and was not influenced by the initial WBC count or French-American-British (FAB) system classification. CONCLUSION These results indicated that when the dose was linked to observed tumor response, the optimal dose of DNR in the induction therapy was approximately 280 mg/m2 (40 mg/m2 for 7 days), which is greater than the conventional dose of 40 to 60 mg/m2 for 3 days.

The demarcation between younger and older acute myeloid leukemia patients: A pooled analysis of 3 prospective studies

Contemporary treatment protocols for adult acute myeloid leukemia (AML) are age‐specific, and older patients are generally treated less intensively than younger patients. However, it remains uncertain whether older but fit patients with AML really need to have their treatment attenuated.

Pseudo-Gaucher Cell Proliferation Associated with Myelodysplastic Syndrome

We report an extremely rare case of pseudo-Gaucher cell proliferation with myelodysplastic syndrome (MDS). A 77-year-old Japanese man was referred to our hospital with splenomegaly and thrombocytopenia, and subsequent bone marrow aspiration revealed infiltrates of foamy vacuolated macrophages without any evidence of other morphologic abnormalities. A karyotype analysis showed the presence of 46,XY,del(20)(q11) in 20 of 20 examined bone marrow cells. We performed a splenectomy, and the resulting pathologic findings revealed massive infiltration of foamy vacuolated macrophages, which were morphologically compatible with Gaucher cells. The activities of β-glucosidase and acid sphingomyelinase were within normal ranges; therefore, the foamy vacuolated macrophages were considered pseudo-Gaucher cells. A diagnosis of MDS, subclassified as refractory anemia, was then made according to World Health Organization classification guidelines. Pseudo-Gaucher cell proliferation and infiltration might therefore be observed in other patients presenting with MDS.

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

Aclarubicin plus behenoyl cytarabine and prednisolone for previously treated acute myeloid leukemia patients.

This study analysed the clinical outcome of salvage therapy consisting of aclarubicin (ACR) plus behenoyl cytarabine (BHAC) and prednisolone (PSL) for patients with acute myeloid leukemia (AML). ACR was administered at a dose of 13 mg/m2 per day for 14 days; BHAC, at 130 mg/m2 per day for 14 days; and PSL was administered orally at a dose of 60 mg/m2 per day for 5 days. Of 47 patients, 25 (53.2%) achieved CR. The CR rates of patients in whom induction failed was 55% and that of relapsed patients was 51.9%. Four patients received allogeneic hematopoietic stem cell transplantation after achieving CR. Five patients achieved long-term survival without relapse. The 10-year relapse-free and overall survival rates were 20% and 10.6%, respectively. ACR in combination with BHAC showed a substantial anti-leukemic efficacy in previously treated AML patients and the role of ACR and BHAC may be considered while devising strategies for AML treatments.

CD2+ tetraploid acute promyelocytic leukemia variant with double (15;17) translocations

We report a patient with a variant form of CD2+ acute promyelocytic leukemia (APL) who had double translocations (15;17) in a single leukemic cell. The patient presented with severe neutropenia, thrombocytopenia, and disseminated intravascular coagulation. The bone marrow showed marked hyperplasia with large leukemic cells that had bizarre nuclear configuration and basophilic, hypogranular cytoplasm. Leukemic cells were positive for CD2, 13, 33, 34, and 56 and negative for HLA-DR.The karyotype of the abnormal clone was characterized as 92,XXYY, t(15;17)(q22;q21)x2. No other additional abnormal clone was found, and the patient’s condition was diagnosed as tetraploid APL variant. Fluorescence in situ hybridization assay revealed 2 promyelocytic leukemia and retinoic acid receptor α (PML/RARA) fusion signals, and reverse transcription-polymerase chain reaction assay revealed short-form PML/RARA fusion transcript. Tetraploidy in APL is a very rare abnormality. Double translocations were an additional abnormality in this case, and this patient’s karyotype might have had some influence on morphological characteristics, expression of CD2, and poor clinical outcome.

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.