Takaaki Chou

Durable Response but Prolonged Cytopenia after Cladribine Treatment in Relapsed Patients with Indolent non-Hodgkin’s Lymphomas: Results of a Japanese Phase II Study

We conducted a phase II study to evaluate the efficacy and safety of cladribine (2-chlorodeoxyadenosine [2-CdA]) for patients with refractory or relapsed indolent B-cell lymphoma or mycosis fungoides. Forty-five patients were enrolled, and 43 patients, including 34 with follicular lymphoma, were eligible. 2-CdA was given by continuous intravenous infusion at a dose of 0.09 mg/kg daily for 7 consecutive days, and this schedule was repeated every 4 weeks up to a maximum of 6 cycles. The overall and complete response rates were 58.1% (25/43; 90% confidence interval, 44.5%-70.9%) and 14.0% (6/43), respectively. The disease progression-free proportions of all 43 eligible and all 25 responding patients at 2 years were 30.3% and 48.1%, respectively. Neutropenia and thrombocytopenia of grade 3 or 4 were observed in 53.3% and 37.8% of patients, respectively, with prolonged cytopenia observed in patients with increased numbers of treatment cycles. Nonhematologic toxicities of grade 3 or greater included diarrhea, arrhythmia, malaise, and gastrointestinal bleeding in 1 patient each, an increase in glutamic-pyruvic transaminase level in 2 patients, and infection in 5 patients. Two treatment-related deaths were observed. Four patients developed myelodysplastic syndrome (MDS) at 13 months to 2 years after completion of the 2-CdA treatments. 2-CdA is an active agent with acceptable toxicity for refractory or relapsed indolent lymphoma; however, prolonged myelosuppression and the potential development of MDS should be carefully monitored.

Clinical profiles of multiple myeloma in Asia—An Asian Myeloma Network study

The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However, the differences in clinical characteristics between ethnic groups are not well‐defined. In Asian countries, although the incidence of MM has been lower than that of Western countries, there is growing evidence that MM is increasing rapidly. The Asian Myeloma Network decided to initiate the first multinational project to describe the clinical characteristics of MM and the clinical practices in Asia. Data were retrospectively collected from 23 centers in 7 countries and regions. The clinical characteristics at diagnosis, survival rates and initial treatment of 3,405 symptomatic MM patients were described. Median age was 62 years (range, 19–106), with 55.6% of being male. Median overall survival (OS) was 47 months (95% CI 44.0–50.0). Stem cell transplantation was performed in 666 patients who showed better survival rates (79 vs. 41 months, P < 0.001). The first‐line treatments of 2,970 patients were analyzed. The overall response rate was 71% including very good partial response or better in 31% of the 2,660 patients those were able to be evaluated. New drugs including bortezomib, thalidomide, and lenalidomide were used in 36% of 2,970 patients and affected OS when used as a first‐line treatment. Am. J. Hematol. 89:751–756, 2014.

Survival of Multiple Myeloma Patients Aged 65-70 Years in the Era of Novel Agents and Autologous Stem Cell Transplantation

Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65-70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy, 88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS (p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208

A randomized controlled trial was conducted to evaluate the efficacy of high‐dose chemotherapy (HDC) as consolidation of the treatment of high‐risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse‐free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27–55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10–49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty‐eight patients in the standard‐dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5‐fluorouracil followed by tamoxifen. Forty‐nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5‐fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment‐related mortality. At a median follow‐up of 63 months, the 5‐year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent‐to‐treat basis, respectively (P = 0.17). Five‐year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival. (Cancer Sci 2008; 99: 145–151)

Management of multiple myeloma in Asia: resource-stratified guidelines

Treatment of multiple myeloma has undergone substantial developments in the past 10 years. The introduction of novel drugs has changed the treatment of the disease and substantially improved survival outcomes. Clinical practice guidelines based on evidence have been developed to provide recommendations on standard treatment approaches. However, the guidelines do not take into account resource limitations encountered by developing countries. The huge disparities in economy, health-care infrastructure, and access to novel drugs in Asian countries hinder the delivery of optimum care to every patient with multiple myeloma in Asia. In this Review we outline the guidelines that correspond with different levels of health-care resources and expertise, with the aim to unify diagnostic and therapeutic guidelines and help with the design of future studies in Asia.

Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma

Reduced-intensity conditioning allogeneic stem cell transplantation for multiple myeloma: results from the Japan Myeloma Study Group.

We conducted a retrospective survey of multiple myeloma (MM) patients who underwent reduced-intensity conditioning allogeneic stem cell transplantation (RIST) at 11 hospitals participating in the Japan Myeloma Study Group. Forty-five patients (median age, 53 years) were included in this study. The conditioning regimen consisted of a fludarabine-based regimen in 24 patients and a regimen based on total body irradiation (1–2 Gy) in 18 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and tacrolimus in 28 and 17 patients, respectively. All patients showed myeloid engraftment. Complete chimerism was obtained in 42 patients. Grade II to IV acute GVHD developed in 28 (65%) of 43 patients evaluated, and chronic GVHD developed in 31 (76%) of 41 patients. Early death before day 100 was observed in 4 patients (8.8%). A complete response (CR) was obtained in 12 patients. The factors affecting overall survival were severe acute GVHD and the response after RIST. To date, 18 patients are alive, with 9 patients remaining in CR at a median follow-up of 25 months. The overall and progression-free survival rates at 3 years were 38.5% and 18.8%, respectively. These observations suggest that RIST is feasible with reliable donor engraftment and relatively low transplantation-related mortality in Japanese MM patients.

Feasibility and efficacy of high-dose melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) chemotherapy with or without rituximab followed by autologous stem cell transplantation for aggressive and relapsed non-Hodgkin's lymphoma.

To investigate the feasibility and efficacy of high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) for patients with newly diagnosed aggressive and relapsed non-Hodgkin’s lymphoma (NHL), we administered LEED, a drug-only HDCT regimen consisting of melphalan, cyclophosphamide, etoposide, and dexamethasone, followed by ASCT in this single-institution trial. Furthermore, rituximab was added to the LEED regimen (R-LEED) for patients with CD20+ NHL.Twenty-six patients in the LEED group and 24 patients in the R-LEED group were enrolled and assessed for this study. All patients achieved complete engraftment after ASCT. As for the nonhematologic toxicities, infection toxicities of grades 3 and 4 were observed in 9 patients (34.6%) of the LEED group and 12 patients (50%) of the R-LEED group. Four patients (15.4%) in the LEED group and 5 (20.8%) in the R-LEED group developed grade 3 toxicity in the elevation of aspartate aminotransferase/alanine aminotransferase levels. Other grade 4 toxicities were rare in both groups. With a median follow-up time from the date of ASCT of 30 months in the LEED group and 18 months in the R-LEED group, the overall survival rates were 66.5% and 78.2%, respectively.These results suggested that LEED, as well as R-LEED, was a safe and feasible high-dose regimen for aggressive and relapsed NHL.

Phase I/II study of tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma

The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2–4 cycles of vincristine–adriamycin–dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m2) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3–6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.

Phase III Study of Ranimustine, Cyclophosphamide, Vincristine, Melphalan, and Prednisolone (MCNU-COP/MP) versus Modified COP/MP in Multiple Myeloma: A Japan Clinical Oncology Group Study, JCOG 9301

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%–53.8%] and to MCNU-COP/MP was 56.1 % (95% CI, 46.1 %–65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9–25.8] versus 15.8 months [95% CI, 14.1–19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95% CI, 32.8–59.8]) ( P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.