Kazuo Tsubaki

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML‐87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher (F=0·006) and bone marrow blasts were fewer (P=0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.

A randomized trial of chemoimmunotherapy of acute nonlymphocytic leukemia in adults using a protein-bound polysaccharide preparation

SummaryThe effect of immunotherapy with a protein-bound polysaccharide preparation termed PSK on remission duration and survival of adults with acute nonlymphocytic leukemia (ANLL) was studied in a prospective randomized cooperative trial. After having achieved complete remission and receiving a consolidation therapy, 73 patients were randomized either to maintenance chemotherapy or to maintenance chemotherapy plus immunotherapy with PSK. Ultimately 36 patients in the chemotherapy group and 31 in the chemoimmunotherapy group were evaluable. Six months after the last entry, immunotherapy with PSK showed a borderline beneficial effect on remission duration (P=0.089) and on duration of survival (P=0.062). When the data were analyzed 12, 18, and 24 months after the last entry there were no significant differences in duration of remission and survival between the two groups. However, analysis of the data of patients who had maintained complete remission for more than 270 days revealed that immunotherapy had a suggestive beneficial effect (P=0.105), prolonging the 50% remission period by 418 days (885 vs 467 days). Thus, immunotherapy with PSK seems to be active in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy, especially in patients with a good prognosis.

A long term follow-up of a randomized trial comparing interferon-α with busulfan for chronic myelogenous leukemia

Abstract To evaluate the long-term effectiveness of interferon- α (IFN- α ) therapy in patients with chronic myelogenous leukemia (CML) in chronic phase, we examined the updated outcomes of 159 patients who had been enrolled between 1988 and 1991 into a randomized trial comparing IFN- α with busulfan. At a median follow-up of 73 months, the median survival was 71 months in the IFN- α group and 55 months in the busulfan group ( P =0.0563), and the median time of remaining in chronic phase was 58 months in the IFN- α group and 39 months in the busulfan group ( P =0.4676). Landmark analysis showed a significant advantage in survival ( P =0.009) and duration of chronic phase ( P =0.0001) in patients with any cytogenetic response among the IFN- α group. About half patients were discontinued IFN- α administration in spite of cytogenetic response in this study. It appears that continuation of IFN- α might possibly confer a survival advantage. Pretreatment factors associated with cytogenetic response included high hemoglobin level, low percentage of peripheral basophils and low leukocyte counts. Multivariate analysis identified lower percentage of bone marrow basophilia ( P =0.007) for survival advantage. If a group with a very good prognosis is predicted by a new prognostic model, it might be an option to wait for bone marrow transplantation.

All-trans retinoic acid therapy for newly diagnosed acute promyelocytic leukemia: comparison with intensive chemotherapy

Abstract We analyzed the results of treating patients with newly diagnosed acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in the JALSG AML-92 study and compared them with those of the AML-87 and AML-89 studies, which consisted of standard chemotherapy. In the AML-92 study, patients were scheduled to receive 45 mg/m2 oral ATRA daily until achievement of a complete remission (CR). If patients had initial leukocyte counts of >3.0×109/l, they received 40 mg/m2 daunorubicin (DNR) for 3 days and 200 mg/m2 behenoyl cytarabine (BHAC) for 5 days in addition to ATRA. During remission induction therapy, if the patients showed peripheral blood myeloblast and promyelocyte counts of >1.0×109/l, they received additional DNR and BHAC on the same schedule. After achievement of a CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. Of 196 evaluable patients, 173 (88%) achieved a CR: 59 of 62 (95%) treated with ATRA alone, 41 of 49 (84%) treated with ATRA plus later chemotherapy, 63 of 73 (86%) treated with ATRA plus initial chemotherapy, and 10 of 12 (83%) treated with ATRA plus both initial and later chemotherapy. The CR rate in AML-92 was significantly higher than that in AML-89, but not than that achieved in AML-87. In addition, the early mortality and relapse rates in AML-92 were significantly lower than those in AML-89, but were not than those in AML-87. At a median follow-up of 36 months the predicted 4-year event-free survival (EFS) rate for 196 evaluable patients and the 4-year disease-free survival (DFS) rate for the CR cases were 54% and 62%, respectively. There was a significant difference in DFS between AML-92 and AML-87 (P = 0.0418) but not between AML-92 and AML-89 (P = 0.0687). In contrast, significant differences in EFS between AML-92 and both AML-87 (P = 0.0129) and AML-89 (P = 0.005) were observed. These results suggest that non-cross-resistant therapy combined with ATRA and intensive chemotherapy for APL contributes synergistically to the significant improvement in EFS.

Nodal Gamma/Delta T Cell Lymphoma in Complete Remission following Allogeneic Bone Marrow Transplantation from an HLA-Matched Unrelated Donor

Gamma/delta T cell lymphoma is very rare, and usually occurs as an extranodal tumor. We describe the case of a 16-year-old Japanese man with an unusual nodal gamma/delta T cell lymphoma with generalized lymphadenopathy and bone marrow involvement. No tumor involvement was observed in the liver, spleen, or nasal cavity. Examination for surface antigens on lymphoma cells revealed a unique phenotype, positive for CD3 and T cell receptor (TCR) gamma/delta, but negative for CD2. Genotypic analysis revealed the tumor to be of monoclonal origin and characterized by TCR gamma-chain gene rearrangement, but there was no rearrangement of the TCR beta-chain gene. Our patient’s tumor responded to combination chemotherapy and subsequent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. He has remained well and free of disease for 35 months.

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment

Micro‐Abstract We describe the results of a prospective trial of the discontinuation of second‐line dasatinib treatment in chronic myeloid leukemia patients who maintained a deep molecular response for > 1 year. The treatment‐free remission rate at 36 months was 44.4%. High natural killer cell counts before discontinuation correlated significantly with successful therapy discontinuation. Introduction We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second‐ or subsequent‐line dasatinib treatment safely at a median follow‐up of 20 months. However, the results from longer follow‐up periods would be much more useful from a clinical perspective. Patients and Methods The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment‐free remission (TFR) were analyzed. Results The median follow‐up period was 44.0 months (interquartile range, 40.5‐48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%‐56.2%). Only 2 patients developed a molecular relapse after the 1‐year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low &ggr;&dgr;+ T‐cell and CD4+ regulatory T‐cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. Conclusion These findings suggest that discontinuation of second‐ or subsequent‐line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

Five-day regimen of azacitidine for lower-risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single-arm phase 2 trial

Although azacitidine is the first‐line drug for higher‐risk myelodysplastic syndrome (MDS) patients, its efficacy for lower‐risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5‐day regimen of azacitidine (AZA‐5) for lower‐risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower‐risk MDS based on the French‐American‐British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51‐88). These patients received AZA‐5 (75 mg/m2; once daily for 5 sequential days). The median number of AZA‐5 courses was 8 (range: 1‐57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA‐5 is feasible and effective for lower‐risk MDS patients as well as for higher‐risk MDS patients.

Once-weekly Bortezomib in Combination with Reduced-dose Dexamethasoneand Continuous Low-dose Oral Cyclophosphamide for Elderly Patients withMultiple Myeloma

CyBorD is one of the most effective triplet regimens for both transplant-eligible and ineligible patients with multiple myeloma. In comparison, once-weekly bortezomib induction therapy with a reduced dosage of dexamethasone (modified-CyBorD) showed less toxicity but an equally high response rate. However, this modification still resulted in bortezomib-induced PN in more than half of patients. We therefore introduced a once-weekly schedule of bortezomib combined with continuous low-dose oral cyclophosphamide and reduced dosage of dexamethasone (reduced-CyBorD) in transplantineligible patients with multiple myeloma in our hospital. A total of 32 patients, including 20 who were newly diagnosed and 12 who were refractory/resistant, were treated with reduced-CyBorD, and the regimen’s efficacy and safety were evaluated. The median age was 72 years; 17 patients were male and 15 were female. The overall response rate was 90.6% with 43.8% complete response/near complete response. The median progression-free and overall survival was 14.9 months and 43 months, respectively. Three patients (9.4%) developed grade 1 peripheral neuropathy, and no patients had to reduce or discontinue bortezomib. In conclusion, our results suggested that this reduced combination therapy might be a safe and effective approach in transplant-ineligible patients with multiple myeloma.

Successful Treatment of Autoimmune Hemolytic Anemia Concurrent With Gastric Cancer by Rituximab: A Case Report of Evans Syndrome

The concurrence of autoimmune hemolytic anemia (AIHA), thrombocytopenic purpura (Evans syndrome) and solid cancer is rare. In this study, we report a diabetic patient with gastric cancer who developed AIHA and idiopathic thrombocytopenic purpura. Steroid therapy for Evans syndrome restored platelet count; however, no improvement in AIHA was observed. Rituximab administration as a second-line therapy resulted in gradual improvement of anemia. Our observation suggested rituximab as an effective therapy for steroid-resistant AIHA.

Successful Third Hematopoietic Stem Cell Transplantation for Blast Crisis of Chronic Myeloid Leukemia After Two Times of Graft Failure

Copyright ©2017 Hanamoto H. This is an open access article distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Volume 1 : Issue 1 Article Ref. #: 1000IMOJ1104 Successful Third Hematopoietic Stem Cell Transplantation for Blast Crisis of Chronic Myeloid Leukemia After Two Times of Graft Failure