Masamitsu Yanada

Background: Even after the introduction of all‐trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL). Methods: To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG). Results: Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 × 10⁹/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5‐yr event‐free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease‐free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage. Conclusions: These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high‐risk features may benefit from more aggressive supportive care.

Background: Although there are two major scoring systems for the clinical diagnosis of disseminated intravascular coagulation (DIC), the validity of these systems for leukemia‐associated DIC remains to be confirmed. Methods: By analyzing 125 newly diagnosed acute leukemia patients, we investigated clinical and laboratory features of leukemia‐associated DIC, and determined the validity of the two established criteria. Results: A total of 36 patients (29%) were diagnosed with DIC according to expert opinion, a method regarded as the de facto gold standard. Leukemia‐associated DIC is characterized by rare manifestation of organ failure because of thrombosis and no relevance of the platelet count for the diagnosis. The results of receiver operating characteristics analysis favored fibrin degradation product (FDP) rather than D‐dimer as the fibrin‐related marker test. Although prothrombin time, plasma fibrinogen, and serum FDP levels were significantly different for patients with and without DIC, multivariate analysis identified FDP levels to be the only factor associated with DIC diagnosis. The cut‐off level of 15 μg/mL for FDP was found to be the most effective to differentiate DIC from non‐DIC, resulting in diagnostic sensitivity and specificity of 92% and 96%, respectively. The diagnostic results for our patients produced with this FDP‐based system were at least comparable with or superior to those obtained with the two currently available scoring systems. Conclusions: Our findings suggest that an FDP‐based criterion may be applicable for the diagnosis of leukemia‐associated DIC. Although it appears to be simple and practicable enough for clinical use, prospective validation of this criterion is needed.

Purpose: A novel therapeutic approach is urgently needed for BCR-ABL–positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib. Patients and Methods: A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL–positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005. Results: Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not. Conclusion: Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL–positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

The prognosis of Philadelphia chromosome-positive (Ph+) and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL) is extremely poor, and for decades allogeneic hematopoietic stem cell transplantation (HSCT) has been considered the only option for a cure. However, the treatment for Ph+ ALL has been rapidly changing since imatinib, a selective inhibitor of the ABL tyrosine kinase, was introduced. Earlier clinical trials in which a moderate anti-leukemic effect of imatinib monotherapy was demonstrated have prompted investigators to explore the combination of imatinib and chemotherapy. The results of multiple studies indicate that chemotherapy combined with imatinib is well tolerated, induces complete hematological remission in almost every patient with newly diagnosed Ph+ ALL, and molecular remission in more than half of the cases. Future clinical studies need to focus on how imatinib can be incorporated into chemotherapy more effectively by determining the optimal dosage of imatinib, the optimal combinational schedule, and the role of allogeneic HSCT.

Disease-free survival in Philadelphia chromosome-positive ALL (Ph+ALL) is very poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently considered the only procedure with curative potential. To identify factors affecting transplant outcome, we analyzed the data from 197 Ph+ALL patients aged 16 years or older who had undergone allo-HSCT. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (PPPP=0.0301, P=0.0412, respectively). Severe acute GVHD increased the risk of treatment-related mortality (TRM) without diminishing the risk of relapse, whereas chronic GVHD reduced the risk of relapse without increasing the risk of TRM. Thus, patients who developed extensive chronic GVHD had better survivals (P=0.0217), and those who developed grade III–IV acute GVHD had worse survivals (P=0.0023) than did the others.

Two distinct forms of fms-like tyrosine kinase (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, have been recognized in a substantial proportion of patients with acute myeloid leukemia (AML). To investigate their prognostic significance, we performed a meta-analysis of the four published studies that provided survival information according to the FLT3 status: ITD, TKD mutation, and wild type. The summary hazard ratios for disease-free survival (DFS) were 1.88 (95% confidence interval (CI) 1.58–2.23; PPPPPP=0.104). Neither white blood cell count at diagnosis nor cytogenetic risk category was a significant source of heterogeneity. These findings indicate that FLT3 mutations have an adverse effect on the outcome for AML, and that the negative impact of TKD mutation seems comparable to that of ITD with regard to DFS. Although it should be borne in mind that this meta-analysis was based on data abstracted from observational studies, these results may justify the risk-adapted therapeutic strategies for AML according to the FLT3 status.

Abstract:  The actual utility of a new classification system of acute myeloid leukemia (AML) recently introduced by the World Health Organization (WHO) has not been thoroughly investigated yet. In this study, we evaluated long‐term outcomes of unselected AML patients categorized according to the new WHO classification. Between 1990 and 2002, 109 adult AML cases were referred to our hospital. For the entire population, the median survival duration was 1.2 yr with a 5‐yr survival rate of 31%. AML with recurrent genetic abnormalities accounted for 26%, AML with multilineage dysplasia for 29%, therapy‐related AML for 13%, and AML not otherwise categorized for 32% of classifiable cases. Among the four groups, a significant difference was observed in terms of overall survival (P < 0.0001). Univariate analysis showed that six variables affected survival: cytogenetic risk, age, multilineage dysplasia, prior chemo/radiotherapy, type of treatment (intensive or palliative), and transplantation. However, in multivariate analysis no adverse prognostic impact of multilineage dysplasia and prior chemo/radiotherapy was detected (P = 0.4979 and 0.8702), whereas cytogenetic risk and patient age maintained their prognostic value (P = 0.0005 and 0.0100). These results indicate that outcomes for AML patients appear to be distinguished on the basis of the WHO classification, but the prognostic significance of multilineage dysplasia and prior therapy is lost after adjusting for cytogenetic risk and age. Our findings suggest that the WHO classification may be strengthened by greater emphasis on genetic/cytogenetic information.

BACKGROUND: The efficacy of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) from a human leukocyte antigen‐identical sibling donor remains controversial for patients with acute myeloid leukemia (AML) in first complete disease remission (CR1). Because the karyotype identified at diagnosis is the most relevant prognostic factor for AML, it should be possible to assess the efficacy more accurately on the basis of cytogenetic risk.METHODS: The authors performed a metaanalysis of five studies, which employed both natural randomization based on donor availability and intention‐to‐treat analysis, with overall survival as an outcome of interest. Metaregression analysis was then performed to identify the efficacy for patients stratified into the favorable, intermediate, and poor cytogenetic risk groups.RESULTS: For the entire cohort, there was a statistically significant advantage with allo‐HSCT in terms of overall survival with a summary hazard ratio of 1.15 (95% confidence interval, 1.01–1.32, P = 0.037) for the random‐effect model. Metaregression analysis showed a significant coefficient of +0.24 for the poor cytogenetic risk group, and −0.25 for the favorable cytogenetic risk group, indicating that the benefit of allo‐HSCT was further increased for the former, and lost for the latter. The coefficient for the intermediate cytogenetic risk group was +0.09, and was not statistically significant.CONCLUSIONS: These findings suggested that the efficacy of allo‐HSCT for patients with AML in CR1 depended on cytogenetic risk. The beneficial effect of allo‐HSCT was yielded for the poor risk group, and probably for the intermediate risk groups, but was absent for the favorable risk group. Cancer 2005. © 2005 American Cancer Society.

(2004). Multiplex Real-time RT–PCR for Prospective Evaluation of WT1 and Fusion Gene Transcripts in Newly Diagnosed De Novo Acute Myeloid Leukemia. Leukemia & Lymphoma: Vol. 45, No. 9, pp. 1803-1808.