Hitoshi Suzushima

Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukemia-Lymphoma: A Multicenter Phase II Study

PURPOSE Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL. PATIENTS AND METHODS A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg. RESULTS Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases. CONCLUSION KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.

Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22)

AML1-MTG8 generated by t(8;21) contributes to leukemic transformation, but additional events are required for full leukemogenesis. We examined whether mutations in the receptor tyrosine kinase (RTK) pathway could be the genetic events that cause acute myeloblastic leukemia (AML) harboring t(8;21). Mutations in the second tyrosine kinase domain, juxtamembrane (JM) domain and exon 8 of the C-KIT gene were observed in 10, one and three of 37 AML patients with t(8;21), respectively. Three patients showed an internal tandem duplication in the JM domain of the FLT3 gene. One patient had a mutation in the K-Ras gene at codon 12. As the occurrence of these mutations was mutually exclusive, a total of 18 (49%) patients showed mutations in the RTK pathway. These results suggest that activating mutations in the RTK pathway play a role in part as an additional event leading to the development of t(8;21) AML. The 6-year cumulative incidence of relapse in patients with RTK pathway mutations was 79.8%, compared with 13.5% in patients lacking such mutations (P=0.0029). Furthermore, the 6-year relapse-free survival in patients with mutations was 18% compared to 60% in those without mutations (P=0.0340), indicating that RTK mutations are associated with the clinical outcome in t(8;21) AML.

Prognostic Index for Acute- and Lymphoma-Type Adult T-Cell Leukemia/Lymphoma

PURPOSE The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI). PATIENTS AND METHODS In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model. RESULTS Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test). CONCLUSION The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.

Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti‐CC chemokine receptor 4 antibody, to mLSG15, a dose‐intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15‐plus‐mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33–71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16–55%) and 75%, respectively. Grade ≥ 3 treatment‐emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15‐plus‐mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15‐plus‐mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

Prognostic impact of immunohistochemical biomarkers in diffuse large B-cell lymphoma in the rituximab era.

We evaluated the usefulness of prognostic markers in patients with diffuse large B‐cell lymphoma (DLBCL) treated with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) ± rituximab (R‐CHOP) in Japan. We studied 730 patients with DLBCL; 451 received CHOP and 279 R‐CHOP. We analyzed biopsy samples immunohistochemically for markers of germinal center B cells (CD10, Bcl‐6), postgerminal center B cells (Multiple myeloma‐1), and apoptosis (Bcl‐2). The median follow‐up period for surviving patients was 56.4 months for the CHOP group and 25.2 months for the R‐CHOP group. DLBCL were categorized as germinal center B (GCB) subtype (352/730; 48.2%) or non‐GCB subtype (378/730; 51.8%). In the CHOP group, the high expression of CD10 (P = 0.022) or Bcl‐6 (P = 0.021), or GCB subtype (P = 0.05) was associated with better overall survival, whereas the high expression of Bcl‐2 (P = 0.001) or MUM1 (P = 0.011), or non‐GCB subtype (P = 0.05) was associated with worse overall survival. In the R‐CHOP group, however, these biomarkers except Bcl‐6 were not significant prognostic factors. The patients with non‐GCB subtype showed improved survival in the R‐CHOP group (P = 0.756). The International Prognostic Index was a useful clinical marker of survival in the CHOP group (P < 0.001) and also in the R‐CHOP group (P < 0.001). Results of improved survival with rituximab addition indicate that the relevance of previously recognized prognostic factors should be re‐evaluated. (Cancer Sci 2009; 100: 1842–1847)

The absence of the p15INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a favourable prognostic factor.

Summary. We examined deletion and methylation of the p15INK4B(p15) and p16INK4A(p16) genes, using Southern blotting and methylation‐specific polymerase chain reaction (PCR), in 70 untreated adult patients with precursor B‐cell acute lymphoblastic leukaemia (PBC‐ALL) and analysed the relationship between their genetic changes and clinical outcome. Methylation and homozygous deletion of the p15 gene were detected in 30 (43%) and 18 (26%) patients, while those of the p16 gene were found in 16 (23%) and 11 (16%) patients respectively. Thirteen out of 17 patients with wild‐type p15 gene showed expression of p15 mRNA, whereas 31 out of 39 patients with alteration (deletion and methylation) of the p15 gene showed no p15 mRNA expression by reverse transcription–PCR, suggesting that alterations of the p15 gene are highly associated with loss of␣p15 mRNA expression. Disease‐free survival (DFS) at 4 years in patients with wild‐type p15 gene is 33%, compared with 4% of those with p15 gene alterations (P = 0·049). Multivariate analysis showed that the absence of p15 gene alterations was an independent significant favourable prognostic factor for longer DFS (P = 0·0001). These results suggest that alterations in the p15 but not p16␣gene can be used as a genetic prognostic indicator in PBC‐ALL.

Inversion of chromosome 16 and bone marrow eosinophilia in a myelomonocytic transformation of chronic myeloid leukemia.

We report a case of chronic myeloid leukemia (CML) in myelomonocytic transformation associated with bone marrow (BM) eosinophilia. At diagnosis, all BM cells showed a Ph chromosome. At the time of blastic phase, more than 50% of Ph+ cells had a pericentric inversion of chromosome 16, inv(16)(p13q22). This case confirms that blastic transformation of CML can involve any committed progenitor, and myelomonocytic leukemia with BM eosinophilia is specifically associated with rearrangement of chromosome 16 at band p13 and q22.

IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation

We examined the incidence and prognostic effect of IDH1 and IDH2 mutations in 233 Japanese adults with acute myeloid leukemia (AML). IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%, 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were associated with normal karyotype AML, cytogenetic intermediate‐risk group, and NPM1 mutations. Five‐year overall survival (OS) rates were significantly lower (15.6%) in patients harboring the IDH mutations than in patients lacking the IDH mutation (32.0%) in the entire cohort of AML (P = 0.005). Among patients aged 59 yr or younger with IDH mutations, 5‐yr OS in patients who underwent allogeneic stem cell transplantation (SCT) was significantly higher than that in those not receiving allogeneic SCT (50% vs. 10.6%, P = 0.020). Of 51 patients with NPM1 mutations, there was no significant difference in 5‐yr OS rates between patients with and those without the IDH mutations. In contrast, among 175 patients lacking the NPM1 mutations, 5‐yr OS rate in patients with IDH mutations was significantly lower than that in those without IDH mutations (0% vs. 34.7%, P = <0.001). These data suggest that IDH mutations have an unfavorable effect in AML, especially AML with the NPM1 wild type and younger AML patients with IDH mutations may benefit from allogeneic SCT.

Myelomonoblastic leukaemia cells carrying the PEBP2β/MYH11 fusion gene are CD34+, c-KIT+ immature cells

To clarify the aspects affected by the PEBP2β/MYH11 fusion gene involved in the inv(16), we analysed immunophenotypes in myelomonoblastic leukaemias. We found high expressions of CD34 and c‐KIT antigens in myelomonoblastic cells from all patients carrying this fusion gene, including two with M4 and one CML blastic phase, in contrast to those with M4 without the fusion gene. These findings indicate that immunophenotyping is useful for detecting a leukaemia with the fusion gene in myelomonoblastic leukaemias and that the PEBP2β/MYH11 gene is involved in immature cells expressing CD34 and c‐KIT antigens.