Shinichi Kageyama

Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group

PURPOSE We conducted a multicenter study of differentiation therapy with all-trans retinoic acid (ATRA) followed by intensive chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL) and analyzed the prognostic factors for predicting complete remission (CR), event-free survival (EFS), and disease-free survival (DFS). PATIENTS AND METHODS All patients received ATRA until CR. If patients had an initial leukocyte count greater than 3.0 x 10(9)/L, they received daunorubicin (DNR) and behenoyl cytarabine (BHAC). During therapy, if patients showed blast and promyelocyte counts greater than 1.0 x 10(9)/L, they received additional DNR and BHAC. After achieving CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. RESULTS Of 198 registered, 196 were assessable (age range, 15 to 86 years; median, 46) and 173 (88%) achieved CR. Multivariate analysis showed that no or minor purpura at diagnosis (P = .0046) and age less than 30 years (P = .0076) were favorable factors for achievement of CR. Predicted 4-year overall survival and EFS rates were 74% and 54%, respectively, and the 4-year predicted DFS rate for 173 CR patients was 62%. Multivariate analysis showed that age less than 30 years (P = .0003) and initial leukocyte count less than 10 x 10(9)/L (P = .0296) were prognostic factors for longer EFS, and initial leukocyte count less than 10.0 x 10(9)/L was a sole significant prognostic factor for longer DFS (P = .0001). CONCLUSION Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group.

PURPOSE We analyzed complete remission (CR), disease-free survival (DFS), and event-free survival (EFS) rates in two groups of patients treated with either N4-behenoyl-1-beta-D-arabinosylcytosine (BHAC) or cytarabine, and analyzed DFS with or without ubenimex, a biologic response modifier. PATIENTS AND METHODS Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either BHAC or cytarabine as remission-induction combination chemotherapy and two courses of consolidation therapy. After maintenance/intensification therapy, patients in CR were randomized to receive either ubenimex and no drug. RESULTS Of 341 patients registered, 326 were assessable. The age of assessable patients ranged from 15 to 82 years (median, 48). The overall CR rate was 77%: 72% in the BHAC group and 81% in the cytarabine group, and there was a significant difference between the two groups (P = .035, chi 2 test). The predicted 55-month EFS rate of all patients was 30%: 23% in the BHAC group and 35% in the cytarabine group, with a significant difference between groups (P = .0253). The predicted 55-month DFS rate of all CR patients was 38% and that of CR patients less than 50 years of age was 47%. There was no significant difference in DFS between the ubenimex group and the group that did not receive ubenimex. CONCLUSION Analyses of our clinical trial showed that the use of BHAC in remission-induction therapy and in consolidation therapy resulted in poorer CR and EFS rates in adult AML patients compared with the use of cytarabine at the doses and schedules tested. Immunotherapy with ubenimex after the end of all chemotherapy did not improve DFS.

Humoral immune responses in patients vaccinated with 1–146 HER2 protein complexed with cholesteryl pullulan nanogel

The CHP‐HER2 vaccine, comprising truncated 146HER2 protein complexed with nanogels of cholesteryl pullulan (CHP), is a novel protein antigen vaccine that elicits 146HER2‐specific CD8+ and CD4+ T‐cell immune responses in patients with HER2‐expressing tumors. We analyzed the humoral responses in patients vaccinated with CHP‐HER2 and those with CHP‐HER2 plus granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). The vaccine was injected subcutaneously at a dose of 300 µg protein. Nine patients received the vaccine alone over the first four injections, followed by CHP‐HER2 with GM‐CSF or OK‐432, whereas six received CHP‐HER2 plus GM‐CSF from the first cycle. 146HER2‐specific IgG antibodies were induced in 14 patients, who were negative at baseline. The antibodies became detectable after the second or third vaccination and reached plateau levels after the third or fourth cycle in patients vaccinated with CHP‐HER2 plus GM‐CSF. In contrast, the antibodies appeared only after the third to sixth vaccination and the plateau appeared after the fourth to eighth cycle in patients vaccinated with the CHP‐HER2 vaccine alone over the first four cycles. The antibodies induced by the vaccine were not reactive with HER2 antigen expressed on the cell surface in any of the patients. Epitope analysis using overlapping peptides revealed a single region in the 146HER2 protein, amino acids 127–146, in eight patients who were initially vaccinated with CHP‐HER2 alone. Similarly, the same HER2 region was recognized dominantly in patients vaccinated with GM‐CSF. Our results indicate that CHP‐HER2 induced HER2‐specific humoral responses in patients with HER2‐expressing tumors and that GM‐CSF seems to accelerate the responses. (Cancer Sci 2008; 99: 601–607)

HER2-Specific T-Cell Immune Responses in Patients Vaccinated with Truncated HER2 Protein Complexed with Nanogels of Cholesteryl Pullulan

Purpose: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4+ T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers. Experimental Design: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 μg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4+ T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein. Results: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8+ and/or CD4+ T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8+ T-cell responses, two patients reacted to previously identified HER263-71 peptide and the other two reacted only to 146HER2 mRNA-transduced cells. Conclusions: CHP-HER2 vaccine was safe and induced HER2-specific CD8+ and/or CD4+ T-cell immune responses.

Successful autologous peripheral blood stem cell transplantation for relapsed intravascular lymphomatosis

We describe a case of relapsed intravascular lymphomatosis (IVL) successfully treated with autologous PBSCT. A 59-year-old Japanese female patient with IVL who had achieved CR after six courses of biweekly CHOP therapy developed lymphoma. She achieved a second CR after six courses of modified biweekly CHOP therapy, followed by autologous PBSCH and high-dose chemotherapy (CBDCA, VP-16, MCNU, CY) with PBSCT. There has not been any evidence of recurrence 48 months after PBSCT. Our case suggests that PBSC is acceptable as a source for stem cell rescue in IVL. Bone Marrow Transplantation (2001) 27, 89–91.

Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer

Purpose: Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene–engineered T cells. Experimental Design: We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4–expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer. Results: TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months. Conclusions: These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy. Clin Cancer Res; 21(10); 2268–77. ©2015 AACR.

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.

Hemostatic abnormalities and changes following bone marrow transplantation.

Hemostatic parameters were examined in 39 patients who underwent allogeneic bone marrow transplantation (BMT). Twenty-six patients survived and 13 patients died within 6 months after BMT. The main causes of death were acute graft-versus-host disease (GVHD: n=6), veno-occlusive disease (VOD: n=2), and thrombotic microangiopathy (TMA: n=2). Plasma levels of D-dimer and thrombomodulin (TM) were significantly elevated in the non-survivor group. Plasma levels of soluble fibrin (SF) and Fas were significantly elevated in the non-survivor group at 1 to 4 weeks after BMT. Plasma levels of thrombin-antithrombin complex (TAT), D-dimer, and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex) were significantly elevated in patients with complications after BMT. Plasma levels of TAT, D-dimer, and tPA-PAI-1 complex were significantly elevated in patients with GVHD. These results suggest that abnormalities of hemostatic parameters might predict poor outcomes or complications in patients with BMT.

High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine.

PURPOSE We conducted a cancer vaccine clinical trial with MAGE-A4 protein. Safety, clinical response, and antigen-specific immune responses were analyzed and the prognostic factors by vaccination were investigated. EXPERIMENTAL DESIGN Twenty patients with advanced esophageal, stomach or lung cancer were administered MAGE-A4 vaccine containing 300μg protein subcutaneously once every 2 weeks in six doses. Primary endpoints of this study were safety and MAGE-A4 immune responses. RESULTS The vaccine was well tolerated. Fifteen of 20 patients completed one cycle of vaccination and two patients showed SD. A MAGE-A4-specific humoral immune response was observed in four patients who had high expression of MAGE-A4 and MHC class I on tumor cells. These four patients showed significantly longer overall survival than patients without an antibody response after vaccination (p=0.009). Patients with tumor cells expressing high MAGE-A4 or MHC class I antigen showed significantly longer overall survival than those with low expression. Induction of CD4 and CD8T cell responses was observed in three and six patients, respectively, and patients with induction of MAGE-A4-specific IFNγ-producing CD8T cells, but not CD4T cells, lived longer than those without induction. CONCLUSIONS The CHP-MAGE-A4 vaccine was safe. Expression of MAGE-A4 and MHC class I in tumor tissue and the induction of a MAGE-A4-specific immune response after vaccination would be feasible prognostic markers for patients vaccinated with MAGE-A4.

Trisomy 10 in Acute Myeloid Leukemia: Three Additional Cases from the Database of the Japan Adult Leukemia Study Group (JALSG) AML-92 and AML-95

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81. 8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.