Feasibility of an intensified myeloablative conditioning regimen consisting of busulfan, fludarabine, cytarabine, and total body irradiation before single cord blood transplantation in elderly patients.

The optimal conditioning regimen for stem cell transplantation in elderly patients remains to be established. We developed a novel preparative regimen using fludarabine 180 mg/m2, intravenous busulfan 12.8 mg/m2, cytarabine 8 g/m2, and 4-Gy total body irradiation before cord blood transplantation (CBT) in patients older than 55 years with various hematological malignancies. All but one patient received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine (CsA) and short-term methotrexate (sMTX). Thirty-three patients were included in this study, with a median age of 64 years (range 56-70). The disease risk index was high or very high in 67% of patients, and 73% had a disease status other than complete remission. The probabilities of overall survival and disease-free survival at 3 years were 60 and 57%, respectively. The cumulative incidences of relapse and non-relapse mortality at 3 years were 18 and 25%, respectively. Regimen-related toxicities were generally tolerable. Disease-free survivors (n = 20) stopped immunosuppressants at a median of 7.4 months (range 2.6-25.0), in all cases by the time of the last follow-up. In conclusion, this highly myeloablative conditioning regimen resulted in a high probability of disease-free, GVHD-free, immunosuppressant-free survival after single CBT.(190 words).

Isolated Pancreatic Myeloid Sarcoma Associated with t(8;21)/RUNX1-RUNX1T1 Rearrangement.

No valid treatment for isolated myeloid sarcoma (IMS) has yet been established, and no thorough genetic examinations have been performed because of its low incidence and unique manner of development. We herein report a 34-year-old man with pancreatic IMS with t(8;21)/RUNX1-RUNX1T1 rearrangement. He was treated with high-dose cytarabine followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This is the first report of pancreatic IMS with t(8;21). Positron emission tomography/computed tomography and genetic study are useful for the diagnosis, and allo-HSCT achieved complete remission in this patient.

Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to acute monoblastic leukemia at relapse.

We present a patient with T-cell lymphoblastic lymphoma (T-LBL) harboring t(6;11)(q27;q23) that converted to acute monoblastic leukemia at relapse. A 27-year-old man developed T-LBL with a mediastinal mass. He exhibited several recurrences in the central nervous system and marrow. A fifth relapse occurred in the marrow, with 42.8% blasts with CD4, CD5, CD7, CD10, CD33, CD34, HLA-DR and cytoplasmic (cy) CD3. While achieving complete remission with nelarabine, sixth relapse occurred in the marrow with 6.8% blasts, which had characteristics of monoblastic features, 2 months later. Marrow blasts were positive for myeloperoxidase, CD4, CD33, CD56, CD64, and HLA-DR, but were negative for cyCD3, CD5, CD7, CD10, and CD34. Marrow cells at both the 5th lymphoid and 6th myeloid relapses had t(6;11)(q27;q23) and the same MLL-MLLT4 fusion transcript. In addition, the MLL-MLLT4 fusion sequences documented in the initial mediastinal cells were the same as seen in peripheral blood cells at the 6th relapse. The patient continues 7th remission after one course of gemtuzumab ozogamicin therapy followed by cord blood transplantation for more than 3 years. Sequential phenotypic and cytogenetic studies may yield valuable insights into the mechanism of leukemic recurrence and possible implications for treatment selection.

Normal karyotype acute myeloid leukemia with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype is a clinically distinct entity with a favorable outcome.

Recently, the presence of CEBPA mutation was identified as an important prognostic factor for normal karyotype (NK) acute myeloid leukemia (AML). Because AML with CEBPA mutation is closely associated with CD7, CD15, CD34, and HLA-DR expression, we investigated the prognostic implications of CD7+ CD15+ CD34+ HLA-DR + immunophenotype in NK-AML. We analyzed the immunophenotype of 329 patients with NK-AML from the Japan Adult Leukemia Study Group (JALSG) AML97 population. NK-AML with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype was classified as the CEBPA type, and NK-AML that did not meet this criterion was considered as the non-CEBPA type. The influence of the CEBPA status on event-free survival (EFS) and overall survival (OS) was assessed using log-rank test and a multivariate Cox proportional hazard regression model. Furthermore, the surface antigen expression profile in AML according to the CEBPA mutation status (monoallelic or biallelic) was also investigated. Of the 329 NK-AML patients that were studied, 39 and 243 were classified as having CEBPA and non-CEBPA type NK-AML, respectively. Patients with CEBPA type NK-AML had significantly better EFS and OS than those with non-CEBPA type NK-AML. Multivariate analysis showed that the CEBPA type and white blood cell (WBC) counts of >20 × 10(9)/L were independent prognostic factors for EFS and OS. Moreover, NK-AML with the biallelic CEBPA mutation was more closely associated with CD34 positivity than that with the monoallelic CEBPA mutation. NK-AML with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype is a clinically discrete entity, and this may have a possible role in risk stratification.

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.

High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia.

Alterations in the IKZF1 gene are associated with poor prognosis in pediatric B-cell acute lymphoblastic leukemia (B-ALL). We examined the relationship between IKZF1 alterations and clinical findings in 78 adult patients with B-ALL. Aberrant isoforms of IKZF1 were detected using RT-PCR. The copy numbers of IKZF1 exons and fusion genes caused by exon deletions were determined using RQ-PCR and genomic PCR, respectively. We detected aberrant IKZF1 isoforms in 20 of the 78 patients (13 Ik6 and seven Ik10) and deletions of the entire or parts of the IKZF1 gene in 40 of 70 patients. No IKZF1 point mutations were detected by direct sequencing. Nineteen Ik6 and Ik10 isoforms had been generated through genomic exon deletions, but one through aberrant splicing. In total, 41 of the 78 (52.6%) patients harbored IKZF1 alterations, which were identified in 20 of 24 (83.3%) patients with Philadelphia chromosome (Ph)-positive B-ALL compared with 21 of 54 (38.9%) Ph-negative B-ALL (P = 0.0004). IKZF1 alterations are highly involved even in adults with B-ALL. To fully detect IKZF1 alterations, several methods with alternative approaches are required. To elucidate the clinical significance of IKZF1 alterations in adult B-ALL, our study warrants prospective clinical studies with a full analysis of IKZF1 alterations.

[Perioperative management for cesarean section in a patient with corrected transposition of the great arteries].

We report anesthetic management for cesarean section in a pregnant (36 weeks) woman with corrected transposition of the great arteries, associated with Ebstein's anomaly and atrial septal defect. She had not received any surgical procedure, and had orthopnea and chest pain which were the signs of congestive heart failure before pregnancy. Her heart failure was ongoing through 34 th week of gestation. Central venous pressure and invasive arterial pressure were monitored perioperatively. A low-dose of fentanyl (3.5 micrograms.kg-1) was injected intravenously 5 minutes before induction, followed by anesthesia induced by thiamylal and suxamethonium chloride. Continuous infusion of propofol and continuous epidural anesthesia were started after delivery, supplemented by isoflurane. No significant cardiovascular changes were observed in the mother during the operation. The infant showed no respiratory dysfunction at birth.