Zhao Y

Unmanipulated HLA-mismatched/haploidentical peripheral blood stem cell transplantation for high-risk hematologic malignancies.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (HSCT) has been increasingly applied in high‐risk hematologic patients due to the absence of HLA‐matched donors. The aim of this study was to investigate the efficacy and safety of unmanipulated haploidentical allogeneic peripheral blood stem cells transplantation (PBSCT) for hematologic malignancies.

AML1-ETO triggers epigenetic activation of early growth response gene l, inducing apoptosis in t(8;21) acute myeloid leukemia

The t(8;21)(q22;q22) translocation is the most common chromosomal translocation in acute myeloid leukemia (AML), and it gives rise to acute myeloid gene 1 (AML1)–myeloid transforming gene 8 (ETO)‐positive AML, which has a relatively favorable prognosis. However, the molecular mechanism related to a favorable prognosis in AML1–ETO‐positive AML is still not fully understood. Our results show that the AML1–ETO fusion protein triggered activation of early growth response gene l (EGR1) by binding at AML1‐binding sites on the EGR1 promoter and, subsequently, recruiting acetyltransferase P300, which is known to acetylate histones. However, AML1–ETO could not recruit DNA methyltransferases and histone deacetylases; therefore, EGR1 expression was affected by histone acetylation but not by DNA methylation. Both transcription and translation of EGR1 were higher in AML1–ETO‐positive AML cell lines than in AML1–ETO‐negative AML cell lines, owing to acetylation. Furthermore, when AML1–ETO‐positive AML cell lines were treated with C646 (P300 inhibitor) and trichostatin A (histone deacetylase inhibitor), EGR1 expression was significantly decreased and increased, respectively. In addition, treatment with 5‐azacytidine (methyltransferase inhibitor) did not cause any significant change in EGR1 expression. Overexpression of EGR1 inhibited cell proliferation and promoted apoptosis, and EGR1 knockout promoted cell proliferation. Thus, EGR1 could be a novel prognostic factor for a favorable outcome in AML1–ETO‐positive AML. The results of our study may explain the molecular mechanisms underlying the favorable prognosis in AML1–ETO‐positive AML.

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies

Hematopoietic stem cell transplantation (HSCT) and consolidation chemotherapy have been used to treat intermediate-risk acute myeloid leukemia (AML) patients in first complete remission (CR1). However, it is still unclear which treatments are most effective for these patients. The aim of our study was to analyze the relapse-free survival (RFS) and overall survival (OS) benefit of allogeneic HSCT (alloHSCT) for intermediate-risk AML patients in CR1. A meta-analysis of prospective trials comparing alloHSCT to non-alloHSCT (autologous HSCT [autoHSCT] and/or chemotherapy) was undertaken. We systematically searched PubMed, Embase, and the Cochrane Library though October 2014, using keywords and relative MeSH or Emtree terms, ‘allogeneic’; ‘acut*’ and ‘leukem*/aml/leukaem*/leucem*/leucaem*’; and ‘nonlympho*’ or ‘myelo*’. A total of 7053 articles were accessed. The primary outcomes were RFS and OS, while the secondary outcomes were treatment-related mortality (TRM) and relapse rate (RR). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for each outcome. The primary outcomes were RFS and OS, while the secondary outcomes were TRM and RR. We included 9 prospective controlled studies including 1950 adult patients. Patients with intermediate-risk AML in CR1 who received either alloHSCT or non-alloHSCT were considered eligible. AlloHSCT was found to be associated with significantly better RFS, OS, and RR than non-alloHSCT (HR, 0.684 [95% CI: 0.48, 0.95]; HR, 0.76 [95% CI: 0.61, 0.95]; and HR, 0.58 [95% CI: 0.45, 0.75], respectively). TRM was significantly higher following alloHSCT than non-alloHSCT (HR, 3.09 [95% CI: 1.38, 6.92]). However, subgroup analysis showed no OS benefit for alloHSCT over autoHSCT (HR, 0.99 [95% CI: 0.70, 1.39]). In conclusion, alloHSCT is associated with more favorable RFS, OS, and RR benefits (but not TRM outcomes) than non-alloHSCT generally, but does not have an OS advantage over autoHSCT specifically, in patients with intermediate-risk AML in CR1.

The efficacy and safety of rabbit anti-thymocyte globulin vs rabbit anti-T-lymphocyte globulin in peripheral blood stem cell transplantation from unrelated donors

The comparative efficacy and safety of antithymocyte globulin (ATG) at fixed doses in patients undergoing allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. In this study, the records of 56 patients and 54 patients who received pre-transplant ATG-Thymoglobulin (ATG-T) at a total dose of 10 mg/kg and ATG- Fresenius (ATG-F) at a total dose of 20 mg/kg, respectively, were retrospectively analyzed. ATG-F patients had a significantly lower probability of developing chronic graft-vs-host disease (cGVHD) than those treated with ATG-T (p = 0.04). ATG-F was associated with a non-significant trend towards lower relapse rates and higher survival at 3- and 5-years of follow-up compared with ATG-T. A significantly greater proportion of ATG-T patients experienced chills and high fever than ATG-F patients (p < 0.01). The current findings suggest that ATG-F may more effectively and safely prevent cGVHD without increasing relapse rates in patients undergoing UR-PBSCT.

Successful management with an effective induction regimen followed by allogeneic hematopoietic stem cell transplantation for promyelocytic blast crisis of chronic myelogenous leukemia

Dear Editor, Promyelocytic blast crisis is a rare occurrence in chronic myelogenous leukemia (CML). We report such a case where long-term survival was achieved after initiating a novel induction regimen followed by allogeneic hematopoietic stem cell transplantation (HSCT). A 31-year-old male developed pain of the right leg accompanied by night sweats in April 2009. He was admitted to another hospital and splenomegaly was observed. Routine blood tests were as follows: white cell blood count (WBC) 191×10/L, hemoglobin (Hb) 188 g/L, and platelet (PLT) count 80×10/L. Bone marrow biopsy confirmed the diagnosis of CML in the chronic phase (CP). Analyses of chromosome and fusion genes showed 46, XY, t(9;22)(q34; q11), BCR-ABL (+), and PML-RARA (−). Quantitative realtime polymerase chain reaction (RT-qPCR) revealed 1,531 copies of the BCR-ABL p210 transcript per 10,000 karyocytes. He was given hydroxycarbamide 2.0–4.0 g daily, and the WBC dropped to 8.0×10/L. He began to take imatinib 400 mg/day on May 12, 2009. However, right leg pain recurred and was associated with decreased blood cell count after 3-month imatinib treatment. On August 19, 2009, the patient was admitted to our hospital. The right leg was normal on physical examination. Blood tests showed WBC 1.25×10/L, Hb 116 g/L, and PLT 35×10/L. Coagulation was normal. Bone marrow smear showed 6% blasts, 32% abnormal progranulocytes with Auer rods, and 17.2% granulocytes (Fig. 1a). Flow cytometry analysis revealed 96.3% CD13+, 97.2% CD33+, 80.9% CD117+, and 49% CD64+ but negative for CD34 and HLA-DR. Fusion gene detection found both BCR-ABL and PML-RARA (Fig. 1b). The positive results were confirmed by FISH analysis (Fig. 1c, d). Quantitative analysis of BCR-ABL and PMLRARA revealed that fusion genes were 88.36% and 25.4% higher than the wild type genes, respectively. The primary diagnosis was promyelocytic blast crisis of CML. The patient was treated with dasatinib 70 mg/day, alltrans retinoic acid (ATRA) 40 mg/day, and arsenic trioxide (ATO) 10 mg/day. On the 11th day after treatment onset, ATO was withdrawn due to nodal tachycardia. On the 14th day, the WBC was 42.3×10/L. An IA regimen was initiated (idarubicin 10 mg/day on days 1–3, cytarabine 100 mg×q12h on days 1–7). Dasatinib was withdrawn on the 23rd day and reinitiated 140 mg/day on the 33rd day following recovery of the hemogram. Bone marrow aspiration revealed complete remission (CR) on the 32nd day. BCR-ABL and PML-RARA genes dropped to 1.76% and 0.09%, respectively. No signs of disseminated intravascular coagulation (DIC) were found. Blood counts remained normal during CR. This patient continued to take dasatinib 140 mg/day and ATRA 40 mg/day until November 2009. RT-qPCR was repeated, and BCR-ABL and PMLBo Cai and Weidong Yang contributed equally to this work.

Post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation: A single-center experience

BACKGROUND Post-transplant lymphoproliferative disease (PTLD) is a rare and serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation. MATERIAL/METHODS We conducted a retrospective analysis of the occurrence of post-transplant lymphoproliferative disease in allo-HSCT recipients over 12 years in a single center in China. A total of 343 patients received allo-HSCT. The conditioning therapy consisted of a busulfan/cyclophosphamide-based regimen, a fludarabine/cyclophosphamide-based regimen, or total-body irradiation and cyclophosphamide. In transplantations from unrelated donors and haplo-identical donors, patients also received antithymocyte globulin (ATG) or thymoglobulin as part of the conditioning. RESULTS Five of the 343 patients (1.46%) were diagnosed with PTLD and all 5 were given ATG as part of conditioning. Among these 5 patients, 4 had lymphoid neoplasm before transplantation. EBV-positivity was confirmed in 4 patients. All 5 PTLD patients received reduction of immunosuppression (RI) as fundamental therapy. At follow-up on April 1, 2013, 1 patient had survived for 2 years and 1 had survived for 9 years. The correlation of PTLD with ATG and underlying diseases were examined by statistical analysis using the chi-squared test or Fishers exact test (P=0.011 and 0.025, respectively). CONCLUSIONS Although only 1.46% of patients progressed to PTLD associated with ATG and underlying diseases, the mortality was still high. Moreover, RI can be an effective therapy for PTLD patients, but other approaches should be further explored.

Long-term outcomes of peripheral blood stem cell transplantation for 38 patients with peripheral T-cell lymphoma.

OBJECTIVE In this study, to investigate clinical characteristics, response, outcome, and prognosis of peripheral blood stem cell transplantation (PBSCT) for patients with peripheral T-cell lymphoma (PTCL). METHODS This study retrospectively analyzed the efficacy of PBSCT in 38 patients with PTCL. Kaplan-Meier methods were used in survival analysis, and the Cox regression model was applied in multivariate analysis. There were ten clinical parameters were analyzed. RESULTS The 2-year overall survival (OS) was 46%, and the 5-year OS was 34% after a median follow-up of 40 months. The patients who received allogeneic PBSCT (allo-PBSCT) had a higher nonrelapse mortality than autologous PBSCT (auto-PBSCT), but they could achieve a longer-term disease-free survival in the former, which OS could achieve 40%. Survival analysis with Kaplan-Meier method showed the pretransplant disease status, B symptoms, serum lactate dehydrogenase (LDH) in early (>275 U/L), Eastern Cooperative Oncology Group (ECOG) score (>1), prognostic index for PTCL score (>2) were all prognostic factors for posttransplant OS. Pretransplant disease status is the only prognostic factor for allo-PBSCT. CONCLUSION The key was to reducing transplant-related mortality of allo-PBSCT by reduced-intensity conditioning. Factors such as level of early serum LDH, extranodal involvement, B symptoms, ECOG score, Ann Arbor stage, and pretransplant disease status were all related to the prognosis of patients treated with PBSCT. Allo-PBSCT maybe suggested as the first line therapy for late-stage PTCL patients who could reach treatment remission before transplantation.

Novel diagnostic biomarker for patients with Non-Hodgkin's Lymphoma by IgH gene rearrangement

AIM OF STUDY Novel biomarkers for improving accuracy could be beneficial for disease monitoring and surveillance of Non-Hodgkins lymphomas (NHL). So we explored the viability of analytical methods for identifying the rearranged immunoglobulin (Ig) H genes sequence. MATERIALS AND METHODS Next-generation sequencing (NGS) was used to sequence deoxyribonucleic acid (DNA) extracted directly from the tumor tissues of patients with NHL, and then specific rearranged DNA fragments from plasma was detected by polymerase chain reaction (PCR). RESULTS By parallel DNA capturing and sequencing of IgH genomic regions (IgCap), the sequence of rearranged IgH loci could be detected and precisely determined in tumor tissues of 12 patients with NHL. The circulating rearranged DNA fragments had been identified in the plasma of one patient. CONCLUSION IgCap may be the favorable diagnostic method for patients with NHL in clinical.

Bilineal Extramedullary Blast Crisis as an Initial Presentation of Chronic Myeloid Leukemia: A Case Report and Literature Review

Patient: Male, 49 Final Diagnosis: T-lymphoid/myeloid bilineal blastic transformation of CML Symptoms: Rapidly enlarging mass in left neck Medication: — Clinical Procedure: Biopsy of the left submandibular lymph nodes Specialty: Hematology Objective: Rare co-existance of disease or pathology Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia chromosome generated by the reciprocal translocation t(9: 22)(q34;q11). CML is usually diagnosed in the chronic phase. Blast crisis represents an advanced phase of CML. Extramedullary blast crisis as the initial presentation of CML with bone marrow remaining in chronic phase is an unusual event. Further, extramedullary blast crisis with T lymphoid/myeloid bilineal phenotype as an initial presentation for CML is extremely unusual. Case Report: Here, we report the case of a 49-year-old male with rapidly enlarged submandibular lymph nodes. Biopsy specimen from the nodes revealed a characteristic appearance with morphologically and immunohistochemically distinct myeloblasts and T lymphoblasts co-localized in 2 adjacent regions, accompanied by chronic phase of the disease in bone marrow. The presence of the BCR/ABL1 fusion gene within both cellular populations in this case confirmed the extramedullary disease represented a localized T lymphoid/myeloid bilineal blastic transformation of CML. After 3 courses of combined chemotherapy plus tyrosine kinase inhibitor treatment, the mass was completely regressed with a 3-log decrease in BCR/ABL1 transcript from baseline. Five months after the diagnosis, the patient showed diminished vision, hand tremors, and weakness of lower extremities. Flow cytometric immunophenotyping of cerebrospinal fluid revealed the presence of myeloid blasts. An isolated central nervous system relapse of leukemia was identified. Following high-dose systemic and intrathecal chemotherapy, the patient continued to do well. Conclusions: The possibility of extramedullary blast crisis as an initial presentation in patients with CML should be considered. Further, an isolated central nervous system blast crisis should be considered if neurological symptoms evolve in patients who have shown a good response to therapy.

Secondary antifungal prophylaxis in hematological malignancy patients with previous invasive fungal disease: a retrospective analysis.

Background Invasive fungal disease (IFD) causes morbidity and mortality in patients with hematological malignancy. Recurrence of IFD after chemotherapy or hematopoietic stem cell transplantation (HSCT) is associated with poor prognosis. The present study aimed to investigate the efficacy of different strategies of secondary antifungal prophylaxis (SAP) for IFD and choose an appropriate SAP regimen. Methods Clinical data of patients with previous IFD who underwent chemotherapy or HSCT between Jan 2008 and Jun 2013 were retrospectively reviewed and followed up to 180 days post-chemotherapy or HSCT. The clinical characteristics and diagnosis were analyzed according to the diagnostic criteria for IFD. The efficacy of different strategies for SAP and risk factors influencing the failure of SAP were evaluated. Results Of the 164 patients enrolled, 121 patients received SAP regimen (73.78%), and IFD recurred in 40 patients: 16.5% (20/121) in SAP group and 46.5% (20/43) in non-SAP group. In SAP group, 58 received SAP agents which were proven effective for their previous IFD, while other 63 patients received other broad-spectrum antifungal agents. There was no significant difference in the recurrence rates between these two subgroups (13.8% (8/58) vs 19.0% (12/63), P = 0.437). The IFD recurrence rates were statistically significant between patients with allogeneic HSCT and chemotherapy or autologous HSCT (25% vs 8.2%, P = 0.013). Multivariate analysis indicated that allogeneic HSCT was the independent risk factor of IFD recurrence after SAP. Conclusions Secondary antifungal prophylaxis is necessary to prevent IFD recurrence in patients with hematological malignancy, especially for patients in the setting of allogeneic HSCT.