Xiaowen Tang

Clinical Characteristics, Biological Profile, and Outcome of Biphenotypic Acute Leukemia: A Case Series

Background: Biphenotypic acute leukemia (BAL) is a rare type of acute leukemia that presents with a high degree of heterogeneity and is not well defined. Methods: We identified 51 cases (3%) of BAL from 1,693 newly diagnosed acute leukemia patients according to the EGIL scoring system. The immunophenotyping, cytogenetics, treatment, and outcome of 39 BAL patients were retrospectively analyzed. Results: There were 23 (59%) cases of the myeloid and B-lymphoid phenotype, 14 (36%) cases of the myeloid and T-lymphoid phenotype, and 1 case (3%) of the trilineage phenotype or B/T phenotype. Abnormal karyotypes were detected in 76% of the 37 validated patients and displayed a high degree of heterogeneity. Combined regimens for both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as ALL type regimens, appeared to achieve a better complete remission rate than AML type regimens (71 and 64 vs. 33%, respectively). BAL patients with complex karyotypes or a rearrangement of chromosome 11 had a significantly reduced survival rate in comparison to patients with normal, t(8; 21), or t(9; 22) karyotypes. The probability of overall survival and disease-free survival at 2 years was 26 and 18%, respectively. Conclusions: Our findings indicate that BAL shows a high incidence of abnormal karyotypes and a poor prognosis. Combined-type regimens or ALL-based protocols are effective for the treatment of BAL.

Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Different Characteristics between Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a contributor to post-transplantation mortality and remains poorly understood, especially the different characteristics of EMR in patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL). To investigate the incidence, risk factors, and clinical outcomes of EMR for AML and ALL, we performed a retrospective analysis of 362 patients with AL who underwent allo-HSCT at the First affiliated Hospital of Soochow University between January 2001 and March 2012. Compared with patients with AML, those with ALL had a higher incidence of EMR (12.9% versus 4.6%; P = .009). The most common site of EMR was the central nervous system, especially in the ALL group. Multivariate analyses identified the leading risk factors for EMR in the patients with AML as advanced disease status at HSCT, hyperleukocytosis at diagnosis, history of extramedullary leukemia before HSCT, and a total body irradiation-based conditioning regimen, and the top risk factors for EMR in the patients with ALL as hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion of peripheral blood stem cells. The prognosis for EMR of AL is poor, and treatment options are very limited; however, the estimated 3-year overall survival (OS) was significantly lower in patients with AML compared with those with ALL (0 versus 18.5%; P = .000). The characteristics of post-allo-HSCT EMR differed between the patients with AML and those with ALL, possibly suggesting different pathogenetic mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further investigation is needed.

Cytomegalovirus Glycoprotein B Genotype in Hematopoietic Stem Cell Transplant Patients from China

Cytomegalovirus (CMV) can be classified into 4 subgroups based on genotype variation of the glycoprotein B (gB) encoded by UL55 gene. Little is known about the CMV gB genotype distribution and its clinical implication in patients who receive hematopoietic stem cell transplant (HSCT) in China. In this study, which comprises 101 HSCT patients with CMV infection, we have found that 36 patients (35.64%) were infected with CMV genotype gB1, 3 patients (2.97%) with gB2, 39 patients (38.61%) with gB3, 1 patient (0.99%) with gB4, and 17 patients (16.83%) were infected with mixed CMV genotypes. We also found that CMV gB3 was associated with a high risk of CMV pneumonitis; nevertheless, there were no significant differences among patients with gB genotypes with respect to the other CMV diseases; no significant differences between patients with gB genotypes with respect to type II-IV acute graft-verses-host disease (aGVHD) and chronic GVHD (cGVHD) was found either. Interestingly, 5 patients (4.95%) were infected with a CMV variant that lacked a signature RsaI digestion site determined by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), subsequent cloning and sequencing identified this CMV RsaI minus variant to be novel, herein designated as gB5. Overall, these findings suggest that CMV gB1 and gB3 are prevalent among HSCT recipients with CMV infections, and gB3 CMV infection is a risky indicator for CMV pneumonitis; furthermore, a novel CMV variant in a subset of Chinese HSCT recipients is identified and designated as gB5.

Combination of a haploidentical SCT with an unrelated cord blood unit: a single-arm prospective study

We conducted a single-arm prospective study in 50 patients who received the combination of an haploidentical stem cell graft and an unrelated umbilical cord blood unit for the treatment of hematological malignancies. The median time for neutrophil engraftment was 13 days (11–20 days), and for platelets was 15 days (11–180 days). All surviving patients attained complete haploidentical engraftment except three patients who presented a mixed engraftment with increasing cord blood and decreasing haplo mismatch chimerism during the first 4 months after transplantation. The cumulative incidence of grade II–IV acute GVHD was 20%±0.327% at day+100, and the incidence of chronic GVHD was 19.26%±1.0% at 1 year. The 1-year cumulative incidence of relapse was 19.78%±1%, and the TRM was 16.2%±0.54%. At 1 year, overall survival was 78.6%±7.6% and PFS 64.0%±11.0%. The BU/CY-based conditional regimen showed a significant superiority over TBI/CY on PFS (relative risk=5.012, 95% confidence interval, 1.146–21.927, P=0.032). In conclusion, the co-infusion of an unrelated cord blood unit may potentially improve the outcome of haploidentical allogeneic hematopoietic SCT.

The Expression of Th17-Associated Cytokines in Human Acute Graft-versus-Host Disease

The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3(+) Treg cells and the expressions of RORγt and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORγt expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-β, IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4(+) T cells were also examined. The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17-associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17-associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3(+) Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD.

The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

RNF6 is a little-studied ring finger protein. In the present study, we found that RNF6 was overexpressed in various leukemia cells and that it accelerated leukemia cell proliferation, whereas knockdown of RNF6 delayed tumor growth in xenografts. To find out the mechanism of RNF6 overexpression in leukemia, we designed a series of truncated constructs of RNF6 regulatory regions in the luciferase reporter system. The results revealed that the region between −144 and −99 upstream of the RNF6 transcription start site was critical and that this region contained a PBX1 recognition element (PRE). PBX1 modulated RNF6 expression by binding to the specific PRE. When PRE was mutated, RNF6 transcription was completely abolished. Further studies showed that PBX1 collaborated with PREP1 but not MEIS1 to modulate RNF6 expression. Moreover, RNF6 expression could be suppressed by doxorubicin, a major anti-leukemia agent, via down-regulating PBX1. This study thus suggests that RNF6 overexpression in leukemia is under the direction of PBX1 and that the PBX1/RNF6 axis can be developed as a novel therapeutic target of leukemia.

Comparison of outcomes in mixed phenotype acute leukemia patients treated with chemotherapy and stem cell transplantation versus chemotherapy alone

The optimal treatment approach for mixed phenotype acute leukemia (MPAL) remains unknown, and prognostic factors for treatment outcomes need to be identified. In this study, 66 patients diagnosed with MPAL according to criteria published by the WHO in 2008 were retrospectively assessed to evaluate the effectiveness of treatment and identify predictive variables. Five patients died of severe infection after the first induction chemotherapy, 29 received alloHSCT after induction (HSCT group), and 32 received only chemotherapy (chemotherapy group). The 3-year OS and DFS estimates for the entire cohort were 45% and 38%, respectively, and the 3-year OS differed significantly between the HSCT and chemotherapy-only groups (77% versus 16%). Using multivariate analyses, we identified disease burden as a prognostic factor for transplantation outcome, with the 3-year OS being 80% among patients who achieved remission and only 45% among patients in cases of nonremission. Our results indicate that alloHSCT after chemotherapy offers a survival advantage compared with chemotherapy only, and patients in remission before transplantation may experience a better outcome.

Low-dose cytarabine and aclarubicin combined with granulocyte colony-stimulating factor for the treatment of relapsed or primary refractory acute lymphocytic leukemia: a retrospective study of 25 Chinese patients

Despite improvements in treatment, the prognosis of relapsed or primary refractory acute lymphocytic leukemia (ALL) remains poor, and outcomes are worse in older adults with the short first complete remission (CR). Attainment of the second CR by salvage therapy would improve the survival of these patients and may enable them to undergo curative treatment with allogeneic hematopoietic stem cell transplantation. The fact that there are diverse salvage protocols for these adult patients but without a striking CR‐induction efficacy indicates that efforts are still needed to indentify new effective reinduction regimens. In this study, the CAG regimen (cytarabine, 10 mg/m2 subcutaneously every 12 h on days 1–14; aclarubicin, 5–7 mg/m2 intravenously daily on days 1–8; and concurrent granulocyte colony‐stimulating factor, 200 µg/m2/day subcutaneously) was administered to 25 patients with relapsed or refractory ALL, including 11 T‐cell ALL (T‐ALL) and 14 B‐cell (B‐ALL) patients (age range, 11–61 years; median age, 26 years), to assess its efficacy as a salvage therapy. One course of the CAG regimen resulted in an overall response [CR or partial remission (PR)] rate of 64%, a CR rate of 56% and generally mild adverse effects. An overall response was observed in all 11 T‐ALL patients (10 CR and 1 PR) and 35.7% of B‐ALL patients (p = 0.0009). The significant treatment potential of CAG regimen for relapsed or primary refractory ALL, especially for T‐ALL patients, described in this report would prepare them for a second CR to pursue longer survival. Copyright

Haploidentical allogeneic hematopoietic stem cell transplantation compared to matched unrelated transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia

To investigate the effect of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcome of 58 patients with Ph+ ALL who received Haplo-HCT (n=42) or matched unrelated donor transplantation (MUD-HCT) (n=16) during the same period were analyzed retrospectively. All patients received a tyrosine kinase inhibitor (TKI)-based regimen before transplantation, and TKI was resumed primarily after transplantation. At the 3-year follow-up, the overall survival (OS), leukemia-free survival (LFS), the cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) rates in Haplo-HCT group were 69.1, 64.3, 19.0, and 14.3%, respectively, without significant differences from that of MUD-HCT. Haplo-HCT was not related to higher incidences of severe acute graft-versus-host disease (GvHD) (17.6±5.2% vs. 20.0±10.0%, P=0.603) or chronic GvHD (19.5±7.1% vs. 13.3±8.6%, P=0.637) as compared to MUD-HCT. Multivariate analysis showed that chronic GvHD was associated with lower relapse rate in Haplo-HCT group. Haplo-HCT is a promising choice for improving the long-term survival in Ph+ ALL patients.

FLT3-ITD with DNMT3A R882 double mutation is a poor prognostic factor in Chinese patients with acute myeloid leukemia after chemotherapy or allogeneic hematopoietic stem cell transplantation

To investigate clinical characteristics and outcomes of transplantation in AML patients with FLT3-ITD/DNMT3A double mutation, we retrospectively analyzed 206 Chinese patients with AML after Sanger sequencing. Our analysis showed that AML patients with FLT3-ITD and DNMT3A R882 mutations had a higher white blood cell count and a lower complete remission (CR) rate after first induction chemotherapy. All 206 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in status of CR. These results indicate that AML patients with FLT3-ITD and DNMT3A R882 double mutation show a higher 2-year cumulative incidence of relapse (CIR), lower 2-year overall survival (OS) rate, and lower 2-year leukocyte-free survival (LFS) after allo-HSCT. The univariate and multivariate analyses confirmed that disease status prior to transplantation, FLT3-ITD, FLT3-ITD, and DNMT3A R882 double mutation were independent factors for poor prognosis after allo-HSCT. In summary, the present cohort study demonstrated that FLT3-ITD and DNMT3A R882 double mutation predicts poor prognosis in Chinese AML patients receiving chemotherapy or allo-HSCT treatment.