Changcheng Zheng

Comparison of outcomes after umbilical cord blood and unmanipulated haploidentical hematopoietic stem cell transplantation in children with high-risk acute lymphoblastic leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with high‐risk acute lymphoblastic leukemia (ALL). Human leukocyte antigen (HLA)‐haploidentical HSCT (haplo‐HSCT) or umbilical cord blood transplantation (UCBT) are both important alternative sources of stem cells for those without an HLA‐identical sibling donor or unrelated matched donor. We aimed to compare the therapeutic effects of single UCBT and unmanipulated haplo‐HSCT in high‐risk ALL children (n = 129). Hematopoietic recovery was significantly faster in haplo‐HSCT recipients than in UCBT recipients. The 2‐year cumulative incidences of relapse in the haplo‐HSCT and UCBT groups were 16.1% and 24.1%, respectively (p = 0.169). The 2‐year cumulative incidences of non‐relapse mortality in the haplo‐HSCT and UCBT groups were 12.8% and 18.8%, respectively (p = 0.277). The 2‐year probabilities of overall survival in the haplo‐HSCT and UCBT groups were 82.0% and 69.6%, respectively (p = 0.071), and the 2‐year probability of disease‐free survival in the haplo‐HSCT group was higher than in the UCBT group (71.0% vs. 57.2%, p = 0.040). However, several variables (such as leukocyte count and cytogenetics at diagnosis) were different between the groups, and a possible center effect should also be considered. In addition, only mild and moderate chronic graft‐versus‐host disease (GVHD) was associated with significantly improved survival compared to those without chronic GVHD in multivariate analysis. Thus, our results show that both unmanipulated haplo‐HSCT and UCBT are valid for high‐risk ALL children lacking a HLA matched donor, and both strategies expand the donor pool for children in need.

The impact of pre-transplant minimal residual disease on outcome of intensified myeloablative cord blood transplant for acute myeloid leukemia in first or second complete remission.

Abstract The impact of pretransplant minimal residual disease (MRD) on outcome of myeloablative cord blood transplant (CBT) for acute myeloid leukemia (AML) in complete remission (CR) has not been reported. Seventy-two AML patients were assessed for MRD before CBT, and the majority (84.7%) of these patients received single-unit CBT. All patients received intensified myeloablative conditioning with BUCY2 or TBICY plus high-dose cytarabine, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic GVHD were comparable between MRD-negative and MRD-positive groups. The cumulative incidence of transplant-related mortality (TRM) and relapse did not differ significantly between the two cohorts (25.6% vs. 32.5%, 16.1% vs. 19.2%; p = 0.52, 0.61). There were no apparent differences in 3-year overall survival (OS) (68.9% in MRD-negative group and 57.9% in MRD-positive group, p = 0.31) and 3-year leukemia-free survival (LFS) (62.5% in MRD-negative group and 52.7% in MRD-positive group, p = 0.42) between both groups. The current study suggests that AML patients in morphological CR1 or CR2 who have detectable MRD might benefit from unrelated CBT with intensified myeloablative conditioning.

Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia

Abstract Objectives The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). Methods Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. Results The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 109/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 109/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30–120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively. Discussion This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival.

Salvaged single-unit cord blood transplantation for 26 patients with hematologic malignancies not in remission

Treatments for patients with hematologic malignancies not in remission are limited, but a few clinical studies have investigated the effects of salvaged unrelated cord blood transplantation (CBT). We retrospectively studied 19 patients with acute leukemia, 5 with myelodysplastic syndrome (MDS with refractory anemia with excess blasts [RAEB]), and 2 with non-Hodgkins lymphoma who received 1 CBT unit ≤2 loci human leukocyte antigen (HLA)-mismatched after undergoing myeloablative conditioning regimens between July 2005 and July 2014. All of them were in non-remission before transplantation. The infused total nucleated cell (TNC) dose was 4.07 (range 2.76-6.02)×107/kg and that of CD34+ stem cells was 2.08 (range 0.99-8.65)×105/kg. All patients were engrafted with neutrophils that exceeded 0.5×109/L on median day +17 (range 14-37 days) and had platelet counts of >20×109/L on median day +35 (range 17-70 days). Sixteen patients (61.5%) experienced pre-engraftment syndrome (PES), and six (23.1%) patients progressed to acute graft-versus-host disease (GVHD). The cumulative incidence rates of II-IV acute GVHD and chronic GVHD were 50% and 26.9%, respectively. After a median follow-up of 27 months (range 5-74), 14 patients survived and 3 relapsed. The estimated 2-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) rates were 50.5%, 40.3%, and 35.2%, respectively. Salvaged CBT might be a promising modality for treating hematologic malignancies, even in patients with a high leukemia burden.

European Group for Blood and Marrow Transplantation Risk Score Predicts the Outcome of Patients with Acute Leukemia Receiving Single Umbilical Cord Blood Transplantation

The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia-free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor-recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor-recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.

A novel mutation in Wiskott-Aldrich syndrome and successfully treated with umbilical cord blood transplantation

We report a novel mutation in a boy with Wiskott-Aldrich syndrome (WAS) who was 4 years and 10 months of age and underwent successful umbilical cord blood transplantation (UCBT). The child presented at 3 months of age with symptomatic thrombocytopenia and eczema. Despite a large dose of intravenous immunoglobulin treatment, no increase in the platelet count was observed. A genetic analysis revealed a deletion mutation at c.410_419del10 in exon 4, which resulted in the replacement of encoded phenylalanine with serine at amino acid 137 and caused an early stop codon at downstream amino acid 121 (p.F137SfsX121), and confirmed a diagnosis of WAS. The only curative treatment for WAS is hematopoietic stem cell transplantation. Because no matched sibling donor was available, he underwent unrelated UCBT. He is currently alive and doing well at fourteen months post-transplant, and he is free of any bleeding episodes. The eczema that was all over his body had disappeared. This case suggests that unrelated UCBT may be safe and technically feasible for the treatment of WAS when an appropriately matched related or unrelated donor is unavailable.

Risk factors of CMV infection in patients after umbilical cord blood transplantation: a multicenter study in China

OBJECTIVE This retrospective study examined risk factors for cytomegalovirus (CMV) infection after umbilical cord blood transplantation (UCBT) and the impact of CMV infection on patient survival. METHODS In all 176 patients, plasma CMV DNA was negative prior to the transplantation, and examined twice a week for 100 d, and then once weekly for additional 300 d. Preemptive antiviral therapy (ganciclovir or foscarnet) was started in patients with >1,000/mL copies of CMV DNA but no full-blown CMV disease, and was discontinued upon two consecutive negative reports of blood CMV DNA test. The survival and risk factors for CMV infection or disease were examined using logistic regression. RESULTS CMV infection developed in 71% (125/176) of the patients, with a median onset of 32 d. Four patients (2.3%) developed CMV disease. Neither the 5-year overall survival (OS) nor event-free survival (EFS) differed significantly in infected patients vs. those with no infection (59.4% vs. 64.8%, P=0.194; 53.4% vs. 59.1%, P=0.226). A stepwise multivariate analysis indicated an association of CMV infection with age, high-dose glucocorticoids, the number of transplanted CD34(+) cells, and the number of platelet transfusion, but not with gender, the conditioning regimen, and the day of neutrophil recovery and chronic graft-versus-host disease (cGVHD). CONCLUSIONS CMV infection is very common after UCBT, but does not seem to affect long-term survival with preemptive antiviral treatment.

Strategy to further increase of cure rate in acute promyelocytic leukaemia: low-dose all-trans retinoic acid and sequential maintenance cycle

Paolo Sportoletti Stefano Baldoni Laura Cavalli Beatrice Del Papa Elisabetta Bonifacio Raffaella Ciurnelli Alain Sylvin Bell Ambra Di Tommaso Emanuela Rosati Barbara Crescenzi Cristina Mecucci Isabella Screpanti Pierfrancesco Marconi Massimo F. Martelli Mauro Di Ianni* Franca Falzetti* Department of Clinical and Experimental Medicine, Haematology and Clinical Immunology Section and Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Department of Experimental Medicine, Molecular Pathology, University La Sapienza, Rome, and Department of Internal Medicine and Public Health, Chair of Haematology, University of L’Aquila, L’Aquila, Italy. E-mail: sportolp@gmail.com *Authors with equal contribution. References

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia

Corticosteroids are essential and one of the mainstays in the treatment of acute lymphoblastic leukemia (ALL). In vitro assays show that dexamethasone(DXM) is five to six times more cytotoxic to leukemic lymphoblasts than prednisolone (PDN) [1], and the use of DXM as an alternative drug for PDN is an important issue in the treatment of childhood ALL. The current randomized comparisons in childhood ALL indicated a statistically significant and clinically important decrease in rate of isolated central nervous system (CNS) relapses and an increase in event-free survival (EFS) with DXM. However, the data were limited in adult ALL. Recently, Labar et al. [2] reported their first investigation in comparison of the antileukemic activity and toxicity between DXM and PDN for adult patients with ALL and lymphoblastic lymphoma (LBL) through a randomized clinical trial (the ALL-4 trial of the EORTC Leukemia Group), and the author concluded that DXM as a steroid therapy for adult patients with ALL/LBL did not show any benefit compared with PDN, which did not support the experience from several other pediatric studies. In Labar’s observation, about 70% of adult patients were high risk (HR) ALL. Most of the patients in pediatric trials were standard risk (SR) ALL. In our study, we also evaluate the role of DXM compared with PDN during induction or subsequent phases of therapy in adult ALL with emphasis on SR group.

Double vs. single cord blood transplantation in adolescent and adult hematological malignancies with heavier body weight (≥50 kg)

ABSTRACT Background: Double-unit cord blood transplantation (CBT) can be used to overcome the limitation of single-unit CBT with low cell content for adults and larger adolescents. However, whether double-unit CBT is superior to single-unit CBT remains controversial. Methods: We reviewed the medical records of 228 consecutive hematological malignancies who received CBT between November 2005 and December 2013. Ninety-seven eligible patients met the criteria (age ≥14 years and body weight ≥50kg) and were enrolled in this study. Results: The incidence of myeloid engraftment in the double-unit CBT group was significantly lower that in the single-unit CBT group (89.2 vs. 96.7%) (p = 0.026), and the incidence of platelet engraftment in the double-unit CBT group was slightly lower (70.3 vs. 86.7%) (p = 0.057). The 5-year transplant-related mortality rate was significantly higher in the double-unit CBT group when compared with that of the single-unit CBT group [54.1 vs. 33.3%, p = 0.026]. The 5-year probabilities of overall survival, disease-free survival and graft-versus-host disease (GVHD) -free/relapse-free survival in the double-unit CBT group were significantly lower than that of the single-unit CBT group (37.8 vs. 56.7%, p = 0.037; 32.4 vs. 55.0%, p = 0.017; 24.3 vs. 50.0%, p = 0.006). The incidences of GVHD and relapse were similar. Conclusions: For adolescent and adult hematological malignancies with heavier body weight (≥50kg), double-unit CBT has an inferior clinical outcome when compared with single-unit CBT having a sufficient cell dose. Double-unit CBT should only reserve for patients who need an urgent transplant but lacking of a related or unrelated donor and without an adequately dosed single CB.