Juan Tong

Pre-engraftment syndrome after unrelated donor umbilical cord blood transplantation in patients with hematologic malignancies.

Pre‐engraftment syndrome (PES) after umbilical cord blood transplantation (CBT) remains poorly characterized, and the prognosis and appropriate management are unclear. Therefore, we retrospectively analyzed the incidence, risk factors, manifestations, and clinical outcomes of PES in CBT recipients, who had been treated for hematologic malignancies at our transplantation center. PES was defined as unexplained fever higher than 38.3°C that is not associated with documented infection and unresponsive to antimicrobial manipulations and/or unexplained erythematous skin rash occurring prior to neutrophil engraftment. A total of 81 patients (median 18 yr, range 3–48) received either myeloablative (n = 72) or non‐myeloablative (n = 9) conditioning. Neutrophil engraftment was achieved in 69 of the 81 cases [86.2%, 95% confidence interval (CI) = 78.9–94.1%], and the median time to more than 0.5 × 109/L ANC was 19 d (range, 12–39). Fifty‐one patients (63.0%) developed PES at a median of 7 d (range 3–15) post‐transplant: 46 patients had both rash and unexplained fever; one patient had unexplained fever alone; and four patients had rash only. Forty‐seven patients (92.2%) received IV methylprednisolone (MP) at a median dose of 1 mg/kg (range 0.4–3). All patients treated with MP responded as evidenced by fever resolution combined with resolution of rash. All patients with PES had high serum levels of C‐reactive protein (CRP), which were significantly reduced after effective steroid treatment. Univariate analysis identified myeloablative conditioning and younger age as significant risk factors for developing PES. Cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) in the PES+ and PES− groups was 51.5% (95% CI = 38.0–70.0%) and 17.0% (95% CI = 6.9–41.7%), respectively. In a multivariate analysis, we found significantly increased risk of grade II–IV aGVHD among PES patients (P = 0.041). However, PES was not associated with sustained donor engraftment, the day to neutrophil recovery, chronic graft‐versus‐host disease, transplant‐related mortality at day 180, and overall survival. Despite of the inherent limitations of this small retrospective study, PES seemed to be common after CBT and associated with high incidence of aGVHD.

Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n= 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P= .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

Successful second transplantation with non-myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.

Liu H, Wang X, Geng L, Tang B, Tong J, Yao W, Wang Z, Sun Z. Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.
Pediatr Transplantation 2010: 14:465–470.

Primary research on unrelated double umbilical cord blood transplantation and implantation kinetics

Abstract Objective This study sought to examine implantation and implantation kinetics in double umbilical cord blood transplantation (DUCBT). Methods Twenty-nine patients who underwent a two-unit unrelated donor cord blood transplantation were included in this study. After transplantation, hematopoietic chimerism of the peripheral blood was evaluated based on the results of short tandem repeat polymerase chain reaction. Using these results, we were able to judge whether the transplanted cells implanted, determine which donors cells implanted, and further examine the kinetics of implantation in DUCBT. The numbers of total nucleated cells (TNCs), CD34+ cells, colony forming units (CFUs), colony forming unit-granulocytes and macrophages (CFU-GMs), and CD3+ cells were compared between the dominant units and the non-dominant units in an attempt to understand the discipline and implantation kinetics of DUCBT. Results Neither the TNC counts nor the counts of CD34+ cells, CFU, CFU-GM, or CD3+ cells were significantly different between the dominant units and the non-dominant units (P values of 0.584, 0.322, 0.842, 0.534, and 0.082, respectively). Conclusions We were able to determine the engraftment status at 14 days after DUCBT, although the implantation kinetics of DUCBT remain uncharacterized and require further research.

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.

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.

Umbilical Cord Blood Transplantation without Antithymocyte Globulin Results in Similar Survival but Better Quality of Life Compared with Unrelated Peripheral Blood Stem Cell Transplantation for the Treatment of Acute Leukemia—A Retrospective Study in China

Although previous studies have demonstrated improved outcomes in umbilical cord blood transplantation (UCBT) by omitting antithymocyte globulin (ATG) in the conditioning regimen, this approach has not been comparatively studied in unrelated peripheral blood stem cell transplantation (UPBSCT). To compare the risks and benefits between UCBT without ATG and UPBSCT in patients with acute leukemia (AL), we conducted a multicenter retrospective study of 79 patients who underwent UCBT (myeloablative conditioning without ATG) and 96 patients who underwent UPBSCT (myeloablative conditioning with ATG). The outcomes were graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), transplantation-related mortality (TRM), relapse, overall survival (OS), and leukemia-free survival (LFS). Follow-up was censored on October 31, 2016. Engraftment was similar between the 2 groups but granulocyte and platelet recovery were slower in the UCBT group (both P < .001). The incidences of aGVHD, TRM, OS, and LFS were similar between the 2 groups (all P > .05). Without ATG, the UCBT group displayed less cGVHD and less moderate and severe cGVHD (P < .001 and P = .004). The incidences of Epstein-Barr virus viremia and post-transplantation lymphoproliferative disease were significantly lower in the UCBT group (P < .001 and P = .037). UCBT recipients had higher activity Karnofsky performance scores and 3-year GVHD-free/relapse-free survival than the UPBSCT group (P = .03 and P = .04). We observed similar survival when comparing UCBT without ATG and UPBSCT, but we also observed better quality of life in patients undergoing UCBT without ATG. We can therefore conclude that patients with primary AL for whom an appropriate HLA-matched sibling donor is not available could select either UCBT or UPBSCT.

Decitabine prior to salvaged unrelated cord blood transplantation for refractory or relapsed childhood acute leukemia.

No clinical studies have investigated the role of decitabine as a part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL in patients in NR status. The aim of this study was to identify the potential benefits of decitabine as a prior therapy before salvaged unrelated UCBT for refractory or relapsed childhood AL. Eight consecutive patients with childhood refractory/relapsed AL were enrolled in our study between 2013 and 2014. All patients were in NR status before the time of transplant and had features associated with poor outcomes, such as CNSL, MDS‐AML, high WBC count at diagnosis, and hypodiploid status (FLT3+/ITD+). Additionally, all patients had one of the following disease statuses: PIF, multiple relapse, or early relapse. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine+Flu/Bu/CY±BCNU or decitabine+Ara‐c/BU/CY2±BCNU. A total of seven patients (7 of 8) achieved neutrophil engraftment and platelet engraftment, and one patient experienced primary graft failure. All eight patients (100%) developed PES at a median of 7 days. Three patients developed stage II‐IV acute GVHD at a median of 18 days. Additionally, three patients developed chronic GVHD, but it was not extensive in any of those three patients. The median follow‐up time after CBT was 19.9 months (range, 9.2–30.7 months). The estimated probability of OS was 75%. Two patients (2 of 8) experienced a testis relapse, and two patients (2 of 8) died. Our experience suggests that the additional application of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL among patients who are not in remission is safe and might be an effective treatment option.