Chen Yh

Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies

Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Here, we report a protocol for haploidentical allo-HSCT that combines granulocyte-colony stimulating factor primed bone marrow (G-BM) and peripheral blood stem cells (PBSC) without in vitro T-cell depletion (TCD). In this study, 171 patients, including 86 in high-risk group, underwent transplantation from haploidentical family donors. All patients achieved sustained, full donor chimerism. One hundred and eleven patients were alive in remission at a median of 682 (253–1502) days. The cumulative incidence of grade III–IV acute graft-versus-host disease (GVHD) was 23% and that of extensive chronic GVHD, 47%; these were not influenced by HLA disparity. Patients younger than 15 years had less grade III–IV acute GVHD than older patients (P=0.044). The 2-year probability of relapse was 12% for standard-risk disease and 39% for high-risk disease. The 2-year probability of leukemia-free survival (LFS) was 68% for standard-risk patients and 42% for high-risk patients (P=0.0009). Grade III–IV acute GVHD was associated with better LFS (P=0.0017). The results require confirmation and show that G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT.

A novel protocol for haploidentical hematopoietic SCT without in vitro T-cell depletion in the treatment of severe acquired aplastic anemia

Mismatched related donors of hematopoietic SCT (HSCT) for severe aplastic anemia (SAA) present challenges mainly associated with graft failure and GVHD. The greater the HLA disparity, the poorer the OS. About 19 consecutive SAA/very SAA (VSAA) patients who received HSCT from haploidentical family donors in our center are reported in this study, 18/19 pairs had 2–3 loci mismatched. All 19 cases failed to respond to previous therapy and were heavily transfused before transplantation. The conditioning regimen before HSCT included BU, CY and thymoglobulin. The recipients received CsA, mycophenolate mofetil (MMF) and short-term MTX for GVHD prophylaxis. The source of stem cell grafts was a combination of G-CSF-primed BM and G-CSF-mobilized peripheral blood stem cells. All patients achieved 100% donor myeloid engraftment; the median time for myeloid engraftment was 12 days (ranging from 10–29 days) and for platelets was 18 days (ranging from 8–180 days) with a cumulative platelet engraftment incidence of 84.21±10.53%. The cumulative incidence was 42.1±11.3% for grade II–IV acute GVHD and 56.2±12.4% for chronic GVHD. The OS was 64.6±12.4% with a median 746-day (90–1970) follow-up for surviving patients. These limited retrospective analysis data suggest that HLA-haploidentical HSCT for SAA patients without an HLA-identical sibling donor might be feasible. Further research to increase OS by decreasing GVHD while maintaining stable engraftment will be needed in the future.

Low-dose methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Summary:Methotrexate (MTX) is commonly used in the prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to evaluate the efficacy and safety of low-dose MTX treatment in patients with GVHD after allo-HSCT, 38 patients with acute GVHD (aGVHD), chronic GVHD (cGVHD) or GVHD post-donor lymphocyte infusion (post-DLI GVHD) after allo-HSCT received intravenous MTX at a dose of 5 or 10u2009mg every 5–7 days until a complete or partial response was seen, or there was treatment failure or intolerable side effects. The overall response rate was 94.7% (18/19 patients) in patients with aGVHD, 76.2% (16/21 patients) in patients with cGVHD and 2/2 in patients with post-DLI GVHD. The response rate for GVHD involving various organs was 100% in skin, 75% in gut, 55.6% in liver, 75% in mouth and 100% in the eye, among all enrolled patients. Side effects were minor. Short-term, low-dose MTX is a tolerable and an effective regimen for patients with aGVHD, cGVHD or post-DLI GVHD after allo-HSCT.

Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial

To evaluate the effect of the different doses of antithymocyte globulin (ATG) on the incidence of acute GVHD among patients receiving hematopoietic SCT without ex vivo T-cell-depletion from haploidentical donors, 224 patients with standard-risk hematological malignancy were randomized in this study. One hundred and twelve patients received 6u2009mg/kg ATG, whereas the remaining patients received 10u2009mg/kg ATG. This study was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761. The incidence of grade III–IV acute GVHD was higher in the ATG-6 group (16.1%, 95% confidence interval (CI), 9.1–23.1%) than in the ATG-10 group (4.5%, CI, 0.7–8.3%, P=0.005, 95% CI for the difference, −19.4% to −3.8%). EBV reactivation occurred more frequently in the ATG-10 group (25.3%, 17.1–33.5%) than in the ATG-6 group (9.6% (4.0–15.2%), P=0.001). The 1-year disease-free survival rates were 84.3% (77.3–91.3%) and 86.0% (79.2–92.8%) for the ATG-6 group and ATG-10 groups, respectively (P=0.88). In conclusion, although 6u2009mg/kg ATG applied in haploidentical transplantation decreased the risk of EBV reactivation compared with 10u2009mg/kg ATG, this treatment exposes patients to a higher risk for severe acute GVHD.

Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis

The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n=61) or did not (n=27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P=0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P=0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P=0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P=0.025). Higher OS was associated with use of prophylactic GPBPCI (P=0.002), AML (P=0.027) and female sex (P=0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT.

Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect

Donor lymphocyte infusion (DLI) exerts a GVL effect, but its use is limited by a high incidence of GVHD. We retrospectively evaluated the efficacy of administering short-term immunosuppressive agents for prophylaxis against DLI-associated acute GVHD, and its influence on the GVL effect. Seventy patients with leukaemia received G-CSF primed DLI after HLA-identical sibling haematopoietic stem cell transplantation (HSCT) for treatment or prophylaxis against leukaemia relapse. Short-term immunosuppressive agents were given to 54 patients for prophylaxis against DLI-associated acute GVHD. Seventeen patients experienced acute GVHD; 30 patients developed chronic GVHD; and no GVHD-related death was observed. A significant difference was observed between the group that did not receive prophylaxis against GVHD or received prophylaxis for less than 2 weeks and the group that received prophylaxis for over 2 weeks (CsA or MTX at 10u2009mg/week) with regard to the incidence of DLI-associated acute GVHD (14/28 vs 3/42, P=0.000); no difference was observed in the relapse rate for prophylactic DLI patients between the two groups (4/10 vs 12/29). Using immunosuppressive agents for 2–4 weeks may reduce DLI-associated acute GVHD without influencing relapse and survival after G-CSF-primed DLI.

Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis.

CML treatment with tyrosine kinase inhibitors (TKIs) has improved many patients’ prognosis, but during the disease’s terminal phase, the blast crisis (CML-BC), has been disappointing. Allo-HSCT is another treatment, but survival rates are still disappointing. Currently, a combination of these two is suggested but with little evidence. This retrospective comparison reports on this combination and TKI alone for treatment of CML-BC. Of the 83 CML-BC patients, 45 received TKIs (imatinib; nilotinb or dasatinib after imatinib resistance; TKIs group) and 38 were treated with allo-HSCT after TKI (TKIs+allo-HSCT group). Treatment success was measured in terms of the hematologic, cytogenic and molecular responses, and subject outcome. Follow-up was 30–126 months or until death. Univariate and multivariate analyses determined EFS and OS predictors. Allo-HSCT significantly improved the 4-year OS (46.7 vs 9.7%, P<0.001) and EFS (47.1 vs 6.7%, P<0.001) compared to TKI treatment alone. Hemoglobin <100u2009g/L, non-return to chronic phase after TKI therapy and TKI treatment alone are independent adverse predictors of OS and EFS. Allo-HSCT with individualized intervention after TKI therapy is superior to TKI alone for CML-BC.

The inferiority of G-PB to rhG-CSF-mobilized blood and marrow grafts as a stem cell source in patients with high-risk acute leukemia who underwent unmanipulated HLA-mismatched/haploidentical transplantation: a comparative analysis

The purpose of this study was to investigate the efficacy and feasibility of unmanipulated haploidentical PBSCT for the treatment of acute leukemia (AL). This study compares the clinical outcomes of high-risk AL patients who received PBSCs harvested from family members sharing at least one common haplotype to outcomes of high-risk AL patients who received a mixture of G-CSF-primed BM (G-BM) and peripheral blood (G-PB) harvests. The results show that PBSCT achieved inferior cumulative myeloid engraftment at 30 days after transplant (89.9±10.1% vs 100%; P=0.04), with lower cumulative incidence of grade II–IV acute GVHD (aGVHD) (37.1±16.5% vs 63.2±6%; P=0.058) compared with G-BM/G-PB transplant. However, both transplant protocols had similar rates of 2-year relapse (29.6±17.1% vs 34.0±5.7%; P=0.954), and PBSCT produced a higher incidence of 2-year non-leukemic mortality (62.5±14.8% vs 35.1±5.1%; P=0.014), as well as lower rates of overall (26.8±12.3% vs 43.2±5.0%; P=0.052) and disease-free survival (26.8±12.3% vs 42.4±5.0%; P=0.071) compared with G-BM/G-PB transplant. These results suggest that haploidentical HSCT is an option for patients with AL who urgently need a graft and do not have matched sibling donors. PBSCT is potentially inferior to G-BM/G-PB transplant, and improvements should be made before PBSCT becomes a routine in unmanipulated mismatched/haploidentical transplant settings.

HLA-mismatched hematopoietic SCT without in vitro T-cell depletion for myelodysplastic syndrome.

Allogeneic hematopoietic SCT (HSCT) is currently the only curative treatment for myelodysplastic syndrome (MDS). However, many patients cannot find an HLA-matched donor. We have developed a new protocol for HLA-mismatched (including haploidentical) HSCT using G-CSF-primed BM plus G-CSF-mobilized PBSCs without in vitro T-cell depletion. A total of 36 patients diagnosed with high-risk MDS (RAEB (refractory anemia with excess blasts) or RAEBt (RAEB in transformation)) underwent transplantation from HLA-mismatched family donors. All patients achieved sustained myeloid engraftment. The cumulative incidence of grades II–IV acute GVHD (aGVHD) was 60% and that of grades III and IV aGVHD was 15%. The 2-year cumulative incidence of chronic GVHD was 56%. After a median follow-up of 17 months, 4 patients had relapsed and died and 25 patients were still alive. The 2-year probability of leukemia-free survival (LFS) was 65%. Patients transplanted within 7 months of diagnosis had better LFS (89 vs 43% ). Severe aGVHD decreased the LFS significantly by increasing non-relapse mortality (NRM). This study confirms that HLA-mismatched HSCT is a treatment option for MDS. Patients with high-risk MDS benefit from receiving HSCT early in the course of the disease.

Long-term outcomes of unmanipulated haploidentical HSCT for paediatric patients with acute leukaemia.

Allogeneic hematopoietic SCT is indicated for children whose disease demonstrates dismal prognosis with chemotherapy. This study aims to analyse the most recent outcomes of unmanipulated haploidentical (HID) HSCT for paediatric patients with acute leukaemia. Those from matched sibling donors (MSD) HSCT provided a parallel cohort to illustrate the benefits of HID. Conditioning regimen was modified BuCy2. Anti-thymoglobulin was used for HID. Mobilised marrow and blood stem cells were used as the grafts. All patients in HID achieved neutrophil recovery and 96.7% platelet recovery. In HID, the incidences of acute GVHD 3–4 and extensive chronic GVHD were 14.3 and 26.6%. Play-performance score 90–100% was recorded in 79.7% of all survivors. The 5-year leukaemia-free survival (LFS) in CR1, CR2, beyond CR2 or non-remission were 68.9%, 56.6%, 22.2% and 82.5%, 59.4%, 42.9% for ALL and AML, respectively. In MSD group, LFS for ALL and AML in CR1 were 62.5 and 71.7%. Outcomes of the HID HSCT for paediatric patients with acute leukaemia showed benefits that were similar to those of the parallel cohort of MSD HSCT.