Dao-Pei Lu

Treatment of Acute Leukemia with Unmanipulated HLA-Mismatched/Haploidentical Blood and Bone Marrow Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the best therapeutic options to cure acute leukemia (AL). However, many patients have no human leukocyte antigen (HLA)-matched donor. Recently, we developed a new method for HLA-mismatched/haploidentical transplantation without in vitro T cell depletion (TCD). This method combined granulocyte-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood with intensive immunosuppression. We analyzed the outcome of 250 consecutive patients with AL who underwent HLA-mismatched/haploidentical transplantation with 1-3 mismatched loci of HLA-A, B, and DR from family donors via our new transplant protocol. Two hundred forty-nine patients achieved sustained, full donor chimerism. The incidence of grade 2-4 acute graft-versus-host disease (aGVHD) was 45.8%, and that of grades 3 and 4 was 13.4%, which was not associated with the extent of HLA disparity. The cumulative incidence of total chronic GVHD (cGVHD) was 53.9% and that of extensive cGVHD was 22.6% in 217 evaluable patients. One hundred forty-one of the 250 patients survived free of disease recurrence at a median of 1092 days (range: 442-2437 days) of follow-up. Seventeen patients received DLI as a treatment for relapse after transplantation and 7 patients achieved leukemia-free survival (LFS). The 3-year probability of LFS for acute myelogenous leukemia (AML) was 70.7% and 55.9%, and for acute lymphoblastic leukemia (ALL) it was 59.7% and 24.8% in standard-risk and high-risk groups, respectively. Lower LFS were associated with diagnosis of acute leukemia in the high-risk group (P= .001, relative risk [RR], 95% confidence interval [CI]: 2.94[1.535-5.631]) and the occurrence of aGVHD of grades 3 and 4 (P= .004). HLA-mismatched/haploidentical HSCT was feasible with unmanipulated blood and bone marrow harvest.

Autologous Peripheral Blood Stem Cell Transplantation for Severe Multiple Sclerosis

We describe the results of a clinical trial to evaluate the feasibility and toxicity of autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with progressive multiple sclerosis (MS). Fifteen patients (all patients with secondary progressive MS) were enrolled. The median expanded disability status scale (EDSS) score at baseline was 6.0 (range, 4.5–7.5). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. In 9 patients, CD34+ cell selection was performed with a CliniMACS cell selection system, and 6 patients accepted infusion of unmodified peripheral blood stem cells. The modified BEAM (carmustine, teniposide, cytarabine, and melphalan) was the sole conditioning regimen used. The adverse effects included infections, mucositis, transient hepatotoxicity, and diarrhea. Three patients had flares of neurologic deterioration during mobilization, 8 patients had the same manifestation during transplantation, and 2 patients had similar flares within 3 months of transplantation. Six patients experienced continuous neurologic improvement after transplantation, 5 patients experienced neurologic progression, and 4 patients had stabilization of their disease. The confirmed progression-free rate was 63.8% at 49 months. The results of lymphocyte purging were no better than for no purging. Auto-HSCT proved to be safe and beneficial for some MS patients. Further studies are needed to establish the merit of this procedure for MS patients.

Adoptive transfer of cytomegalovirus/Epstein-Barr virus-specific immune effector cells for therapeutic and preventive/preemptive treatment of pediatric allogeneic cell transplant recipients.

This report describes a safe and effective therapy through adoptive transfer of donor cytomegalovirus (CMV)/Epstein-Barr virus (EBV) immune effector cells. The patients, from 3 to 10 years of age, suffering from hematologic diseases received haploidentical transplantation. All 3 patients developed varying levels of viremia from days 13 to 31 and 2 patients developed CMV-interstitial pneumonitis or interstitial inflammation after transplantation. Tapering down the dose of immunosuppressives together with intensive antivirus therapy and escalated infusions of donor-derived CMV/EBV immune effector cells effectively controlled virus-related diseases. All 3 patients survived and remained CMV/EBV-free 14-16 months after transplantation.

Prophylactic infusion of donor granulocyte colony stimulating factor mobilized peripheral blood progenitor cells after allogeneic hematological stem cell transplantation in patients with high-risk leukemia

Prophylactic infusion of donor granulocyte colony stimulating factor mobilized peripheral blood progenitor cells after allogeneic hematological stem cell transplantation in patients with high-risk leukemia

Surveillance of Active Human Herpesvirus 6 Infection in Chinese Patients after Hematopoietic Stem Cell Transplantation with 3 Different Methods

Human herpesvirus 6 (HHV-6) reactivation was studied in 72 consecutive allogeneic hematopoietic stem cell transplant (HSCT) recipients and 53 “healthy” donors. The feasibilities of real-time quantitative polymerase chain reaction (RQ-PCR), nested-PCR, and antigenemia assays in the assessment of HHV-6 reactivation were also evaluated. HHV-6 DNA was detected in 62.5% and 48.6% of post-HSCT patients with the nested-PCR assay and RQ-PCR analysis, respectively, and HHV-6B was identified as the predominant variant. The incidence of HHV-6 infection peaked from the second to the seventh week, whereas the HHV-6B DNA loads peaked from the second to the third week. Compared with RQ-PCR analysis, the sensitivity and specificity of the nested-PCR assay were 100% and 88%, respectively, with positive and negative predictive values of 60% and 99%, respectively. For the HHV-6 antigenemia assay, the sensitivity and specificity were 89% and 97%, respectively, and the positive and negative predictive values were both 94%. Conditioning with antithymocyte globulin in HLA-mismatched or unrelated HSCT increased the possibility of HHV-6B reactivation after HSCT (hazard ratio, 5.92; 95% confidence interval, 1.99-17.59; P = .001). In conclusion, HHV-6B reactivation is commonly encountered after HSCT. Of the 3 methods we adopted for HHV-6 detection, both RQ-PCR analysis and the antigenemia assay could be seen as essential tests for predicting HHV-6 reactivation.

Risk Factors for Graft-Versus-Host Disease After Transplantation of Hematopoietic Stem Cells from Unrelated Donors in the China Marrow Donor Program

Background We identified risk factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) in recipients after hematopoietic stem cell transplantation (HSCT) from unrelated donors in the China Marrow Donor Program (CMDP). Material/Methods We analyzed follow-up clinical information from 1824 patients who underwent HSCT between 2001 and 2010. Results The incidence of aGVHD and cGVHD after transplantation was 49.29% and 27.3%, respectively. aGVHD incidence decreased as HLA matching increased (p<0.001). Incidence of aGVHD and cGVHD was higher in 2 HLA-A locus donor/recipient groups (02: 01/02: 06 and 02: 01/02: 07; p≤0.022). aGVHD incidence was associated with patient age, absence of rabbit anti-thymocyte globulin (ATG) pretreatment, and disease status (p≤0.040). aGVHD appeared to be a risk factor for cGVHD, and total body irradiation (TBI) was also associated with cGVHD. Patients with cGVHD after transplantation had a higher survival rate than patients without cGVHD (p<0.001), which may be due to reduced relapse rates. Survival was also associated with ATG prophylaxis and disease status. Conclusions The incidence of GVHD after HSCT from unrelated donors in the Chinese population is similar to the results reported from other countries. A high degree of HLA matching, a conditioning regimen without TBI, and the use of ATG may reduce the incidence of aGVHD.

Sequential allogeneic and autologous CAR-T–cell therapy to treat an immune-compromised leukemic patient

Key Points CAR-T–cell therapy normally requires the patient’s own healthy T cells. An allogeneic CAR-T bridging therapy could rescue lymphopenic patients.

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Achieved Outcomes Comparable with Matched Unrelated Donor Transplantation in Young Acquired Severe Aplastic Anemia

Salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered in patients with severe aplastic anemia (SAA) if a matched unrelated donor (MUD) is unavailable. However, studies on haplo- and MUD transplantation in SAA are lacking. The present study retrospectively analyzed the outcomes of 89 young SAA patients who underwent unmanipulated alternative HSCT between September 2012 and September 2016 at our single center. Forty-one patients received haploidentical donors and forty-eight patients MUDs for HSCT. Most were heavily transfused and refractory to previous immunotherapy. The median durations for myeloid engraftment in the haplo- and MUD cohorts were 14 (range, 10 to 21) and 13 (range, 10 to 18) days, respectively. Compared with the MUD cohort, haplo-HSCT cohorts had an increased cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV (43.9% ± 7.8% versus 12.5% ± 4.8%, P = .001) and grades III to IV (21.1% ± 6.7% versus 6.6% ± 3.7%, P = .045) and similar limited chronic GVHD (47.7% ± 8.5% versus 38.5% ± 7.3%, P = .129) and extensive chronic GVHD (12.1% ± 6.8% versus 9.1% ± 4.3%, P = .198). The median follow-up time of the surviving patients was 26 months (range, 6 to 45). No significant differences were observed between haplo-HSCT and MUD HSCT cohorts in 3-year overall survival (80.3% ± 5.1% versus 89.6% ± 7.0%, P = .210), disease-free survival (76.4% ± 5.1% versus 89.4% ± 7.7%, P = .127), and GVHD-free failure-free survival (79.0% ± 8.6% versus 71.6% ± 9.3%, P = .976). Thus, haplo-HSCT, as salvage therapy, achieved similar outcomes as MUD HSCT in young SAA patients, thereby rendering it as an effective and safe option for SAA.

195. Allogeneic CD19-CART Therapy to the Rescue of a Pediatric Patient with Relapsed and Refractory Acute B Lymphoblastic Leukemia

Acute B lymphoblastic leukemia (B-ALL) is a common hematological malignancy in children. Using a fourth generation, safety-switch inserted, chimeric antigen receptor (4SCAR) technology, we have treated more than 200 patients with B-ALL in China, with an overall complete remission rate of more than 80% (ASH 2015). Here we report the case of a 7-year-old girl with a high load of refractory B-ALL, who was heavily pretreated with chemotherapy but relapsed with >80 leukemic blasts in her bone marrow. The patient received CD19-4SCAR T cells generated from her mothers peripheral blood T cells (allo-4SCAR19) for three times at total of 0.76 x106 CART/kg on day 0, 4, and 7, followed by an infusion of autologous 4SCAR19 (auto-4SCAR19) at total of 0.16 x106 CART/kg on day 56, which was derived from the patients own T cells after her immune recovery. Complete remission was achieved as revealed by bone marrow examination on day 77. Graft versus host disease signs were not observed throughout the days following the infusions, and the syndrome of suspected cytokine storm was generally mild. The only adverse responses were intermittent fever and skin rashes following allo-4SCAR19 infusions which lasted for about 20 days. The outcome of this case suggests that allo-4SCAR19 may be a safe approach in treating B-ALL patients who could not provide their own T cells for CART engineering, and allo-4SCAR19 combined with auto-4SCAR19 is a novel strategy that may rescue chemo-refractory, high-risk and highly immune suppressed leukemia patients.