Donor-derived CD 19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD 19-positive B-ALL after Allogeneic Hematopoietic Stem Cell Transplantation

Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant

Background In haploidentical hematopoietic stem cell transplantation （HSCT）, the duration of graft-versus-host disease （GVHD） prophylaxis after modified donor lymphocyte infusion （DLI） was the only risk factor of DLI-associated grades 3-4 acute GVHD. However, the successful application of modified DLI depended not only on the reduction of severe GVHD, but also on the preservation of graft-versus-leukemia （GVL） effect. Therefore, this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for 〈6 weeks on GVL effect after modified DLI in haploidentical HSCT. Methods A total of 103 consecutive patients developing hematological relapse or minimal residual disease （MRD）-positive status after haploidentical HSCT and receiving modified DLI were investigated retrospectively. Fifty-two patients received prophylaxis for 6-8 weeks after modified DLI; the remaining 51 patients received prophylaxis for 〈6 weeks. Results First, compared with prophylaxis for 〈6 weeks, prophylaxis for 6-8 weeks reduced incidence of relapse in total patients （26.6% vs. 69.0%, P 〈0.001）. Besides, prophylaxis for 6-8 weeks also reduced incidence of relapse in 54 patients developing hematological relapse post-transplant （P=0.018） and in 49 patients developing MRD-positive status post-transplant （P 〈0.001）. Second, prophylaxis for 6-8 weeks reduced incidence of acute GVHD （P 〈0.05）, reduced the therapeutic application of immunosuppressive agents （P=0.019）, but increased the incidence of chronic GVHD （P〈0.05）. Third, prophylaxis for 6-8 weeks improved overall survival and disease-free survival in total patients, as well as in patients developing hematological relapse post-transplant and in patients developing MRD-positive status post-transplant （P 〈0.05）. Conclusions In haploidentical HSCT, prophylaxis for 6-8 weeks after modified DLI does not reduce GVL effect, but reduces the incidence of DLI-associated acute GVHD compared with prophylaxis for 〈6 weeks. This strategy will probably improve the safety and efficacy of modified DLI further.

Interferon a： the salvage therapy for patients with unsatisfactory response to minimal residual disease-directed modified donor lymphocyte infusion

Background Minimal residual disease （MRD）-directedmodified donor lymphocyte infusion （mDLI） is used to treat relapse after hematopoietic stem cell transplantation （HSCT）. For patients who experience an unsatisfactory response tomDLI relapse is usually inevitable. Therefore we sought to evaluate the efficacy ofinterferon a therapy in these patients. Methods Regular MRD monitoring was carried out after the HSCT. The patients who were MRD-positive underwent mDLI. Patients with an unsatisfactory response to mDLI received interferon a therapy （3 million units, twice weekly） with regular monitoring of MRD. To ensure the immunomodulatory effects of interferon a, immunosuppressant treatment would be stopped before interferon a treatment. Results Five patients with an unsatisfactory response to mDLI treatment received interferon a （3 had t（8;21） chromosomal translocation acute myeloid leukemia, and 2 had common acute leukemia）. They had significantly reduced or resolved MRD. Four patients developed chronic graft-versus-host disease. Two of the 5 patients reported transient fevers, and no significant bone marrow suppression was observed. All of them were in continuous complete remission after interferon a treatment. The median survival time was 469 days （range 368-948 days）. Conclusions In patients with an unsatisfactory response to MRD-directed mDLI, interferon a may directly or indirectly induce the graft-versus-leukemia effect to improve mDLI efficacy and clear MRD. Chin Med J 2014;127 （14）： 2583-2587

Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia:a real-world study

Prophylactic/preemptive donor lymphocyte infusion(p/pDLI)and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia(RRAL),but real-world data remain scarce.We conducted a multicenter,population-based analysis of 932 consecutive patients.The three-year leukemia-free survival(LFS)rates were 56%for patients receiving both p/pDLI and intensified myeloablative conditioning(MAC)(intenseMAC)and 30%for those who received neither therapy per landmark analysis.Multivariable analyses were run separately for acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL),and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality.IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL,while there was no impact of intenseMAC observed in AML.p/pDLI achieved superior outcomes in both matched-sibling donor(MSD)and haploidentical donor transplantation,while intenseMAC only influenced MSD outcomes.Data suggest that RRAL patients receiving“total therapy”by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS,with p/pDLI being safer with a more extensive impact relative to intenseMAC.Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.

Second unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia post-chemotherapy plus modified donor lymphocyte infusion

Relapse is the main problem after allogeneic hematopoietic stem cell transplantation(allo-HSCT).The outcome of a second allo-HSCT(HSCT2)for relapse post-HSCT has shown promising results in some previous studies.However,little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia(AL)post-chemotherapy plus modified donor lymphocyte infusion(post-Chemo+m-DLI)after the first allo-HSCT(HSCT1).Therefore,we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo+m-DLI in our center.With a median follow-up of 918(457–1732)days,26 patients(92.9%)achieved complete remission,and 2 patients exhibited persistent disease.The probabilities of overall survival(OS)and disease-free survival(DFS)1 year after HSCT2 were 25.0%and 21.4%,respectively.The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1%±4.9%and 25.0%±8.4%.The cumulative incidences of relapse were 50.0%±9.8%and 53.5%±9.9%at 1 and 2 years post-HSCT2,respectively.Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2,and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2.Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo+m-DLI.

Treatments of disease relapse after allogeneic stem cell transplantation focusing on donor lymphocyte infusion

Hematopoietic stem cell transplantation （SCT） is a potentially curative treatment for patients with hematologic malignancies, such as acute myeloid leukemia （AML） and myelodysplastic syndromes （MDS）. There has been tremendous progress in the past several decades in allogeneic SCT with better outcomes through improvements in supportive care, expansion of stem cell donor options （HLA-matched unrelated donors （MUD）, haploidentical related donors, and cord blood units （CBUs） etc.）, and introduction of better tolerated reduced intensity conditioning （RIC） regimens.

Anti-T-lymphocyte globulin-based non-myeloablative stem cell transplantation followed by HLA-identical donor lymphocyte infusion for hematologic malignancies

Objective To evaluate the application of anti-T-lymphocyte globulin (ATG) based nonmyeloablative but profoundly immunosuppressive regimens followed by donor lymphocyte infusion (DLI) for the treatment of hematologic malignancies.Methods The protocol was designed to minimize the intensity of the conditioning regimen to the range of nonmyeloablative therapies based on ATG with low-dose busulfan (Bu) and Cytoxan (CTX) (15-19.5 mg/kg, 8 mg/kg and 80 mg/kg, respectively). The patients received the first lymphocytic infusion from HLA-identical sibling donors on days 28-30 after transplant, and the first T cell dosage of 10 6/kg followed by the escalated dosage in the range of (0.5-1.5)×10 8/kg. The total number of procedures were performed at a median of 4.2 procedures (range of 2-8 procedures).Results Engraftment was documented in all six patients in the form of donor-recipient hematopoietic cells mixed chimera at early-stage posttransplant, which was converted gradually into complet chimera by DLI in four patients. Graft-versus-host disease (GVHD) developed in three of six cases, only one of which was severe. To date,four patients are disease free and alive.Conclusions Allogeneic donor stem cell engraftment into host can be achieved by nonmyeloablative conditioning regimen based on ATG. Transient mixed donor-recipient hematopoietic cell mixed with chimeras may be successfully converted into complete chimerism by DLI posttransplant. GVHD remains major clinical concern in our study.

Infusions of recipient-derived cytokine-induced killer cells of donor origin eradicated residual disease in a relapsed leukemia patient after allo-hematopoietic stem cell transplantation

A female patient diagnosed with acute myelocytic leukemia M5a （AML-M5a） relapsed 986 days after her allogeneic peripheral blood stem cell transplantation （alIo-PBSCT） from an unrelated male donor with matched human leukocyte antigen （HLA）. Three re-induction chemotherapies were administered, and partial remission was achieved. The patient was given repetitive infusion of cytokine-induced killer （CIK） cells expanded from recipient peripheral mononuclear cells of full donor chimerism due to loss of contact of quondam donor for donor lymphocyte infusion （DLI） and rejection of second transplantation. The patient achieved complete cytogenetical remission. This strategy might overcome the obstacle of donor unavailability and present an appealing new therapeutic alternative to donor-recruited adoptive immunotherapy for relapsed disease at post-transplantation.