Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study

T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6–8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3–22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.

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Unrelated Donor Hematopoietic Stem Cell Transplantation for High-Risk Leukemia.

Blood ◽

10.1182/blood.v108.11.5407.5407 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5407-5407

Author(s):

De Pei Wu ◽

Xiaowen Tang ◽

Aining Sun ◽

Zheng-zheng Fu ◽

Huiying Qiu

Keyword(s):

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Mixed Chimerism ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Donor Chimerism

Abstract objective: To investigate the efficacy of unrelated donor hematopoietic stem cell transplantation(URD-HSCT) for high-risk leukemia. Methods: From 2001 to March, 2006, 24 patients of high-risk leukemia underwent HSCT with unrelated donor. Patients between 6 and 49 years of age(median age 21.5 years) There were 16 unrelated donor’s grafts came from Buddhist Tzu Chi Stem Cells center in Taiwan, and 8 unrelated grafts came from Red Cross Society of China Hematopoietic Stem Cell Marrow Donor Program Administration Center. Fifteen patients received bone marrow transplantation and another 9 patients received peripheral blood stem cell transplantation. Eighteen patients were fully matched with their donors for HLA loci A and B as well as for HLA-DRB1. Four of 24 patients had 1 molecular loci mismatch and 2 of 24 patients had 2 molecular locus mismatch. The conditioning regimen consisted of modified BU/CY or modified total body irradiation(TBI) plus CY. Eleven patients received cyclosporine (CSA), short-term methotrexate(MTX) and mycophenolate mofetil (MMF) as the regimen of prophylaxis of GVHD. Ten patients received CSA, MTX and MMF plus ATG/ALG for GVHD prophylaxis. The combination of CSA, MTX, MMF,ATG/ALG and CD25 monoclonal antibody for preventing GVHD in 3 patients. Results: The incidence and severity of regimen-related toxicity were mild. The median number of MNC and CD34 positive cell was 4.18×108/kg and 7.75×106/kg respectively. The median time of the engraftment of neutrophil and platelet was 13 days and 19 days posttransplant respectively. The incidence of infection posttransplant was 70%(17/24). The complicated pneumonitis occurred frequently (13/17, 76%), The incidence of grade I-II and grade III-IV acute GVHD was 33% and 41% respectively. Limited chronic GVHD occurred in 25% patients and extensive cGVHD presented in 31% patients. Median follow up was 16 (range 1~57) months after transplantation. 75% patients achieved full donor chimerism(FDC) detected by STR-PCR and FISH. While 25% patients presented mixed chimerism(MC) and 2 of them converted to unstable MC. Decreasing values of donor chimerism were detected prior to the relapse of disease. Furthermore the treatment related mortality(TRM) was 33%(8/24), The incidence of relapse was 8%. Until now 14 patients are still alive. The median overall survival time were 26 months and 5-years expected survival was 47.7%. Conclusion: URD-HSCT can be an effective and curable approach for leukemia with higher incidence of GVHD and infection. The treatment for the severe and deadly GVHD and pulmonary infection are still major problems need to be resolved in the future.

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Donor Chimerism Is a Key Predictor of Graft Failure and the Response of Adoptive Immunotherapy Following Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.4939.4939 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4939-4939

Author(s):

Xiaowen Tang ◽

Qiurong Zhang ◽

Yufeng Feng ◽

Ziling Zhu ◽

Yaojun Liu ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Adoptive Immunotherapy ◽

Graft Rejection ◽

Graft Failure ◽

Mixed Chimerism ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Quantitative Monitoring

Abstract Objective: In order to evaluate the usefulness of chimerism quantitative monitoring for the early diagnosis of graft failure in different allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) settings, as well as to predict the response to treatment with adoptive immunotherapy. Methods 235 patients who received allo-HSCT were evaluated. Serial and quantitative analysis of donor chimerism (DC)both prior to and following allo-HSCT or/and adoptive immunotherapy(AIT) were performed by STR-PCR. Samples obtained on days +7, +14, +21, + 28, +60, +90, +180, +270, +360 of transplantation or AIT and once a year thereafter, included bone marrow (BM) and peripheral blood (PB).Furthermore, chimerism was analyzed in T lymphocytes, CD3+ isolated by immunomagnetic means for 28 patients. 12 patients who experienced graft rejection or delayed engraftment received adoptive immunotherapy including immunosuppression withdrawal and/or donor lymphocyte infusions (DLI). Results Ten of 235 patients appeared graft failure(3 patients with initial en graft ment failure, 7 patients with graft rejection) and 2 patients presented delayed engraftment (4 ablative sibling BMT, 4 RIC-HSCT, 2 URD-PBSCT, 1 URD-CBT, 1 haploidentical-HSCT). Median age was 31.5 years(range:8–55). Donor chimerism remained low level(DC< 40%) during all the process of transplantation for three patients of graft failure(GF). One of them died for pancytopenia and other 2 patients restored autologous hematopoiesis. In addition, after initial engraftment(full donor chimerism or stable mixed chimerism were achieved at the beginning in these patients), graft rejection(GR) was diagnosed in 7 patients. Relapse was excluded by means of bone marrow smear, cytogenetics, molecular biology and minimal residual disease(MRD). Unfractionated chimerism of whole blood or bone marrow declined progressively at the median time of 3 months post transplantation. In 3/7 patients studied, T cells showed persistent MC with high %R(>60% in 2/7 and >82% in 1/7)).All these 10 patients with GF or GR received G-CSF. Meanwhile 8 of 10 patients accepted mobilized PBSC or donor lymphocyte infusion. A response to immunotherapy was achieved in 3 patients. One of them presented III° GVHD and chimerism converted to stable full donor chimerism(FDC) shortly after immunotherapy. DC of 2 patients who response to AIT converted to stable mixed chimerism(MC). While in the 5 patients without response, the level of DC decreased persistently. Furthermore, two patients received unrelated-PBSCT presented delay engraftment. Unfractionated chimerism inferior to 85% and converted to FDC following withdrawal of mycophenolate mofetil (MMF) and Cyclosporin A. Conclusion The results demonstrate that the decreasing value of DC (especially T cell chimerism) can identify the patients who have high risk of graft failure and can be used to guide adoptive immunotherapy intervention at early stage (including G-CSF and AIT).Sometimes, unfractionated chimerism or T cell chimerism is the only parameter to predict graft failure for the patient without specific tumor markers. As well as the sequential and quantitative monitoring of DC has been shown to be a valuable tool to early evaluate the efficacy of AIT. Furthermore, AIT is an effective treatment to prevent GR and to maintain full donor chimerism. Response of early AIT is superior to that of delay intervention therapy.

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