A Pilot Prospective Single-Arm Clinical Study on Decitabine Plus CAG or IA Followed with HLA-Mismatched Nonmyeloablative Transplantation (micro transplantation) on De Novo Elderly Acute Myeloid Leukemia and Int-2/High Risk Myelodysplastic Syndrome Patients

Objective: To observe the efficacy and safety of Decitabine plus CAG or IA followed with HLA-mismatched nonmyeloablative transplantation (micro transplantation) on de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients

Methods: Till submission of this article, 10 patients were enrolled in this prospective clinical study. Patients were admitted from January 2017 to June 2018 to our centre. 6 of whom were elderly AML (≥60 years) and 4 were Int-2/high risk MDS according to IPSS-R scoring system. Induction chemotherapy were decitabine (15 mg/m2) for 5 days followed with CAG (cytarabine 10 mg/m² q12h; aclarubicin 10 mg/day and G-CSF at 300 μg/day x 6 days for AML and 4 days for MDS), then followed with a transfusion of HLA-mismatched (≤7/10 matched HLA loci) related donor peripheral stem cells (micro transplantation) 24 hours after chemotherapy. Consolidation therapy was another 3 courses of chemotherapies which were decitabine (15 mg/m2) for 5 days with IA (3+7) for AML or CAG (6 days) for MDS, followed by micro transplantation 24 hours after each course. Till now, the total observable treatment courses were 21.

Results: The average age of the patients was 63.5 years (range from 55 to 71 years). The average number of transfusion mononuclear cells (MNC) at per course was 3.26 (1.87-5.25) x 10⁸/kg, the average CD34⁺ cells was 1.12 (0.34-3.16) x 10⁶/kg, and the average of CD3⁺ T cells was 3.93 (1.87-7.17) x 10⁷/kg. Among them, 5 cases (50%) obtained CR (CR+CRi), 3 cases obtained PR (30%). The ORR was 83.3% for elderly AML patients, 75% for MDS patients and 80% for all patients. The median recovery time of neutrophil (from the end of chemo to neutrophil ≥0.5 x 10⁹) was 9 days and was 8.5 days for platelets (from the end of chemo to platelets ≥20 x 10⁹). 1 patient developed severe aGVHD and died, 1 patient died of heart failure, no other serious adverse events were observed in rest patients. 7 of 10 cases developed peripheral T cell increase after stem cell transfusion, including the total CD3⁺ T cells, CD4⁺ and CD8⁺ T cells, with an average peak at day7. The increased T cells were verified as host origin by short tandem repeat (STR) detection performed on 1 patient. 8 of 10 cases occurred cytokine related fever (CRF) after stem cell transfusion. The fever was usually happened within 24 hours after stem cell transfusion, with an average duration of 5 days and a mean peak temperature at 39.7 ℃. With CRF there was an increase of cytokines with different patterns in different patients but majorly on IL-6, IL-2, IFN-r and TNF-a. Also there was an increase of C-Reactive Protein (CRP) which reached an average peak level as 116.9 mg/L. Patients with CRF had a CR+CRi rate at 62.5%.

Conclusion: Our preliminary results of this study indicate that Decitabine plus CAG or IA followed with micro transplantation have an ORR at 80% in de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients with controllable recover time of neutrophils and platelets. Although the incidence of acute graft versus host disease (aGVHD) in micro transplantation was as low as 1-2% according to reports, it is still possible. How to predict and avoid severe aGVHD is still under investigate. The presence of cytokine related fever may associate with the increase of hosts' T cells, which may relate to the improvement of therapeutic response. Larger cohorts and more investigates need to be done to clarify above findings.