HLA-partially matched cellular therapy (stem-cell microtransplantation) for acute myeloid leukaemia: description of four cases

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Donor leucocyte infusions (DLI) after conventional chemotherapy have been proposed as a treatment for acute myeloid leukaemia (AML). This procedure has been successfully employed in AML elderly patients (Guo et al, 2011; Cignetti et al, 2013), low and intermediate-risk AML as post-remission therapy (Guo et al, 2012) and myelodysplastic syndromes (MDS) (Ai et al, 2012). In our centre, using a similar approach, we have performed nine human leucocyte antigen (HLA)-partially matched donor leucocyte infusions (PM-DLI) in four elderly patients, three of which were HLA-haploidentical (Table 1). 1- Ida + Ara-C 2- Ara-C Alive 12+ months Early relapse Alive 11+ months CR Alive 8+ months CR Alive 7+ months CR After obtaining institutional ethics approval, one or two apheresis of related donor peripheral mononuclear cells were collected after granulocyte colony-stimulating factor (filgrastim) mobilization. The procedure was employed as post-remission therapy in three cases (2 de novo intermediate-risk AML and 1 post-essential thrombocythaemia JAK2-positive AML with high risk cytogenetics); all of them received 2 cytarabine cycles (1 g/m2/12 h intravenously days +1, +3 and +5) following PM-DLI at day +7. The remaining patient, with AML secondary to MDS (refractory cytopenia with multilineage dysplasia), received one PM-DLI after the induction course (5-azacitidine 100 mg/m2/d subcutaneously for 5 d following cytarabine 100 mg/m2/d for 7 d plus idarubicin 12 mg/m2/d for 3 d) with prolonged cytopenias and circulating blasts. Subsequently, he received two more courses of 5-azacitidine (100 mg/m2/d for 5 d) following PM-DLI, achieving complete remission after the first course. The median numbers of mononuclear, CD34+ and CD3+ cells infused per course were 3·57 × 108/kg (range 1·7–5·43 × 108/kg), 3·19 × 106/kg (range 1·05–6·58 × 106/kg) and 1·42 × 108/kg (range 0·35–2·42 × 108/kg ), respectively. The procedure was well tolerated in three patients, only transient fever without documented infection was observed. Patient 3 presented fever with central venous catheter infection during induction therapy, minimal skin rash and transient increase in liver function tests. During the subsequent PM-DLI this patient suffered from early infusional reaction that resolved with support treatment. None of the patients have shown acute or chronic graft-versus-host disease (GVHD) or donor engraftment in chimerism tests. Currently all four of these patients are alive: three in complete remission (CR) with no flow cytometry minimal residual disease (MRD) and one in early relapse (MRD 3% blasts). Several forms of cellular therapy for AML patients have been developed (Reagan et al, 2012). In agreement with previous reports (Guo et al, 2011, 2012), we found PM-DLI (also called microtransplantation) a safe, well tolerated and inexpensive therapy for AML elderly patients. We detected no engraftment, GVHD, significant infections or relevant adverse effects, despite the high dose of CD3+ lymphocytes infused (total >1 × 108/kg). We did not observe a shortened period of post-chemotherapy cytopenia following infusion, in contrast with previous reports (Guo et al, 2011). PM-DLI post-chemotherapy in AML can be used in the induction course or as post-remission therapy. Surprisingly, patient 3 achieved CR after the second infusion (post-azacitidine). Although the exact mechanism of PM-DLI response remains unclear, a host-versus-tumour effect induced by graft-rejection was suggested (Reagan et al, 2012). In the four cases reported here, killer-cell inhibitory receptor (KIR)-ligand disparity between donor and recipient varied greatly (Table 1), which argues against a key role of natural killer (NK)-cell alloreactivity in the outcome of this therapy. Despite these encouraging results, longer follow-up and larger patients cohorts are necessary to assess the efficacy of this procedure. R. Forés, M. Piris and J. R. Cabrera participated in the conception and design of the work; C. Vilches and R. de Pablo performed HLA-typing; J. A. García-Marco performed chimerism and molecular studies; C. Regidor and R. Forés performed donor cell processing and flow cytometry studies; A. de Laiglesia, A. Lario, N. Dorado and R. Forés were responsible for clinical work; N. Dorado analysed the data and wrote the first draft and all the authors contributed to it. The authors declare that they have no potential conflict of interests.

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