Correspondence
HLA-partially matched cellular therapy (stem-cell microtransplantation) for acute myeloid leukaemia: description of four cases
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 I). 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 357 9 108/kg (range 17– 543 9 108/kg), 319 9 106/kg (range 105–658 9 106/kg) and 142 9 108/kg (range 035–242 9 108/kg ), respectively.
Table I. Patient characteristics. Patient 1
Patient 2
Patient 3
Patient 4
Age (years) Diagnosis Cytogenetics Previous chemotherapy
65 De novo AML 46 XY 5-Aza + Ida + Ara-C
64 De novo AML 46 XY Ida + Ara-C
72 AML secondary to MDS 46 XY No
PM-DLI cycles (n) Total MNC (9 108/kg) Total CD3+ (9 108/kg) Total CD34+ (9 106/kg) Total CD3-/CD56+ (9 108/kg) Recipient HLA type†
2 705 259 977 031 A*02,*31 B*51,*58K C*02, *07 DRB1*01,*04 A*02,*68 B*14,*35 C*04, *08 DRB1*01,*04 Recipient versus Donor
2 452 272 530 015 A*02,*30 B*35,*13K C*04,*06 DRB1*01,*16 A*02,*11K B*35 C*04 DRB1*01,*04 Recipient versus Donor + Donor versus Recipient None Alive 11+ months CR
3 107 347 700 015 A*02,*11K B*39,*55 C*07,*03 DRB1*08,*14 A*02,*30 B*39,*38K C*07,*12 DRB1*08,*13 Recipient versus Donor + Donor versus Recipient None Alive 8+ months CR
65 AML secondary to ET 46 XY, +11 1- Ida + Ara-C 2- Ara-C 2 845 302 878 – A*11,*29 B*35,*14 C*04,*08 DRB1*13,*03 A*11,*31 B*35,*07 C*04,*07 DRB1*13,*04 None
Donor HLA type† Expected NK-cell alloreactivity Donor engraftment Follow-up
None Alive 12+ months Early relapse
None Alive 7+ months CR
AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome; ET, essential thrombocythaemia; PM-DLI, partially matched donor leucocyte infusion; MNC, mononuclear cells; HLA, human leucocyte antigen; NK, Natural killer; CR, complete remission; 5-Aza, azacitidine; Ida, idarubicin; Ara-C, cytarabine. †HLA alleles encoding ligands for KIR are marked with K when present in the recipient, but not in the donor, or vice versa. In addition, HLA mismatches potentially targeted by T lymphocytes of donor and recipient are underlined, regardless of whether they derive from incompatibilities at broad, split or allele (as in DRB1 of Patient 1) levels.
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Correspondence 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 9 108/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 I), 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.
References Ai, H., Hu, K, Sun, Q., Li, X., Guo, M., Yu, C., Qiao, J., Qiao, J., Liu, G., Dong, Z. & Qiao, Z. (2012) Microtransplantation with decitabine and cytarabine improves patient outcomes in myelodysplastic syndromes. Blood (ASH Annual Meeting Abstracts), 120, 1709. Cignetti, A., Ruella, M., Elia, A.R., Tassi, V., Redoglia, V., Gottardi, D. & Tarella, C. (2013) Haploidentical cellular therapy in elderly patients with acute myeloid leukemia: description of his
Author contributions R. Fores, 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. Garcıa-Marco performed chimerism and molecular studies; C. Regidor and R. Fores performed donor cell processing and flow cytometry studies; A. de Laiglesia, A. Lario, N. Dorado and R. Fores were responsible for clinical work; N. Dorado analysed the data and wrote the first draft and all the authors contributed to it.
Financial disclosure The authors declare that they have no potential conflict of interests. Rafael Fores1 Nieves Dorado1 Carlos Vilches2 Carmen Regidor1 Jose A. Garcıa-Marco1 Rosario de Pablo2 Almudena de Laiglesia1 Ana Lario1 Miguel Piris1 J. Rafael Cabrera1 1
Department of Haematology, Hospital Universitario Puerta de Hierro,
and 2Immunogenetics-HLA Laboratory, Department of Immunology, Hospital Universitario Puerta de Hierro, Majadahonda, Comunidad de Madrid, Spain. E-mail:
[email protected]
Keywords: acute myeloid leukaemia, immunotherapy, stem cell transplantation, cellular therapies First published online 20 February 2014 doi: 10.1111/bjh.12771
use in high risk patients. American Journal of Hematology, 88, 720–721. Guo, M., Hu, K.X., Yu, C.L., Sun, Q.Y., Qiao, J.H., Wang, D.H., Liu, G.X., Sun, W.J., Wei, L., Sun, X.D., Huang, Y.J., Qiao, J.X., Dong, Z. & Ai, H.S. (2011) Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukaemia in elderly patients. Blood, 117, 936–941. Guo, M., Hu, K.X., Liu, G.X., Yu, C.L., Qiao, J.H., Sun, Q.Y., Qiao, J.X., Dong, Z., Sun, W.J., Sun, X.D., Zuo, H.L., Man, Q.H., Liu, Z.Q., Liu,
ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 165, 573–581
T.Q., Zhao, H.X., Huang, Y.J., Wei, L., Liu, B., Wang, J., Shen, X.L. & Ai, H.S. (2012) HLAmismatched stem-cell microtransplantation as posremission therapy for acute myeloid leukemia: long-term follow-up. Journal of Clinical Oncology, 30, 4084–4090. Reagan, J.L., Fast, L.D., Safran, H., Nevola, M., Winer, E.S., Castillo, J.J., Butera, J.N., Quesenberry, M.I., Young, C.T. & Quesenberry, P.J. (2012) Nonengraftment haploidentical cellular therapy for hematologic malignancies. Advances in Hematology, 2012, 1–6.
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