Haploidentical cellular therapy in elderly patients with acute myeloid leukemia: Description of its use in high risk patients

Abstract

Guo et al. reported an innovative approach for the treatment of acute myeloid leukemia (AML) in a 2011 issue of Blood 1. The report showed for the first time that the infusion after chemotherapy of peripheral blood stem cells (PBSC) from haploidentical donors significantly improved the outcome in elderly AML patients, without major toxicities. After an initial engraftment, haploidentical donor cells are rejected by the host immune response. Indeed, the precise mechanism of action of this cell-therapy procedure is not fully understood and several mechanisms have been hypothesized to explain its beneficial effects: (i) donor allogeneic Natural killer (NK)- or T-cells might exert a direct cytotoxicity on leukemic cells; (ii) a proinflammatory effect of the allogeneic host–donor interaction might trigger an autologous antitumor immunity; and (iii) cell-therapy might induce modifications in leukemic cells or in stromal/vascular cells that ultimately elicit an autologous immune responses. So far, the data obtained, Guo et al. have not been confirmed by other groups worldwide. We recently treated with this protocol three elderly patients with high-risk AML. Compared to the Chinese experience, the patients were all affected by high-risk AML. As summarized in Table 1, Patient #1 had treatment-related AML following prolonged chemotherapy (six total lines) for ovarian cancer and her blasts had a mixed phenotype with complex karyotype. Patients #2 and #3 had AML with myelodysplasia-related changes, one of them (Patient #2) had received four azacitidine courses, with poor response and worsening of both hematological and clinical conditions. Institutional ethics approval was obtained for the use of this treatment protocol. All three patients received an induction regimen (a “3+7” regimen with mitoxantrone and ara-C) followed by the infusion of Granulocyte colony-stimulating Factor (G-CSF)-mobilized PBSC from haploidentical familial donors, according to the original protocol 1. The potential reactivity of patient T-cells against their haploidentical counterparts was proved in vitro by mixed lymphocyte reaction. This in vitro reactivity resulted in vivo in graft-rejection, with detectable microchimerism in only one patients and absence of acute or chronic Graft versus Host Disease (GVHD) in all patients. As detailed in Table 1, Patient #1 had a partial response, with Bone Marrow (BM) blast reduction from 90 to 45%. She then received an intensified salvage regimen (high-dose ara-C and idarubicin plus cyclosporine to overcome Minimal Residual Disease (MRD) resistance) 2, followed by a second infusion of haploidentical PBSC. After this cycle, she had a complete hematological recovery, and the BM aspirate showed complete remission of disease at flow cytometry. Six weeks later, AML relapsed; the patient was not further treated and died shortly thereafter. Patient #2 and #3 received 1 infusion of haploidentical PBSC after induction chemotherapy. Patient #2 was refractory, he refused further treatment and died few weeks later. Patient #3 achieved Complete Remission (CR); however, she was unable to receive consolidation therapy due to the development of fungal endophthalmitis and chronic sinusitis by Fusarium. She completely recovered within 3 months, with a mild residual chronic renal insufficiency. Despite lack of consolidation therapy, she is still in CR at 11 months of follow up. Our observation in high-risk elderly AML patients confirms that infusion of haploidentical-mobilized PBSC following induction chemotherapy is feasible and safe. Compared to Guo et al. 1, 3, we applied the strategy in AML patients with very unfavorable prognosis, two of them previously treated either with multiple chemotherapy lines or with repeated azacitidine courses. In spite of previous treatments, the haploidentical infusion did not induce acute GVHD. Considering the presenting features, the achievement of CR in two of three patients was encouraging and somehow unexpected, especially for the long-surviving patient who achieved CR after a single course of chemotherapy followed by haploidentical PBSC infusion. Finally, the two patients achieving CR had a leukothrombocytopenia duration shorter than one might have expected, suggesting a possible role of the infused cells in favoring hematopoietic recovery. We conclude that the “nonengraftment haploidentical cell-therapy” is feasible also in high-risk and previously treated AML patients, although the real efficacy in this setting needs to be further investigated 4. Indeed, based on our preliminary experience, a prospective trial will be launched soon to evaluate the procedure in elderly AML patients, including AML secondary to myelodysplasia, either untreated or after azacytidine, therapy-related AML as well as de novo AML A. Cignetti,1,2* M. Ruella,1,2 A. R. Elia,2 V. Tassi,3 V. Redoglia,4 D. Gottardi,1C. Tarella1,2 1University Division of Hematology and Cell Therapy, Mauriziano Hospital and University of Torino, Torino, Italy 2Molecular Biotechnology Center (M.B.C.), University of Torino, Torino, Italy 3Blood Bank, Molinette Hospital and University of Torino, Torino, Italy 4Division of Hematology, Molinette Hospital and University of Torino Torino, Italy