Abstract
Acute myeloid leukemias (AML) with complex karyotype (≥ 3 abnormalities) and/or monosomy 7/del(7q) are a subset of AML with extremely poor prognosis. Hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment, but relapse rate is high (most often above 50%) and negatively impacts on patients' survival. (Ciurea et al. Cancer 2018) Such poor results are even questioning the role of HSCT and rise the need of new transplant procedures for these patients. To this end, we are performing a clinical trial of haploidentical HSCT with adoptive immunotherapy with regulatory T cells (Tregs) and conventional T cells (Tcons) in the absence of post-transplant pharmacologic immune suppression (Treg-Tcon haplo-HSCT). Such approach allows for an extremely low relapse rate in patients with high-risk acute leukemias transplanted in complete remission. (Martelli et al. Blood 2014)
In this study we analyzed the outcome of all the patients that were referred to our center from January 1st 2007 to May 31st 2018 with a diagnosis of AML with complex karyotype and/or monosomy 7/del(7q) and that were fit for receiving an induction treatment.
49 patients were included. Median age at diagnosis was 52; 22 were female, 27 were male. 20/49 had chromosome 7 abnormalities (isolated in 12 patients; in a complex karyotype in 8 patients). 11 patients received a hypomethylating agent as first line treatment, while the other 38 patients received high-dose chemotherapy. We performed 30 HSCT procedures in 25 patients; 5 patients received a second transplant (4 after disease relapse and 1 after rejection). 6 underwent a HLA-matched HSCT, 6 a T-depleted haploidentical HSCT, and 18 a Treg-Tcon haplo-HSCT. Median age at transplant was 42 with a median follow up of 40 months.
Regarding disease status at transplant, 26 HSCT were performed in patients that were in 1st or 2nd hematological remission and 4 in patients with refractory disease. Cytogenetic analysis (karyotype and/or FISH analysis) revealed the presence of abnormal clones in 11 patients and multiparametric flow cytometry analysis detected minimal residual disease in 16 patients. Thus, most of the patients (17/30, 57%) were transplanted with detectable disease.
15/49 patients were disease-free and alive at the time of the analysis, all of them after receiving HSCT (HSCT vs Non-HSCT, p<0.01, Fig. A). Treg-Tcon haplo-HSCT allowed for a markedly better disease free survival as compared to the other transplant procedures (p=0.01, Fig. B). Such survival advantage was only due to a reduced rate of disease relapse (31% vs 79%, p=0.02, Fig. C), as transplant related mortality was similar between the 2 groups (9% vs 9%). 17/18 Treg-Tcon haplo-HSCT patients engrafted and only 2/17 developed acute GvHD grade ≥ 2. 4/17 patients relapsed and none of them received a transplant from a NK alloreactive donor. (Ruggeri et al. Science 2002) Multivariate analysis that included chromosome 7 involvement, presence of disease at multiparametric flow cytometry and/or cytogenetic analysis, and blast count at transplant confirmed that Treg-Tcon haplo-HSCT was the only predictor of a better survival.
In conclusion, our results not only confirm that HSCT is the only potentially curative treatment for AML with complex karyotype and/or chromosome 7 involvement, but also demonstrate that Treg-Tcon haplo-HSCT allows for a strong antileukemic effect, the only needed for a long term control of such unfavorable AMLs with high disease burden at transplant. While it is necessary to confirm these results in a larger cohort of patients, Treg-Tcon haplo-HSCT could represent the best transplant option for this subset of very high-risk AML patients.
No relevant conflicts of interest to declare.
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