Complex Aberrant Karyotype in Patients with Post-Transplant Relapses of Acute Myeloid and Lymphoid Leukemias Evaluated By Serial Cytogenetic Assays, Including mFISH

Background. Prognosis of acute myeloid leukemia (AML) with complex aberrant karyotype (CAK) is poor. These patients (pts) are often refractory to both chemotherapy and allogeneic HSCT (alloHSCT). At diagnosis the proportion of these pts is about 6-8 %, but their frequency essentially increases in relapses after chemotherapy and alloHSCT. Mechanism of CAK development and its effect on relapses have been studied insufficiently.

Material and methods. Serial cytogenetic assays, including multicolor FISH, were performed on bone marrow cells from 99 patients with post-transplant relapses (PTR) AML (n=61) and ALL (n=38). Median ages for AML and ALL pts at HSCT were 23 and 17 years (range, 2-60 and 0.8-51 years), respectively.

Results. Aberrant karyotypes were found in 90 % AML and 97 % ALL pts, respectively (Table 1). Of note, the proportion of CAK in general group of ALL patients, as well as in that with more 4 chromosomal abnormalities was significantly higher, compared to AML (66% vs. 36%, P=0.003 and 61% vs. 33%, P=0.006, respectively).

NS - not significant

The above difference in frequency of CAK in ALL and AML might be explained by higher frequency of myeloablative conditioning regimes in the ALL group, compared to AML (55% vs. 36 %, respectively; P=0.09). Of notice also, that fraction of CAK with 4 and more chromosomal abnormality in the group of children from 1 to 18 years was significantly higher in patients with ALL, as compared with AML (60% vs. 30%, respectively; P=0.03). Furthermore, a similar tendency was revealed also in the group of patients aged 19-40 years (difference insignificant; P=0.08) (Table 2).

Finally, our data demonstrate, the proportion of CAK to be significantly higher in PTR of ALL pts compared with those of AML, when they were transplanted in active disease phase (70% vs. 32%; P=0.007; Table 3).

Discussion. Our study shows that number of karyotype abnormalities in acute leukemia with CAK+ is closely associated with previous chemotherapy and/or conditioning regimes. Despite it, only alloHSCT gives a hope for treatment of these pts. In order to improve overall results of treatment several modifications of alloHSCT and post-transplant treatment have been recently suggested. The main of them, called as early alloHSCT, includes modified FLAMSA-RIC conditioning regime, alloHSCT before obtaining results of standard courses chemotherapy followed by DLI in escalating doses at post-transplant period (Schmid et al., 2012). If such a possibility for early alloHSCT is lost, another variant of PTR prevention may be used. The latter can include the same DLI, hypomethylating agents, ATRA etc. As for PTR prevention in CAK+ ALL it may be different from AML. In our opinion, in these pts should be treated at the first with such target agents as tyrosine-kinase inhibitors, rituximab, ATRA etc.

Conclusion. According to our data, the frequency of CAK in PTRs is high not only in AML, but ALL too. Mechanisms of CAK formation as well as treatment of CAK+ leukemia began to elucidate. In our opinion, the leading place in this treatment is to be given an early alloHSCT.

Reference. Schmid C., et al. Early allo-SCT for AML with a complex aberrant karyotype – results from prospective pilot study. Bone Marrow Transplantation 2012; 47: 46-53.