The presented data are showing the crucial role and great prognostic significance of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses (PTR) in acute myeloid leukemia patients with different cytological variants. For evidence simultaneous serial measurements of BAALC and WT1 transcript copy numbers by means of quantitative real time polymerase chain reaction were used at diagnosis, before conditioning regimen as well as at PTR in 50 patients treated with allogeneic hematopoietic stem cell transplantation (alloHSCT). Thirty-eight of them were adults and twelve pediatric patients aged 1-60 years (median – 25.8 years). It was shown, that BAALC gene overexpression to be presented in all studied cytological and being combined with increased level of WT1 expression at PTR in most of them. This combination was prognostically poor since it is largely associated with increased cumulative incidence of PTR (p<0.0001), and shortened event free (p<0.0001) and overall survival (p=0.002).
There is evidence that relapses of acute myeloid leukemia (AML) are closely related to heterogeneous population of leukemic precursors. At least, two classes of the leukemia-initiating cells (LIC) may be discerned, according to recent experimental studies with hematopoietic cell transplants to immunodeficient mice. The main class of LICs is presented by immature precursors with CD34 + CD38immunophenotype which, in turn, are capable of selective expression of BAALC gene. The second class of LICs is presented by relatively mature precursors with more differentiated immunophenotypes. According to indirect findings, they are able of WT1 gene expression, along with blast cells. Since both BAALC and WT1 mRNAs may be quantitatively evaluated by means of standardized quantitative polymerase reaction in real time (qRT-PCR), this approach may be effective for specifying the mechanisms of relapses and resistance to therapy in AML patients. The aim of this work was to perform simultaneous dynamic evaluation of BAALC and WT1 genes expressions along with determination of blast numbers in the tested bone marrow samples in 14 AML patients treated at our Center with Gemtuzumab ozogamicin (GO, Mylotarg), which was combined with high-dose chemotherapy (ChT), followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our preliminary results are as follows: a) superior 3-year overall survival (OS) in general group of patients with normal or nearly-normal karyotypes, and FLT3-mutated AML variants as compared to those with more complex karyotypes and EVI1 gene overexpression (85.7% vs 16.7%; p=0.032); b) highly sensitive response of immature BAALC-expressing precursors to combined ChT and GO treatment; c) hypothetical participation of some mature precursors, along with blast cells, in WT1 gene expression; d) real evidence for switching hematopoietic regulation from immature BAALC-expressing precursors to more mature WT1-expressing progeny. These results suggest diagnostic utility of combined BAALC/ WT1/blast counts panel for quantitative studies and assessment of distinct precursors in AML progression and emergence of relapses.
Evaluation of BAALC-and WT1-expressing leukemic cell precursors in pediatric and adult patients with EVI1-positive AML by means of quantitative real-time polymerase chain reaction (RT-qPCR)
Background. Chromosomal abnormalities (CA) are the most prognostic factor in acute myeloid leukemia (AML). However, it is still not clear whether the cytogenetic risk groups established for patients (pts), treated by standard chemotherapy, are so optimal for pts undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Recent studies have confirmed negative effects of both monosomal and complex karyotypes (MK, CK) on outcomes after alloHSCT [1,2]. Meantime, some investigators consider that immune effects of alloHSCT can reduce negative impact of these CA [3]. Aim. To evaluate impact of the CA in AML pts with adverse cytogenetic risk group on outcome after alloHSCT. Material and Methods. In this study, outcomes of alloHSCT, which were performed in a single institution between 2009 and 2014 years for 97 AML pts have been analyzed. Patients and transplantation characteristics are presented in Table I. The probabilities of overall survival (OS), leukemia free survival (LFS), cumulative incidence of relapse (CIR) were evaluated for different cytogenetic groups. Results. According to univariateanalysis, the probabilities of 4-year OS in pts with 5q-, KMT2A translocations and monosomy 7 were 66%, 59% and 56%, respectively. At the same time, OS in pts with CK, 7q- and 3q26 rearrangements were lower i.e. 33%, 25% and 25%, respectively (p=0.01). Multivariate analysis showed, that clinical stage at HSCT, age and HSC source are independent predictors of OS in AML pts (Table 2). Four-year LFS were various in pts with different CA. The higher LFS was noted in pts with 5q- and KMT2A translocations (66% and 52%, respectively), whereas lower LFS were in pts with 3q26 rearrangements, CK, monosomy 7 and 7q- (0, 18%, 23% and 37%, respectively) (Fig. 1). Besides, LFS distinguished between groups with CK+ and CK- (18% vs 41%, p=0.008), as well as with MK+ and MK- (17% vs 30%, p=0.04). Multivariate analysis evidenced clinical stage at HSCT, cytogenetic groups, MK and number of transplanted CD34+ cells to be independent predictor of LFS in AML pts (Table 2).Cumulative incidence of relapses in pts transplanted in remission (n=42) was higher in those with CK+ (55% vs 14%, p=0.03) and MK+ (75% vs 31%, p=0.013). Discussion. The study showed that 4-year OS in AML pts with 5q-, KMT2A translocations and monosomy 7 significantly distinguished from those with CK, 7q- and 3q26 rearrangements. Furthermore, OS depended on clinical stage at HSCT, patient's age and HSC source. On the other hand, EFS differed from all above-mentioned cytogenetic groups, including MK. Finally EFS depended on clinical stage at HSCT and number of transplanted CD34+ cells. Conclusion. On the basis of this data, a conclusion may be drawn that alloHSCT in AML pts with adverse CA should be performed at complete remission, with bone marrow as HSC source and enough number of transplanted CD34+ cells. Reference. 1. Hemmatti et al. Eur J Haematol. 2013; 92:102-10. 2. Fang et al. Blood 2011; 118:1490-4. 3. Guo et al. Biol Blood Marrow Transplant 2014; 20: 690-5. Table 1. Patients and Transplant characteristics Patients, n (%) 97 (100) Gender, n (%)MaleFemale 53 (54.6)44 (45.4) Age at HSCT, median, (range) years 25 (1.5-60) Cytogenetics, n (%) 3q26 rearrangementsDeletion 5q (sole)Monosomy 7 (sole)Deletion 7q (sole)KMT2A translocationComplex karyotype ³3 CA Monosomal karyotype 4 (4)10 (10.3)12 (12.4)4 (4)11 (11.3)56 (58)18 (18.5) Time from diagnosis to HSCT, median (range) days 477 (47 - 3482) Clinical stage at HSCT, n (%)CR1³CR2Active disease 29 (30)13 (13)55 (57) HSC source, n (%)Bone marrowPeripheral bloodBM+PB 54 (56)34 (35)9 (9) Conditioning regimen, n (%)MANon-MA 35 (36)62 (64) Donor type, n (%)HLA-id siblingMatched unrelatedHaploidentical 17 (17.5)53 (54.6)27 (27.8) Number of transplanted CD34+ cellsmedian (range), x106/kg 6.1 (1.5-17.9) Table 2. Multivariate analyses HR 95% CI P Overall survival Clinical stage at HSCT 2.65 1.72-4.09 0.00001 Median age<18 years) 2.05 1.05-3.99 0.034 HSC source 1.66 1.12-2.45 0.011 Cytogeneticgroups 1.72 0.81-3.66 0.15 Median number of transplanted CD34+ cells>6x106/kg 1.77 0.91-3.42 0.08 Leukemia-free survival Clinical stage at HSCT 2.59 1.8-3.7 0.0001 Cytogeneticgroups 1.31 1.03-1.69 0.031 Monosomal karyotype 1.88 0.97-3.66 0.044 Median number of transplanted CD34+ cells>6x106/kg 2.78 1.51-5.11 0.0003 Figure 1. Leukemia-free survival for AML patients with different cytogenetic groups after alloHSCT Figure 1. Leukemia-free survival for AML patients with different cytogenetic groups after alloHSCT Disclosures No relevant conflicts of interest to declare.
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). Table 1. Frequency and characteristics CAKs in AML and ALL patients with the PTRs Leukemia type AML ALL P Patients, n 61 38 Karyotype, n (%) Normal 6 (10 %) 1 (3 %) NS Abnormal 55 (90 %) 37 (97 %) NS Complex karyotype, n (%) 22 (36 %) 25 (66 %) 0.003 3 abnormalities 2 (3 %) 2 (5 %) NS ³4 abnormalities 20 (33 %) 23 (61%) 0.006 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). Table 2. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs in different age groups. Patients, n (%) Age (years) AML ALL P 1-18 7/23 (30 %) 15/25 (60 %) 0.03 19-40 8/25 (32 %) 7/11 (64 %) 0.08 41-60 5/13 (39 %) 1/2 (50 %) 0.5 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). Table 3. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs, depending on the clinical status at alloHSCT. Patients, n (%) P Clinical status at HSCT AML ALL CR 1 3/13 (23 %) 2/7 (29 %) 0.6 CR ³2 6/14 (43 %) 7/11 (64 %) 0.2 Active disease 11/34 (32 %) 14/20 (70 %) 0.007 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. Disclosures No relevant conflicts of interest to declare.
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