SummaryParoxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventyfour patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0Á60% in granulocytes and 0Á15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH-patients, both after first-and second-line IST: 68% vs. 45%, P = 0Á0164 and 53% vs. 13%, P = 0Á0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH-patients (P = 0Á0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2Á56, P = 0Á0180) and baseline absolute reticulocyte count (ARC) ≥30 9 10 9 /l (odds ratio 5Á19, P = 0Á0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 9 10 9 /l showed significant distinctions for cumulative incidence of response, overall and failure-free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.

The only proven cure for Shwachman–Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.

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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