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Objective Overexpression of ABCG2 and CD200 has been independently associated with poor outcome in acute myeloid leukemia ( AML). However, no data are available on the role of these two factors in patients with core-binding factor ( CBF)-positive or FLT3-negative/ NPM1-mutated cytogenetically normal ( CN) AML. Methods We analyzed 65 adult AML patients with CBF+ (n=16) or FLT3−/ NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival ( LFS) and overall survival ( OS). Results ABCG2 was expressed in 36 (55%) cases, and CD200 was positive in 33 (51%) cases, six at high levels. Both ABCG2 and CD200 positivity have a negative impact on relapse risk: 3-year LFS was 51% vs 82% in ABCG2+ cases ( RR 3.3), 49% vs 82% in CD200+ patients ( RR=4.4), and 25% in CD200− high cases ( RR=17.1). ABCG2 and CD200 affected also OS with 3-year OS of 39% in ABCG2+ (compared to 71% in ABCG2−; RR=2.6) and CD200+ (compared to 68% in CD200−; RR=2.5) patients. Conclusions Our data confirm a negative impact of ABCG2 and CD200 overexpression also in AML patients considered at favorable risk according to ELN cytogenetic/molecular classification. [ABSTRACT FROM AUTHOR]

Background Acute myeloid leukaemia not responsive to first induction chemotherapy ( PIF- AML) still remains a challenge, and there are only few recent epidemiological data regarding the outcome of these patients. In this multicentre survey, we evaluate the prognosis and outcome of patients with PIF- AML, who were diagnosed and treated in the last 5 yrs in four Italian institutions. Results One hundred PIF- AML were recorded, 57 males and 43 females, with a median age of 63 yrs (19-79), 42% were younger than 60 yrs; 42% had a secondary AML and 40% had an adverse karyotype. According to cytogenetic/molecular risk stratification at diagnosis, 33% of patients were classified as favourable/intermediate-1 risk and 56% as intermediate- 2/adverse risk. After a median follow-up of 11 months (1-49), 77% of patients died, while 23% were alive (with 12/23 in cCR). Thirty-six patients underwent allogeneic SCT, and of these, 11 of 36 (31%) were alive at last follow-up. The 12- and 24-month OS probability of the whole population was 45% and 21%, respectively. In multivariate analysis, the probability of OS of the whole population was significantly improved by Allo- SCT procedure (12-month OS probability 60% vs. 35%; P < 0.0001) and was better in patients with favourable/intermediate-1 risk at diagnosis (12-month OS probability 58% vs. 40%; P = 0.028). In transplanted cases, a pretransplant responsive disease was the only significant factor to predict a favourable outcome after Allo- SCT ( P = 0.006). Conclusion Treatment options of PIF- AML still are limited and the prognosis, even recently, remains extremely poor. This survey shows that PIF- AML is still rarely cured without Allo- SCT and confirms the importance of initiating an urgent unrelated donor search in cases without a matched sibling donor. Moreover, the outcome of Allo- SCT is better in patients who achieve a good AML debulking before transplant. To reach this goal, new predictive scores and new protocols of salvage therapy (with target drugs or combinations) need to be explored urgently in PIF- AML. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms associated with FIP1L1- PDGFR rearrangements represent a rare subset of myeloid and lymphoid malignancies, characterised by the presence of eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 genes. The fusion product of such genes is a tyrosine kinase oncoprotein sensitive to imatinib, which to date results to be the standard of care for FIP1L1- PDGFRA-positive chronic myeloproliferative disorders with eosinophilia. However, the coexistence of FIP1L1- PDGFRA rearrangement associated with acute myeloid leukaemia is extremely rare. Here, we report a rare case of FIP1L1- PDGFRA-positive acute myeloid leukaemia, with marked peripheral blood and bone marrow eosinophilia, treated with low dose of imatinib monotherapy, achieving a rapid and long-lasting complete cytologic and molecular remission, without need for intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Candoni A, Toffoletti E, Gallina R, Simeone E, Chiozzotto M, Volpetti S, Fanin R. Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia. Clin Transplant 2011: 25: 308-316. © 2010 John Wiley & Sons A/S. WT1 is well-known to be a panleukemic marker that is expressed in 90% of acute myeloid leukemias (AML). Quantification of WT gene expression in bone marrow (BM) samples may be useful as a marker of minimal residual disease (MRD) during and after treatment for early prediction of relapse. We evaluated the validity of this AML-MRD marker after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). The quantitative assessment of WT1 expression by real-time quantitative PCR (RQ-PCR) was measured in 25 patients (pts) with AML at diagnosis, at the time of RIC-SCT and after transplant at precise time points. All pts showed high WT1 levels at diagnosis with a mean of 4895 (SD 4462) and a median of 3679 (range 454-16 853) copies WT1/10 ABL. At transplant, 18/25 pts (72%) were in complete cytologic remission (CcR) and 7/25 (28%) had refractory AML. At the pre-SCT evaluation, BM samples from pts transplanted in CcR showed significantly lower WT1 expression levels compared to the samples from pts with refractory AML (p = 0.002). Median follow-up after RIC-SCT was 18 months (range 2-54). On 18 pts transplanted in CcR, those (17/18) who maintained CcR after RIC-SCT displayed a WT1 copy number persistently low during all the follow-up period. In patients who received RIC-SCT with active disease obtaining a sustained CcR after transplant (3/25), WT1 levels decreased to normal range in the first two months after RIC-SCT and remained low through the entire study period. All pts who relapsed after RIC-SCT (4/25) had a high WT1 copy number before the cytologic relapse. In 50% of these cases, an increase in WT1 expression was documented before molecular chimerism decreasing. With this experience, taking into account the limited number of pts, we confirmed a concordance between WT1 expression levels (measured by RQ-PCR at precise and sequential time points) and status of AML before and after RIC-SCT and we found a concordance between WT1 expression levels and hematopoietic chimerism status. Our data suggest that, in the RIC-SCT setting, the sequential and quantitative analysis of WT1 may be useful as a leukemia marker for monitoring MRD and as a predictor of overt AML cytologic relapse. [ABSTRACT FROM AUTHOR]

Introduction: WT1 overexpression is described in several oncological diseases including acute myeloid leukemia (AML). Quantification of WT1 in bone marrow samples may be useful as a marker of minimal residual disease (MRD) and may predict the relapse of AML after allogeneic hematopoietic stem cell transplant (HSCT). Methods and results: The quantitative expression of WT1 was measured in 38 AML patients (16 males and 22 females) at diagnosis, at the time of transplant and after the allogeneic HSCT (at precise time points). All cases showed high WT1 expression levels at diagnosis with a mean of 4189 (SD 3325) and a median of 3495 (range 454–13923) copies WT1/104 Abl. At transplant, 25 patients (66%) were in complete cytologic remission (CcR) and 13 (34%) had refractory or relapsed AML. Bone marrow samples from patients transplanted in CcR showed significantly lower WT1 expression levels during HSCT compared with the samples from patients with a relapsed or refractory AML ( P = 0.004). After HSCT, a rapid decline in WT1 expression levels was observed in all patients who attained or maintained a condition of CcR. Six of 38 patients (13%) relapsed after HSCT and all of them had an increase in WT1 expression at/or before relapse. Five of these six patients died of leukemia and one was successfully reinduced with donor lymphocyte infusion (DLI) + chemotherapy with a rapid reduction of WT1 levels. Besides, we found a complete concordance between WT1 expression levels and other disease markers (when available). Conclusions: In our experience, there was a complete concordance between WT1 expression levels (measured by quantitative RT-PCR at precise time points) and status of AML before and after allogeneic HSCT. WT1 may be useful as a non-specific leukemia marker for monitoring MRD and as a predictor of AML clinical relapse. Based on these results, cases with increase of WT1 levels after HSCT and without graft vs. host disease may be candidate to discontinuation of immunosuppression and/or DLI therapy. [ABSTRACT FROM AUTHOR]

The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18–58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m2/d (days 1–3) in 11/25 pts (44%) and in a dose of 100 mg/m2/d (days 1–3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m2 (days 1–5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis ( P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens. [ABSTRACT FROM AUTHOR]