FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation

Abstract Abstract 1974 Most available data on the relative value of allogeneic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) in first complete remission (CR1) in the past, were generated from donor versus no-donor comparisons, focusing on documented tissue-typed patients and their siblings. The inclusion of patients who are not HLA-typed, for instance all those without siblings, causes bias of unknown magnitude. Additionally, concerns about the equivalence of related and unrelated donors should no longer be a problem in contemporary evaluation of allo-SCT. Using data of the prospective AMLCG 1999 trial, we performed a matched-pair analysis, to evaluate outcome in patients with AML according to post-remission allo-SCT or conventional postremission chemotherapy (PRT). 165 patients pairs in CR1 were identified, who matched for the following criteria: AML type (de novo AML, s-AML, t-AML, high-risk MDS); cytogenetic risk group [unfavorable (UNF-CG), intermediate (INT-CG), and favorable with the exclusion of t(15;17)]; age (± 5 years); and time in CR1 to account for the time to transplant in allo-SCT patients. If possible, patients were also matched for sex and assigned induction treatment (TAD-HAM versus HAM-HAM). 34 patient pairs had an UNF-CG, 122 pairs INT-CG, and 9 pairs had favorable cytogenetics. Median patients age at diagnosis was 45 years (range: 16–59). In the allo-SCT cohort, 105 patients had a related donor (matched related donor [MRD] 104, haploidentical 1) and 60 a matched unrelated donor (MUD). Median follow-up of surviving patients after first diagnosis of CR1 was 7.5 years. Projected 7-year relapse-free survival (RFS) was 56% in the allo-SCT group and 39% in the control group (p <.0001, log-rank test). Overall survival (OS) was 58% and 45% (p=.143), respectively. RFS was significantly improved by allo-SCT in patients with UNF-CG (23% vs. 12% at 7 years; p=.005) or INT-CG (58% vs. 37%; p=.001). OS was 31% in allo-SCT patients with UNF-CG versus 18% in matched controls (p=.052) and 64% in INT-CG patients with allo-SCT versus 54% in matched controls (p=.403). Dividing the 330 patients into age groups by decades, revealed an age dependent, increasing risk of relapse for patients receiving conventional post-remission therapy, with cumulative relapse incidences of 51% (<31 years), 47% (31–40 years), 60% (41–50%) and 87% (51–60 years) at 7 years, whereas allo-SCT patients had similar relapse incidences of 32%, 34%, 25% and 34% respectively. The higher relapse incidence in control patients >50 years of age, resulted in a significantly better OS of allo-SCT patients with 27% versus 58% (p=.022) in this age group. In the subset of patients with INT-CG, allo-SCT patients with non-normal karyotype had both a significant better OS and RFS after 7 years compared to control patients, whereas patients with normal karyotype had similar RFS and OS regardless of NPM1 and FLT3 mutational status. Of note, 48 of 99 patients with AML relapse in the control cohort, received an allo-SCT (18 from a MRD, 30 from a MUD) beyond CR1 (9 with UNF-CG, 38 with INT-CG, 1 with favorable CG). Median OS of 48 matched patients receiving an allo-SCT in CR1 was 54%, while it was 39% in paired patients with allo-SCT beyond CR1 (p=.289). We conclude that allo-SCT is the most potent post-remission therapy for AML with UNF-CG and INT-CG. Its impact on OS is difficult to assess, as about a third of patients initially treated with conventional PRT, underwent allo-SCT beyond CR1. In contrast to results from donor versus no-donor comparisons, our data highly suggest a benefit of allo-SCT in CR1, particularly for elderly patients, and in line with such comparisons, for patients with intermediate-II (according to the European LeukemiaNet [ELN] recommendation) or unfavorable ELN cytogenetic risk. Ultimately, the gold standard for the evaluation of allo-SCT in patients with INT-CG in CR1 is a randomized controlled trial, which is now feasible with unrelated donors becoming widely available and is conducted by the German Cooperative Transplant Study Group (ETAL-1 study). Disclosures: No relevant conflicts of interest to declare.

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Presence of FLT3 Mutations Does Not Impair Stem Cell Mobilization and Feasibility of Autologous Peripheral Blood Stem Cell Transplantation in Acute Myeloid Leukemia

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2006.05.017 ◽

2006 ◽

Vol 12 (9) ◽

pp. 981-986 ◽

Cited By ~ 10

Author(s):

Felicetto Ferrara ◽

Salvatore Palmieri ◽

Filiberto Pollio ◽

Catia Lo Pardo ◽

Daniela Graziano ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Peripheral Blood Stem Cell ◽

Flt3 Mutations ◽

Cell Mobilization ◽

Blood Stem Cell Transplantation ◽

Acute Myeloid

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Mlecular Monitoring of Acute Myeloid Leukemia Patients Carrying Nucleophosmin (NPM1) Mutations Undergoing An Autologous Peripheral Blood Stem Cell Transplantation

Blood ◽

10.1182/blood.v112.11.4864.4864 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4864-4864

Author(s):

Valentina Gianfelici ◽

Daniela Diverio ◽

Saveria Capria ◽

Silvia maria Trisolini ◽

Sonia Buffolino ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Peripheral Blood ◽

Copy Number ◽

Myeloid Leukemia ◽

Peripheral Blood Stem Cell ◽

Normal Karyotype ◽

Blood Stem Cell Transplantation ◽

Acute Myeloid

Abstract Nucleophosmin (NPM1) gene mutations represent the most common genetic alterations in adult acute myeloid leukemia (AML), accounting for about 30% of cases and 50–60% of AML with normal karyotype. In addition to their recognized prognostic value (when combined with analysis of the FLT3 gene), NPM1 mutations represent an ideal marker for monitoring of minimal residual disease (MRD) since they are very stable during the course of the disease. PCR quantitative monitoring of NPM1 mutant copies has been mainly restricted to patients treated with conventional chemotherapy. In our study, we retrospectively analyzed, by RQ-PCR, MRD in 12 consecutive NPM1-mutated AML patients who underwent an autologous peripheral blood stem cell transplantation (PBSCT) between September 2000 and March 2008 at the Division of Hematology, “Sapienza” University of Rome. By sequencing of the region encompassing NPM1 exon 12, we demonstrated the presence of a type A mutation in 10/12 patients and of a type B in the remaining 2. Moreover, at diagnosis molecular analysis of the FLT3 gene revealed an internal tandem duplication (ITD) in 7/12 patients. Cytogenetic analysis showed a normal karyotype in 11/12, whereas 1 patient presented a minor karyotype aberration (trisomy 4). RQ-PCR was retrospectively performed on bone marrow samples in all patients at diagnosis, in 11/12 patients before the transplant and in 9/12 after the graft. Six of the 12 patients are at present in continuous complete remission (CCR) with a median follow-up of 54 months (range 4–89), 1 patient has died in CCR 55 months after PBSCT due to a pancreatic carcinoma and 5/12 have relapsed. Four of the latter 5 patients relapsed shortly after the transplant (range 3–10 months); 2 of them died of disease progression and 2 of salvage chemotherapy toxicity. One patient, who relapsed 92 months from PBSCT, is alive in second hematological remission following re-induction and consolidation chemotherapy. No significant differences in median levels of transcript at diagnosis were found between relapsing and non-relapsing patients (93,000 and 68,000; range: 86,000–103,000 and 37,000–116,000, respectively). Nine patients were analyzed after PBSCT: 3 persistently positive relapsed and the copy number of the transcript was always higher than at diagnosis. In the other 6 patients, the transcript was undetectable (3 of them were already in molecular remission pre-transplant): 5 are still in CCR while 1 patient relapsed 92 months after the graft. Regarding the FLT3-ITD status at diagnosis, 3/7 patients are in CCR whereas 4 have relapsed. The retention of NPM1 mutations even at relapse further confirms that NPM1 alterations are highly stable, pointing to this event as critical for leukemia growth and survival. Moreover, in our study long-term survival was always associated with a copy number of NPM1 mutant transcripts below the detectable level of the method, suggesting that disappearance of the transcript should be the primary clinical endpoint. Prospective studies and larger case series are necessary in an attempt to identify a cut-off level during treatment which could be predictive of the clinical outcome of AML patients harboring NPM1 mutations and help in therapeutic choices.

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