20 research outputs found
Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome
To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS)
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SWOG S0919: A phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukemia (AML)
7028
Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ≥ 18 yrs, relapsed AML, cardiac ejection fraction ≥ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ≥ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m
2
/d IV Days 4-6, and cytarabine 1.5 g/m
2
/d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ≥ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level = 4.8% if true CR rate = 30% and power of 90% if true CR rate = 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1
st
: 17 pts (47%), 2
nd
: 15 (42%), 3
rd
: 2 (5.5%), and 4
th
: 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10
-8
. Duration of last CR (≤ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177
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Impact of allogeneic hematopoietic stem cell transplant (HSCT) on patients harboring the spliceosome mutation SRSF2
7008
Background: Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations (mut) in spliceosome genes U2AF1 and SRSF2 predict poor outcome in MDS and related diseases. The purpose of this study was to investigate the role of HCT on the prognostic impact of U2AF1 and SRSF2 in myeloid malignancies. Methods: 123 patients (pts) with MDS (33%), AML (51%), MPN (10%), and MDS/MPN (5%) receiving an allogeneic HCT from 2003-2012 for whom genomic DNA was available from a time when the disease was active, were evaluated for mut in U2AF1 and SRSF2 by direct sequencing. Data were analyzed using competing risks methods (relapse and non-relapse mortality, NRM), proportional hazards (overall survival, OS) and logistic regression models (GVHD). Results: Median time of follow up was 38 months (range 1.5-108). Median age at HCT was 51 yrs (range 18-71). 53 (43%) pts were in remission and 70 (57%) had active disease prior to HCT. 20 (16%) pts had low, 48 (39%) intermediate and 32 (26%) high risk cytogenetics respective to their disease, (per CALGB criteria for AML, IPSS-MF for MPN and IPSS-R for MDS), with missing data on 23 (19%) pts. 89 (72%) had myeloablative transplants, and 34 (28%) received reduced intensity regimens. 54 (44%) had related, 52 (42%) unrelated and 17 (14%) cord blood donors. SRSF2 mut were detected in 13 (11%) pts and U2AF1 in 2 (2%) pts. Due to the low incidence of U2AF1 mut in our cohort, further analysis was focused on SRSF2. There were no significant differences in baseline characteristics between mut and wild-type (wt) pts except SRSF2 mut tended to occur in older AML pts (median age 64 vs 50 yrs, p=0.0004). SRSF2 mut and wt had similar OS (p=0.95), relapse (p=0.28), NRM (p=0.45) and rates of acute (p=0.41) and chronic (p=0.67) GVHD. Results were similar, adjusting for factors such as age, disease type, cytogenetics, comorbidity, transplant type and stem cell source. Conclusions: SRSF2 has previously been associated with dismal outcomes in MDS pts, with 5 yr-OS of <20%. In this cohort of transplanted pts, SRSF2 mut had similar outcomes to wt, suggesting HSCT may compensate for the adverse impact of SRSF2
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New TET2, ASXL1 and CBL Mutations Have Poor Prognostic Impact In Systemic Mastocytosis and Related Disorders
Abstract
Abstract 3076
Mastocytosis is a heterogeneous hematopoietic neoplasm characterized by proliferation and organ infiltration by clonal mast cells (MC). The disease spectrum encompasses chronic indolent forms such as cutaneous mastocytosis (CM)/indolent systemic mastocytosis (ISM) to more aggressive types such as SM with associated clonal hematologic non-mast-cell disease (SM-AHNMD), the latter most closely related to myeloproliferative neoplasms (MPN) or MDS/MPN overlap syndromes. Molecular pathogenesis of mastocytosis involves acquisition of c-KIT mutations, particularly D816V, which is present in many cases and confers resistance to imatinib. TET2 mutations are often found in MPN and MDS/MPN and also in ∼20% of SM patients without noticeable impact on survival. We have hypothesized that analysis of molecular defects in mastocytosis may shed light on disease pathogenesis and possibly convey prognostic information that may help in diagnosis and selection of rational therapies. To investigate these molecular events, we have applied single nucleotide polymorphism array-based karyotyping (SNP-A) (Affymetrix 6.0) to identify recurrent areas of loss of heterozygosity and performed a broad screen for mutations which could be present in mastocytosis including c-KIT, TET2, CBL gene family (CBL, CBLB, CBLC), ASXL1, IDH1/IDH2, which have been found in hematologic disorders related to or associated with SM. Overall survival (OS) was analyzed using the Kaplan-Meier method (Log-Rank). We studied a total of 35 mastocytosis patients classified using WHO criteria (CM, N=9; ISM, N=14; SM-AHNMD, N=9; [CMML, N=6; AML, N=1; NHL, N=2], aggressive SM (ASM) N=2; MC sarcoma, N=1). Median age of the cohort was 51 yrs (13-71). SNP-A showed a total of 20 new lesions (13 gains, 3 losses and 4 uniparental disomy [UPD]) in 10 patients (CM=1, ISM=4, SM-AHNMD=4, ASM=1). The most frequently affected chromosomes were 2, 7, 12, 13, 14 and X. UPD was only found in SM-AHNMD and ASM and it involved chromosomes 2p, 4q, 7p and 13q. No OS difference were observed between patients with new SNP lesions compared to those without (47 mo vs. 38 mo; p=.84). c-KIT sequencing showed D816V in 29% of patients (ISM=29%; SM-AHNMD=44%, ASM=100%). A total of 15 additional mutations were found in 9/35 patients. TET2 mutations were found in 8/35 (23%), including 2 patients with biallelic mutations (3 frameshift, 2 nonsense and 5 missense). TET2 mutational frequencies for CM, ISM and SM-AHNMD (only CMML) were 22% (2/9), 7% (1/14) and 56% (5/9). Majority of TET2 mutations were heterozygous, except one that was homozygous. These mutations have not been previously described in mastocytosis. We have also detected ASXL1 mutations in 3/35 (9%) patients, with biallelic mutation seen in one patient (1 frameshift, 1 nonsense and 2 missense). ASXL1 mutations were seen in 1/14 ISM and 2/9 SM-AHNMD (with CMML). To our knowledge, ASXL1 mutations have not been described in mastocytosis. A heterozygous CBL mutation was found in 1/35 patients with SM-AHNMD (CMML). No mutations were found in CBLB, CBLC and IDH1/IDH2. Interestingly, 5 patients were found to have >1 mutation, c-KIT and TET2 in 2, c-KIT/TET2/ASXL1 in 2 and TET2/CBL in 1 patient. The median OS of the cohort was 18 mo (1-85). As expected, for patients with only SM (excluding CM cases), c-KIT mutants had a worse OS than wild type (WT) c-KIT patients (17 mo vs. 52 mo; p=.02). SM patients with TET2, ASXL1 or CBL mutations, independently of c-KIT, had a worse OS than those with WT genes (17 mo vs. 52; p=.01). SM patients with c-KIT mutation who carry additional mutations had a worse OS, c-KIT + any mutation [11 mo] vs. TET2/ASXL1/CBL mutant [32 mo] vs. c-KIT mutant alone [NR] vs. WT [NR]; p<.0001. Similarly, when TET2 and c-KIT mutations were analyzed independent of CBL and ASXL1, patients with mutant c-KIT and TET2 had the poorest OS in the group (c-KIT plus TET2 [10 mo] vs. TET2 alone [32 mo] vs. c-KIT alone [NR] vs. WT [NR]; p<.0001). All patients with CM were still alive at the time of analysis. In conclusion, SNP-A lesions including UPD are karyotypic changes also seen in mastocytosis. TET2 mutations are frequently found in mastocytosis, particularly in SM-AHNMD (CMML). Novel molecular mutations frequently found in MDS and MPN, as ASXL1 and CBL, are also found in mastocytosis but at lower frequencies. More importantly, these new mutations may affect prognosis, as demonstrated by poor OS in patients who carry these mutations independently of c-KIT.
Disclosures:
No relevant conflicts of interest to declare
Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes
BACKGROUND.
Mutational inactivation in cancer of key apoptotic pathway components, such as
TP53
/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly,
TP53
mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.
METHODS.
In this clinical trial, patients with myelodysplastic syndrome (
n
= 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m
2
/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.
RESULTS.
The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.
CONCLUSION.
Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.
TRIAL REGISTRATION.
Clinicaltrials.gov NCT01165996.
FUNDING.
NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program)