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  • 1
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    Association of smoking with poor risk ELN 2017, cytogenetics/molecular profile, and survival outcomes in acute myeloid leukemia.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 7002-7002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 7002-7002
    Abstract: 7002 Background: Smoking increases the relative risk of AML by 40% and 25% in active and former smokers, respectively, compared with non-smokers (Fircanis et al., 2014). While the relationship of smoking with AML development is recognized, whether smoking impacts underling AML biology and clinical outcome remains ill-defined. Methods: Newly diagnosed, treatment naïve AML pts seen at MDACC between 2012 and 2017 with available smoking history were evaluated, along with baseline parameters, co-occurring mutations, cytogenetics and clinical outcome. Results: We identified 858 pts [486 (57%) male; median age 67 yrs (14-97)], representing 535 (62%) treatment naïve and 323 (38%) salvage pts. Smoking status was recorded as smokers (active = 39 pt, former = 380 pt), versus never smoker (439 pt). In tx naïve group, smoking is associated with lower remission rates (OR 0.63, 95% CI 0.43-0.94, p = 0.02) and inferior OS (HR = 1.6, 95% CI 1.27-2.02, p 〈 0.001). Smoking status was not significant in multivariate analysis including AML biologic characteristics and ELN 2017 risk stratification. Therefore we postulated that worse OS may be driven by smoking associated AML biology rather than smoking associated comorbidities. Indeed, in univariate analysis smoking was associated with poor ELN risk (p = 0.015), complex karyotype (p = 0.0002), and TP53 mutation (p = 0.0235) while negatively associated with NPM1 (p = 0.018), FLT3-ITD (p = 0.032) and GATA2 (p = 0.0497). Age was a significant cofounder between smokers vs non-smoker ( 〈 0.0001). After controlling for age, significance was retained for ELN risk, complex karyotype and GATA2 at p = 0.0454, p = 0.0006, p = 0.048 respectively, while significance was lost for NPM1 (p = 0.079), FLT3-ITD (p = 0.1) and TP53 (p = 0.084). In analysis of young pts ( 〈 60 yr), smoking is positively associated with complex karyotype (p = 0.0042) and TP53 (p = 0.0289), and negatively associated with RUNX1 (p = 0.0143) and IDH2 (p = 0.0357). Conclusions: We report the largest analysis of smoking status and impact on molecular, cytogenetics, and AML clinical outcomes. Smoking history is associated with poorer risk molecular and cytogenetics, lower response rate and shorter survival in treatment naïve patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.7002
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 2
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    Patterns of leukemic transformation in patients with TP53 -mutant myelodysplastic syndromes.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 7054-7054
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 7054-7054
    Abstract: 7054 Background: TP53 is the most frequently mutated gene in human cancers, including 7-13% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Although it is associated with transformation to AML in patients with MDS, the additional genomic events leading to transformation are poorly understood. Methods: We retrospectively evaluated 312 patients with TP53-mutated AML or MDS diagnosed between 2013-2016. Patient characteristics and bone marrow data, including cytogenetic and next generation sequencing information, were assessed at the time of diagnosis and progression to AML. Results: There were 151 TP53-mutated MDS patients and 161 TP53-mutated de novo AML patients with a median follow-up time of 34.1 months. Forty-one patients with TP53-mutated MDS transformed to AML. Sequencing data at transformation was available in 17 patients (41%). At diagnosis, median age was 67 with 2 patients with intermediate-risk, 7 patients with high-risk, and 32 patients with very high-risk MDS by IPSS-R. Complex karyotype was seen in 40 patients, and 12 patients had 1, 25 patients had 2, and 4 patients had 3 TP53 abnormalities. Predictors of transformation to AML include TP53 loss of heterozygosity (p = 0.008), 3 TP53 abnormalities (p = 0.049), complex cytogenetics (p = 0.023), and female gender (p = 0.002). Median time to transformation was 10.4 months. At transformation, an increase in TP53 variant allelic frequency was observed in 7 patients (41%), and new mutations, particularly NRAS, IDH1, TP53, MLL, KDM6A, TET2, and NOTCH1, were acquired by 10 patients (59%). Cytogenetic evaluation revealed identical clones in 5 patients, linear acquisition of cytogenetic abnormalities in 12 patients, and new clones in 8 patients. Patients with TP53-mutated AML from MDS also had worse median overall survival than patients with TP53-mutated de novo AML at 2.5 months vs. 5.7 months respectively (p 〈 0.001). Conclusions: TP53 mutations confer a worse prognosis, especially in the setting of AML transformed from MDS. This may be due to the acquisition of new mutations and cytogenetic abnormalities. Further exploration of the biological mechanisms leading to transformation in TP53-mutant MDS is warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.7054
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Quizartinib (QUIZ) with decitabine (DAC) and venetoclax (VEN) is active in patients (pts) with FLT3-ITD mutated acute myeloid leukemia (AML): A phase I/II clinical trial.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 7036-7036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7036-7036
    Abstract: 7036 Background: QUIZ, a potent 2nd generation FLT3 inhibitor (FLT3i) demonstrated synergy with VEN in AML cell lines and PDX models (Mali Haematologica 2020). We evaluated the safety and efficacy of DAC + VEN + QUIZ triplet in patients with newly diagnosed (ineligible for intensive induction chemotherapy) or relapsed/refractory (R/R; up to 5 prior chemotherapies) FLT3 ITD mutated AML. Methods: All pts received 10 days of DAC (20 mg/m2) in Cycle 1. Pts underwent day 14 bone marrow (BM) biopsy, and VEN (400 mg/day starting from day1) was put on hold in pts with BM blasts ≤ 5% or aplasia. Those with day14 BM blast 〉 5% continued VEN for 21 days during cycle 1. In subsequent cycles, DAC was reduced to 5 days. QUIZ (30 or 40 mg/day) was administered daily continuously. Results: Overall, 28 pts were enrolled and evaluable at the time of this report. Of the 23 pts with R/R AML (median 3 [range 1-5] prior therapies, 78% with ≥1 prior FLT3i including prior gilteritinib (GILT) in 70%, and 39% had a prior ASCT), 78% achieved CRc (3 CR, 15 CRi) with 6/16 and 5/18 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Pts with RAS/MAPK mutations had the lowest response rates (Table). Interestingly, no emergent TKD mutations were noted at relapse after the triplet but 3/8 evaluable pts had emergent RAS/MAPK mutations. 60-day mortality rate was 5%. Of 5 patients with newly diagnosed AML (median age 69), all achieved CRc (2 CR, 3 CRi) with 4/5 and 2/4 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0. 2 pts developed hematologic DLT with 40 mg/day QUIZ dose (grade 4 neutropenia with a 〈 5% cellular BM lasting ≥42 days). Hence, QUIZ 30 mg/day dose was determined as RP2D for the triplet. Grade 3/4 non-hematologic toxicities included lung infections (42%) and neutropenic fever (30%). No QTcF prolongations 〉 480 msec were noted. With a median follow-up (f/u) of 13 months, the median OS was 7.6 months in R/R cohort (1-year OS of 30%). 8/18 responding R/R pts (including 5/8 prior GILT exposed pts) underwent ASCT with a median OS of 19 vs 8 months in those who underwent ASCT versus not (p=0.26). Of the 5 frontline responding pts median OS was 14.5 months, 2 were alive in CR, 1 died in CR1 post-ASCT, 2 died due to relapsed disease at the last f/u. Conclusions: DAC + VEN + QUIZ is active in R/R FLT3-ITD mutated AML pts, with CRc rates of 78% and the median OS of 7.6 months. Interestingly, RAS/MAPK mutations but not emergent TKD mutations were associated with primary and secondary resistance to the triplet. Accrual continues, and updated clinical, NGS, and mass cytometry (CyTOF) data will be presented. Clinical trial information: NCT03661307. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.7036
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
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    A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS7076-TPS7076
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS7076-TPS7076
    Abstract: TPS7076 Background: CD123 is a marker of leukemic stem cells that is differentially overexpressed in most patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In contrast, CD123 is expressed at negligibly low levels on normal hematopoietic progenitors, making it a potentially promising therapeutic target. Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has established clinical activity in relapsed/refractory AML. In a phase I study, the overall response rate was 14.8% in patients who received vibecotamab at a dose of ≥ 0.75 µg/kg (Ravandi F et al. ASH 2020 abstract #460). Response rates were notably higher in those with lower disease burden (bone marrow blasts ≤ 25%) where the overall response rate was 25.9%. In light of the activity of vibecotamab in relapsed/refractory low-blast AML, we designed this phase II study to evaluate vibecotamab in other low-blast states, including CD123-positive, MRD-positive AML and in MDS or CMML after failure of hypomethylating agents. Methods: This is a two-arm, open-label, phase II study of vibecotamab in patients with AML in first or second morphological remission with detectable MRD at a level of ≥0.1% by flow cytometry and in patients with MDS (intermediate or higher-risk by IPSS-R) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents. CD123 expression ≥20% on aberrant myeloid blasts is required for study eligibility. Vibecotamab is given IV in a ramp-up dose schedule on days 1, 3, 5 and 8 of cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7 µg/kg. Patients may receive up to 4 cycles of vibecotamab in 28-day cycles. The primary objective of the AML MRD cohort is to determine the MRD negativity rate after 4 cycles; the primary objective of the MDS/CMML cohort is to determine the response rate (CR + mCR + PR + HI + clinical benefit) after 4 cycles. The target MRD response in the AML MRD cohort is 50%, and the target response rate in the MDS/CMML cohort is 30%. Secondary endpoints include remission duration, duration of MRD response (AML MRD arm), CR rate (MDS/CMML arm), relapse-free survival, overall survival, and safety. Exploratory endpoints include correlation of clinical outcomes with CD123 expression and the dynamics of CD123 expression at treatment initiation and at the time of relapse. Additional immunological correlatives will be performed, including 1.) determination of molecular immune states that predict response or resistance, 2.) functional interrogation of TCR-antigen interactions, and 3.) nomination of leukemic neo-antigens. The planned enrollment is 40 patients (20 in each of the two cohorts). To date, 13 patients have been enrolled (7 in the AML MRD cohort and 6 in the MDS/CMML cohort). The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.TPS7076
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
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    Superior outcomes after allogeneic stem cell transplantation (SCT) among patients (Pts) ≥ 60 years (yrs) treated with cladribine (CLAD), low dose cytarabine (LDAC) plus venetoclax (Ven) for newly diagnosed acute myeloid leukemia (AML).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 7047-7047
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 7047-7047
    Abstract: 7047 Background: CLAD/LDAC/VEN alternating with AZA-VEN has shown promising outcomes in older pts with AML ( Kadia, JCO Nov 2022). Improved disease control and preserved performance status achieved with CLAD/LDAC/VEN treatment, may translate into superior post-SCT outcomes. Methods: We compared outcomes of pts ≥ 60 yrs of age treated on the phase II study of CLAD-LDAC-VEN who underwent SCT in 1st remission (CR1) to a retrospective cohort of pts ≥ 60 yrs treated with hypomethylating agent (HMA)-VEN based or intensive (INT) therapy who underwent SCT in CR1 between 2013-2022. Relapse free survival (RFS) was from response to relapse/death & overall survival (OS) from start of therapy to death. Results: 35 pts treated with CLAD-LDAC-VEN were compared to 42 pts treated with INT & 40 pts with HMA-VEN therapy for remission induction prior to SCT at our center (Table). The median age of pts in the low-intensity arms were similar (68 yrs), but lower on the INT arm (62 yrs). More pts post INT therapy received a myeloablative conditioning (MAC). At a median follow up of 17+ months (m) for CLAD-LDAC-VEN arm, 59 m for INT arm, and 30 m for HMA arm, the median RFS (NR vs. 50 m vs. 20 m respectively, p 〈 0.01) and OS (NR vs. 58 m vs. 32 m respectively, p 〈 0.01) was superior for the CLAD-LDAC-VEN arm. 3-yr cumulative incidence of relapse & NRM (as competing events) were both significantly lower with CLAD-LDAC-VEN (4% and 7%) compared to INT (17% and 23%) or HMA-VEN (41% and 27%) therapy. Conclusions: Older pts with AML proceeding to SCT after CLAD-LDAC-VEN therapy had significantly improved survival, characterized by significantly lower rates of NRM and relapse compared to HMA-VEN or INT therapies. Larger studies and longer follow up is needed to confirm its benefit. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.7047
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 6
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    A phase II trial of ponatinib and blinatumomab in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e19013-e19013
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e19013-e19013
    Abstract: e19013 Background: Ponatinib and blinatumomab are both active in Ph+ ALL. A combination of these agents may lead to durable remissions when given in the frontline setting and may eliminate the need for chemotherapy or stem cell transplant (SCT). Methods: In this phase II study, patients (pts) with newly diagnosed Ph+ ALL received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for at least 5 years. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Pts also received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2023, 54 pts were with newly diagnosed Ph+ ALL were treated. Baseline characteristics are shown in the table. Among 35 pts evaluable for hematologic response, 23 (97%) achieved CR/CRi; 1 pt had early death. Among 48 pts evaluable for molecular response, 34 (71%) achieved CMR after 1 cycle, and 43 (90%) achieved CMR at any time. After 2 weeks of therapy, 18/35 tested pts (51%) achieved CMR in the peripheral blood. 34/38 tested pts (89%) achieved MRD negativity by next-generation sequencing at a level of 10 -6 . Four of these pts who were MRD-negative by NGS had detectable low-level BCR:ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). The median follow-up is 16 months (range, 1-55 months). Three patients relapsed after a median of 9 months of remission (range, 8-23 months), 1 in bone marrow with new E225V mutation and 2 extramedullary-only. Three pts have died (1 from intracranial hemorrhage, 1 from post-procedural hemorrhage, and 1 from brain aneurysm). There have been no leukemia-related deaths, the estimated 2-year EFS and OS are both 90%. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently low-level BCR:ABL1 positivity. Among the 47 pts in ongoing remission without SCT, the median duration of response is 15 months. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab is safe and effective in newly diagnosed Ph+ ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for SCT. Clinical trial information: NCT03263572 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e19013
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 7
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    RAS mutation acquisition at transformation from myelodysplastic syndrome to acute myeloid leukemia to predict poor outcome.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 7052-7052
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 7052-7052
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.7052
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 8
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    Targeting microenvironment-mediated resistance in leukemias: Phase I trial of mobilization and elimination of FLT3-ITD+ acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor/g-CSF/sorafenib.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. TPS6635-TPS6635
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. TPS6635-TPS6635
    Abstract: TPS6635 Background: FLT3-ITD AML are associated with poor prognosis. We identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with overexpression of chemokine receptor CXCR4 and we found increased in vivo activity of S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report first data testing this concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1 - 28(one cycle). G/P was held when blasts 〉 5x10 4/ uL. CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by flow cytometry. Results: 10 patients have been treated so far : 2 achieved CRp, 4 PR and 4 failed (NR), for an overall response rate of 6/10; 3/6 responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10 pts. developed hyperleukocytosis (and missed 1 to 5 doses of G/P), 6 skin rash and 3 hypertension. Analysis of cells mobilized in 22 cycles revealed a 29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes. Increase in circulating stem/progenitor cells was as follows: CD34+: 231-fold, CD34+/38- : 90-, CD34+/38-/123+(LSC) : 148-, CXCR4+: 139-, VLA-4+ : 68- and CD44+: 82-fold. Increase in LSC was correlated with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization of leukemic cells. Increased levels of pERK and pAKT were observed in mobilized cells. Conclusion: The combination of G-CSF+Plerixafor appears superior in increasing circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10 CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical report of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment. The initial results are providing proof-of–principle of this concept.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.tps6635
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 9
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    Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) therapy in accelerated-phase CML (CML-AP).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 6587-6587
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6587-6587
    Abstract: 6587 Background: For patients (pts) presenting with CML-AP, TKIs are recommended. Although generally well tolerated, dose reductions and/or interruptions are often required. The impact of TKI dose intensity (DI) on CML-AP outcome has not been described. Aim: To determine impact of TKI dose interruptions and/or reductions on outcome in de novo CML-AP. Methods: Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or parallel clinical trials with TKIs as initial therapy: imatinib (n=36), dasatinib (n=5), or nilotinib (n=17). CML-AP features included: blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets 〈 100x10 9 /L (n=3), cytogenetic clonal evolution (n=22), or 〉 1 feature (n=3). We examined the impact of dose reductions, treatment interruptions, and DI (ratio of the dose received vs. the intended dose for the entire treatment duration) on event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: Among 58 pts, 37 required treatment interruptions and/or dose reductions (29 required dose reductions). 12 pts required dose reductions and/or interruptions due to hematologic toxicity and 23 for non-hematologic toxicities. Pts were divided into 3 DI tiers: 100% (n= 21), 90-99%, (n=10), and 〈 90% (n=27). Outcomes were analyzed based on DI tiers and presence or absence of dose reductions as shown in the table. Pts with dose reductions and/or interruptions for hematologic toxicities vs. non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% (p=0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo or later were 100% and 91%, respectively (p =0.7). Conclusions: DI has no significant impact on de novo CML-AP outcome. However, dose interruptions and/or reductions for hematologic toxicities are associated with worse 24-mo EFS, suggesting myelosuppression may in some patients be more a feature of the disease than toxicity from therapy. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.6587
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Phase II study of omacetaxine (OM) and low-dose AraC (LDAC) in older patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 6592-6592
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6592-6592
    Abstract: 6592 Background: Treatment of AML in patients (pts) 〉 70 yrs of age with intensive chemotherapy is associated with high rates of early mortality and little benefit. Newer, lower-intensity approaches with novel mechanisms are needed. OM is a semisynthetic plant alkaloid which has demonstrated activity in AML as a single agent and with chemotherapy. Methods: We studied a low intensity program combining subcutaneous (SQ) OM with SQ LDAC in pts 〉 /= 60 yrs, with AML or MDS, a performance status (PS) of 〈 /=2, and adequate organ function. Initially, 6 pts were enrolled at the following doses: OM 1.25 mg/m2 SQ Q12 hrs x 3 days with AraC 20 mg SQ Q12 hrs x 7 days on a 4 week cycle. If safety is confirmed, the phase II portion would commence at the safe dose levels. Up to 12 courses can be given. The primary endpoint was to determine the complete remission (CR) rate. Secondary endpoints were: CR duration, DFS, OS, safety, and early mortality. Results: 17 pts were enrolled on study so far. The median age was 74 yrs (range, 64-81); the median PS was 1 (0-1). The karyotypes in these pts were: diploid in 6 (35%), complex with chromosome (chr) 5 and/or 7 abnormality (abnl) in 4 (24%), complex without chr 5 and/or 7 abnl in 2 (12%), 11q abnl in 1 (6%), poor metaphases in 1 (6%), and other in 3 (18%). Four pts with prior MDS were treated with a median of 2 prior therapies (1-3). Median bone marrow blast % at the start of therapy was 40 (15-87). The median WBC, hemoglobin, and platelets were 2.1 (0.4–24.8), 8.9 (7.7–10.7), and 45 (14–104), respectively. These pts have received a median of 1 (1-3) cycle of therapy. Of the 11 pts evaluable for response, there were 2(18%) CR, 1(9%) CRp, 1(9%) PR for an ORR of 4/11 (36%). Five pts had no response and were taken off study. Two pts died on study: 1 on day 6 and 1 on day 27. Both pts were 74 yrs with a complex karyotype. One died of pneumonia and multi-organ failure and the 2 nd died from cardiac arrest. Other than the deaths, serious adverse events included grade 3 transaminitis in 1 and grade 3 heart failure in 1. Conclusions: OM and LDAC appears to be tolerable in older pts with AML. The combination appears to have activity. Stopping boundaries for futility and safety have not been breached. Enrollment is ongoing.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.6592
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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