13 research outputs found
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Phase 2 Study of Decitabine in Combination with Tretinoin in Myelodysplastic Syndromes and Acute Myelogenous Leukemia: Interim Results
Abstract
Abstract 3815
Background:
The activity of DNA methyltransferase inhibitor (DNMTI) monotherapy is suboptimal for most patients (pts) with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). DNMTI combinations studied to date have not convincingly produced higher response rates compared to DNMTI monotherapy, although time to response appears to be improved in some studies. We combined decitabine (DAC) with tretinoin (ATRA), an RAR ligand which can recruit histone acetyltransferases to gene regulatory regions, as a means to upregulate gene expression, and to induce apoptosis or differentiation, as is seen in in vitro studies of non-M3 AML. Our previous phase 1 study established 65 mg/m2/day of ATRA as the MTD (headache was DLT at 85 mg/m2/d) when given on days 10–19 following standard dose decitabine (20 mg/m2/d), given on days 1–5 of a 28-day cycle (Klimek VM, et al. Leuk Res, 2011;35:S70-S).
Materials and Methods:
MDS pts with any FAB or WHO subtype were enrolled if they had an IPSS score ≥ 0.5, were ineligible for allogeneic stem cell transplant (AlloSCT) at study entry, and had adequate hepatic and renal function. Prior DAC or 5-azacytidine (5-aza) responders who then progressed off treatment, and pts whose MDS progressed on 5-aza were eligible. Pts received up to 10 cycles of DAC (given on days 1–5) and tretinoin (65 mg/m2/d on days 10–19 of a 28-day cycle), allowing for delays due to infection or to allow count recovery as deemed necessary by the treating physician. Those with an ongoing response after 10 cycles continued DAC alone off-study. The primary endpoint is efficacy, assessed after even-numbered cycles using the 2006 Modified International Working Group MDS response criteria. Kaplan-Meier methodology was used to estimate duration of best response due to the censoring for patients undergoing AlloSCT.
Results:
36 eligible pts (27M, 9F; median age 66, range 45–84 yrs) were enrolled in the phase 2 cohort as of 6/2012. FAB/WHO subtypes included: RA/RCMD, n=3 (8%); RARS/RCMD-RARS, n=1 (3%); RAEB/RAEB-1 & 2, n= 24 (67%); RAEBt/AML, n= 6 (17%); CMML/CMML-1, n=2 (6%). IPSS risk categories included: Int-1, n=5 (14%); Int-2, n=16 (44%); High Risk, n=11 (31%), and pts with ≥ Int-1 (n=3) or ≥ Int-2 (n=1) risk disease who could not be definitively classified using the IPSS. Most pts (n=20) had IPSS poor risk cytogenetics (CG), 11 had IPSS good risk CG (all with normal karyotype), 3 had intermediate risk CG, and CG results were unknown in 2 pts. 15/36 (42%) had therapy-related disease (t-MDS/AML), all with IPSS poor risk CG and either IPSS Int-2 (n=9) or High Risk (n=6) disease. Marrow blasts were ≥ 5% in 26/36 pts: (5–10%, n=13; 11–20%, n=13; 21–30%, n=6). Prior MDS therapy included lenalidomide (n=2), thalidomide (n=1), 5-aza (n=3), DAC (n=1), and lintuzumab (n=1). Pts received a median of 4 cycles of therapy (range, 1–10), and started therapy 0.6–180 months (median, 1.42 months) from the time of diagnosis. Two pts were classified as treatment failures since they died during the first cycle of therapy. One pt with CMML-1 at baseline progressed to AML during the screening period, and was deemed ineligible. Two pts on study have not yet had a full response assessment. Best responses in the evaluable intent to treat cohort (n=33) include: CR, n=7 (21%); PR, n=1 (3%); mCR, n=3 (9%); mCR+HI, n=3 (9 %); HI alone, n=3 (9 %); Stable disease, n=10 (30%); Disease progression, n= 3 (9%). The composite CR rate (CR+mCR±HI) was 39% (13/33), and the overall response rate (CR+PR+mCR±HI+HI) is 51% (17/33). Median time from diagnosis to start of therapy for responders was 1.7 months (range, 0.8–180). The ORR for the 13 t-MDS/AML pts was 46% (6/13), including 5 pts with monosomy 17 and/or p53 loss by FISH. The median time to initial response and best response is 1.1 months and 2.3 months, respectively. The median response duration is 7.8 months, incorporating the 7 pts censored at the time they came off study to undergo AlloSCT.
Conclusions:
DAC/ATRA is active in IPSS Int-2 and High Risk MDS and in t-MDS/AML, which is characterized by poor risk cytogenetics and an increased frequency of p53 or chromosome 17p loss. Although our interim ORR appears similar to DAC and 5-aza monotherapy trials, our results were achieved in a higher risk cohort, and the CR rate is equal to or greater than some earlier monotherapy studies with a shorter median time to response. Ongoing and planned correlative studies may define pre-treatment biomarkers for response.
Disclosures:
Off Label Use: Tretinoin
Sequential Cytarabine and a-Particle Immunotherapy with Bismuth-213¿Lintuzumab (HuM195) for Acute Myeloid Leukemia
Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with ß-emitters, the a-particle¿emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to
determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted a-emitter, after partially cytoreductive chemotherapy.
Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg).
Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade =2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi-lintuzumab was achieved after partial cytoreduction with cytarabine.
Conclusions: Sequential administration of cytarabine and 213Bi-lintuzumab is tolerable and can produce remissions in patients with AMLJRC.E.5-Nuclear chemistr
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Administration of All-Trans Retinoic Acid (ATRA) to Newly Diagnosed Patients (pts) with Acute Promyelocytic Leukemia (APL) Is Delayed Even At Experienced Centers and Associated with An Increased Early Death Rate (EDR): A Retrospective Analysis of 205 Pts
Abstract
Abstract 942
Background:
Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration.
Methods:
To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel's largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration.
Results:
We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC >10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later.
Conclusions:
(1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era.
Disclosures:
No relevant conflicts of interest to declare