25 research outputs found
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A Phase II Trial of Combination Therapy with Arsenic Trioxide (ATO) and Gemtuzumab Ozogamicin (GO) in Patients with High-Risk Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) Arising from MDS
Abstract
Background: Bone marrow findings in high-risk MDS are similar to those found in AML. MDS-associated myeloblasts are just as likely to express CD33 as AML myeloblasts, and cytogenetic abnormalities are similar to those of older AML patients (pts). Therapies effective in AML may also have activity in advanced MDS. GO is an anti-CD33 monoclonal antibody covalently linked to calicheamicin, a cytotoxic agent. ATO works through apoptotic and pro-differentiating mechanisms, and may allow for enhanced GO cytotoxicity.
Methods: We conducted a multicenter trial in pts with high-risk MDS (IPSS score >1.5, or FAB or WHO classification with >5% CD33+ myeloblasts) or AML arising from MDS (with CD33+ myeloblasts) who had not received previous induction therapy, from 2/04 – 6/06. Pts received ATO (0.25mg/kg IV d1–5 during week 1, then twice weekly weeks 2–12) and GO (3mg/m2 on day 8) for 1 or 2 12-week cycles. Pts who had stable disease or improvement on a week 12 bone marrow biopsy received a second 12-week cycle, and then another week 24 biopsy. The primary endpoint was response as defined by the Modified International Working Group (IWG) criteria for MDS or, for AML patients, the IWG response criteria for AML.
Results: Twenty-two pts have been enrolled; 21 are evaluable for response. The median age was 69 years. Fourteen pts (64%) had MDS (4 RAEB-1, 8 RAEB-2, 2 CMML-2,) with IPSS cytogenetic risk groups of good (2), intermediate (6), poor (4) and no growth (2), and IPSS classifications of high (5), Int-2 (5), and Int-1 (2). Eight pts (36%) had AML with cytogenetic risk groups as defined by CALGB 8461: intermediate (4), adverse (3), and unknown (1). Fifteen pts received prior therapies, including growth factors (10), 5-azacytidine (5), hydroxyurea (3), prednisone (1), anagrelide (1), thalidomide (1), and lenalidomide (1). Pts had a median of 15% blasts: 11.5% for MDS pts; 43.5% for AML pts. Of the 21 pts, 11 (52%) completed 1 cycle of therapy; an additional 5 (24%) completed 2 cycles. Reasons for discontinuing therapy included: withdrawing consent (5), progressive disease (7), and toxicity (4). Responses occurred in 8 patients (38%): 8 (38%) by the IWG MDS criteria; 2 of 8 AML pts (25%) by the IWG AML criteria; and 2 (9%) by both criteria. Using the modified IWG MDS criteria, 2 patients had a partial remission, 3 had a neutrophil response, 2 had a platelet response, and 1 had both platelet and neutrophil response. Using the IWG AML Criteria, 2 AML pts achieved a partial remission. Grade3/4 non-hematologic toxicities included neutropenic fever or infection (6), fatigue (4), pulmonary complications (3), hepatotoxicity (1), renal failure (1), prolonged QTc (1), nausea (1), epistaxis (1), hypoxia (1). Of 20 pts evaluable for 6 month survival, 15 (75%) were alive, 7 (47%) of whom responded to treatment. Of 12 patients evaluable for 1-year survival, 4 (33%) were alive, 2 of whom responded to treatment. Pts who completed two cycles of therapy spent a median of 13 days in the hospital.
Conclusion: The combination of ATO + GO is well-tolerated and yields hematologic responses, particularly in neutrophils and platelets. This combination may be a viable alternative to high-dose, inpatient therapy in pts with high-risk MDS or secondary AML
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Assessing eligibility for non-intensive chemotherapy (IC) randomized clinical trials (RCT) in patients (pts) with newly diagnosed (ND) AML from the Connect Myeloid Disease Registry
7029 Background: Pts with AML in RCTs often do not reflect the population seen in clinical practice due to strict eligibility criteria. This study evaluated criteria from a recent RCT of non-IC against a broad cohort of real-world pts with AML from the Connect ® Myeloid Disease Registry (NCT01688011). Methods: Pts were stratified into 3 groups based on the non-IC phase 3 VIALE-A trial eligibility criteria: 1) “eligible” pts who would have met all VIALE-A inclusion criteria; 2) “unfit” pts who would have been ineligible for VIALE-A due to ≥ 1 of the following: abnormal liver/kidney function, high ECOG, recent prior malignancy, comorbidities score ≥ 2 by ACE-27, hepatic grade ≥ 1, AIDS grade ≥ 1; 3) “fit” pts who would have been ineligible for VIALE-A because they would have qualified for IC (defined as: ≤ 74 y of age, low ECOG, no apparent cardiovascular/renal comorbidities, and did not meet any criteria in #2). Baseline characteristics were summarized by eligibility group. Overall survival (OS) by group was estimated using the Kaplan–Meier method. Induction regimens were categorized as IC (any regimens containing 7+3, MEC, CLAG, FLAG) or venetoclax (VEN)-based. Hazard ratios (HRs) for induction regimens among each group were estimated using Cox models adjusted for age, ELN risk, ECOG, frailty score, and comorbidity index. Results: Of 734 enrolled pts with AML (Dec 2021), most were male (61%) and white (84%); median age 71 y (range 55–97). Only 26% of pts (n = 192) were eligible for a non-IC RCT, 45% (n = 327) were ineligible due to unfitness, and 29% (n = 215) were ineligible due to overall fitness. The main reason for non-IC RCT ineligibility was high overall comorbidity grade (n = 265 [36%]). Fit pts intended to undergo transplant more often compared with unfit pts. Median OS for eligible, unfit, and fit pts were 14, 10, and 22 months, respectively. Among unfit pts, those receiving IC had significantly longer OS compared with pts receiving a VEN-based regimen (median OS 14 vs 6 months, respectively; HR: 0.51, 95% CI: 0.27–0.98, P = 0.042; Table). Eligible pts who received IC tended to have shorter median OS (13 months) vs pts who received VEN-based therapies (23 months; not sig.). Conclusions: The majority of pts with ND AML in the Registry would have been ineligible for a non-IC RCT due to being too fit or unfit. Pts ineligible for an RCT due to unfitness but who received IC maintained an OS benefit vs those receiving VEN-based therapies. This analysis suggests that non-IC RCTs may be excluding pts who appear unfit but can potentially tolerate IC and experience improved survival outcomes. Clinical trial information: NCT01688011. [Table: see text
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Phase 3 (P3) study of quizartinib (Q) or placebo (P) with induction (IND) and consolidation chemotherapy (CON) and as maintenance (MN) in patients (pts) with newly diagnosed (NDx) FLT3 -ITD–positive acute myeloid leukemia (AML): the QuANTUM-First study
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Ivosidenib (IVO) prior to hematopoietic cell transplant for patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (R/R AML)
7521 Background: Allogeneic hematopoietic cell transplantation (HCT) provides a potentially curative option for patients (pts) with R/R AML. Disease status at the time of transplant is a major determinant of long-term prognosis, with pts typically receiving salvage chemotherapy prior to HCT to induce a remission. However, older and/or heavily pre-treated pts frequently cannot tolerate intensive chemotherapy (IC) or do not obtain adequate disease control to permit an HCT. IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥75 y of age or ineligible for IC, and those with R/R AML. We assessed HCT outcomes in pts with m IDH1 R/R AML who proceeded to HCT after treatment with IVO in a phase I study (NCT02074839). Methods: Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with m IDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported. m IDH1 variant allele frequency (VAF) from bone marrow mononuclear cells was assessed using BEAMing digital PCR (0.02–0.04% VAF detection limit). Results: Among 179 pts with R/R AML treated with IVO, 18 proceeded to HCT: median age, 61.5 y (range 36–68); 56% male; 16.7% had secondary AML; 27.8% had ≥3 prior regimens; 11.1% had a prior HCT. The median duration of IVO treatment prior to HCT was 3.9 mo (range 2.1–15.2). The last reported response prior to HCT was 50.0% CR. Six- and 12-mo post-HCT survival rates were 77.8% and 50.0%; median relapse-free survival post HCT was 7.3 mo (range 2.6–NE). Median OS from start of IVO was 16.8 mo (95% CI 9.2, NE) for HCT pts vs 9.0 mo (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time, 33.2 mo (range 3.2–41.9). Eight HCT pts were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Median OS was not estimable (95% CI 9.1, NE) for the 12 HCT pts who achieved CR after IVO therapy and was 20.5 mo (95% CI 16.4, NE) for the 31 CR pts who did not undergo HCT. m IDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT. Conclusions: IVO monotherapy is a putative treatment option to induce remissions prior to HCT for m IDH1 R/R AML pts who are not considered candidates for intensive salvage therapy. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combination salvage therapies prior to HCT. Clinical trial information: NCT02074839
Seven-year follow-up for energy/vitality outcomes in early stage Hodgkin’s disease patients treated with subtotal lymphoid irradiation versus chemotherapy plus radiation: SWOG S9133 and its QOL companion study, S9208
PurposeWe describe 7 years of follow-up for the energy/vitality outcome in early-stage Hodgkin's disease patients treated on a randomized clinical trial that compared subtotal lymphoid irradiation (STLI) with combined modality treatment (CMT) (SWOG 9133). Survivorship research questions involved the extent to which symptoms/side effects endured over a follow-up period of 7 years for this early-stage patient group.MethodsTwo hundred thirty-nine patients participated in the quality of life (QOL) companion study (SWOG 9208) and completed the SF-36 vitality scale, SF-36 health perception item, Cancer Rehabilitation Evaluation System-Short Form (CARES-SF), and symptom distress scale. This paper reports vitality outcome results obtained from randomization, 6 months, and annually for 7 years. To assess changes in vitality over time, we used linear mixed models with patient as a random effect.ResultsPatients receiving CMT had lower observed vitality at 6 months than did the STLI patients (p < .0001). However, beginning at year 1, vitality results did not differ significantly by treatment over the 5-year (p = .13) and 7-year (p = .16) follow-up periods. Vitality only slightly improved over baseline in either group after treatment. The results were similar after accounting for patterns of recurrence and missing data.ConclusionsThis study demonstrated that patients with early-stage Hodgkin's disease experience a short-term (at 6 months) decrease in vitality with treatment, which is more severe with CMT, but that after the first year, vitality scores were similar between the two treatment groups. Enduring fatigue results for patients receiving these therapies were not observed. Implications for cancer survivors These data provide comprehensive 7-year follow-up vitality information, an important symptom for early-stage lymphoma survivors
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Ivosidenib in patients with IDH1 -mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy
7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text