A B S T R A C T PurposeRelapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated highdose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and MethodsSixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m 2 , without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). ResultsThe CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single-and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). ConclusionHigh-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.
Background CPX-351 is a liposome-encapsulated fixed-molar ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance anti-leukemic efficacy. Methods This Phase II study randomized 125 patients 2:1 to CPX-351 or investigator’s choice of first salvage chemotherapy. Patients with acute myeloid leukemia in first relapse after initial CR lasting ≥1month were stratified per European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based upon duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with one or more additional agents. Survival at 1-year was the primary efficacy endpoint. Results Patient characteristics were well balanced between the two study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs. 27.6%), improvements in event-free survival (HR=0.63, p=0.08) and overall survival (HR=0.55, p=0.02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs. 24.1%). Conclusion Taken together, the data suggest possible improved outcome in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.
Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult AML patients from six urban cancer centers and revealed inferior survival among NHB (HR=1.59, 95% CI: 1.15, 2.22) and Hispanic (HR=1.25, 95% CI: 0.88, 1.79) compared to NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across six composite variables: structural racism (census tract disadvantage, affluence and segregation), tumor biology (ELN risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization) and ICU admission during intensive chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, as well as treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.
Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).
Early treatment of CLL/SLL does not impact survival-reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic-based prognostic model. Fifty-nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL-10, IL-5, sIL-2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL-17, IL-23, IFN-γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL-2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow-up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL-17/sIL-2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy.
CD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor,
CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar drug ratio, achieved superior efficacy compared with conventional chemotherapy in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML) in phase 2 and 3 studies. Prior to CPX-351 commercialization, an expanded access program (EAP) provided CPX-351 access for this population in the United States. In this phase 4, single-arm, openlabel study (NCT02533115), 52 patients were treated with CPX-351 for 1-2 induction cycles and 4 consolidation cycles. The primary endpoint was safety. The most common serious adverse events were febrile neutropenia (19%), pneumonia (10%), and infection (8%). The 30-and 60-d mortality rates were 0% and 6%, respectively. Remission was achieved by 44% of patients; 90% of patients were alive at study completion. Overall, these results support outcomes from prior studies and the use of CPX-351 in older adults with newly diagnosed, high-risk/secondary AML.
Our objective was to explore associations of circulating factors implicated in insulin-like growth factor- 1 receptor (IGF-1R) signaling with clinical outcomes of patients with acute myeloid leukemia (AML). Pretreatment blood samples from patients with non-M3 AML (n = 30) were collected prospectively and levels of IGF binding proteins (IGFBPs) 1-7 and IGF-1 (free and total) were established at diagnosis and statistically evaluated. Baseline levels of IGFBP-1 and -6 below respective thresholds of 8.8 ng/mL and 237 ng/mL were associated (p = 0.0347 and 0.0099, respectively) with superior progression-free survival, whereas baseline levels of IGFBP -1, -2, -6 and -7 below the respective thresholds of 8.8, 28.8, 237 and 119 ng/mL were strongly associated (p = 0.0004, 0.0085, 0.0031, 2.46 × 10(- 7), respectively) with improved overall survival. These findings provide promising evidence that IGFBP signatures could be used as predictive tools in AML, with applications in remission surveillance and the development of IGFBP-directed biologic therapy.
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