Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation ...acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in “landscaping” genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in “proliferative” genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Internal (eg, design) and external (eg, SCT) factors affect endpoint interpretation.•OS is the gold standard in AML endpoints, but other endpoints are gaining ground.•Time-to-event endpoints are ...often interpreted using the HR and associated P values.
Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial’s statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, ...nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings. Patients receiving TKI agents for CML should be monitored for signs and symptoms of toxicity throughout therapy. Preemptive assessment, early toxicity recognition, and prompt management of cardiovascular, metabolic, and pulmonary toxicities can minimize treatment-limiting complications and improve outcomes in patients with CML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in ...DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
•Enasidenib, a selective inhibitor of mutant IDH2 enzymes, was safe and well tolerated in patients with IDH2-mutated myeloid malignancies.•Enasidenib induced hematologic responses in patients with relapsed/refractory AML in this dose-escalation and expansion study.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine ...clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute ...myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.
In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.
Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).
Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.
Is there a standard of care for relapsed AML? Medeiros, Bruno C.
Best practice & research. Clinical haematology,
December 2018, 2018-12-00, 20181201, Volume:
31, Issue:
4
Journal Article
Peer reviewed
Despite advances in treatment for acute myeloid leukemia (AML), the prognosis for patients with relapsed disease is extremely poor. The median overall survival for patients with relapsed AML ranges ...from 4–6 months and long-term survival from the time of relapse ranges from 5%–20%. Much of the difficulty in establishing a standard of care for relapsed AML is that the disease is clinically and genomically diverse. Nevertheless, significant progress has been made over the past 12 months with the approval of several agents, and the expectation is that additional therapies will be available soon. A brief review follows on the progress made in establishing a standard of care for relapsed AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations ...specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the ...pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.
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•IL-1β signaling has paradoxical growth effects on AML and normal progenitors•AML patients are dependent on IL-1 signaling regardless of mutation status•Targeting the IL-1 receptor inhibits AML cell growth and disease progression in vivo•Blocking IL-1 via p38MAPK suppresses AML growth and enhances normal hematopoiesis
Carey et al. show that most AML patients are dependent on IL-1 and suggest that an IL-1-rich environment promotes the expansion of AML progenitors while suppressing normal progenitors by differently influencing cell proliferation, survival, and differentiation. AML patients with aberrant IL-1 signaling may benefit from therapeutically targeting this pathway to enhance normal hematopoiesis while inhibiting AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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