scholarly journals Modified Intensive Induction Treatment for Elderly Acute Myeloid Leukemia Patients Based on Peripheral Blast Clearance Rate: A Phase II Single-Arm Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1260-1260
Author(s):  
Ya Li ◽  
Xiaoyang Li ◽  
Hongming Zhu ◽  
Yunxiang Zhang ◽  
Yu Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Event Free Survival ◽  
Free Survival ◽  
Elder Patients ◽  
Lost To Follow Up ◽  
Acute Myeloid

Abstract Background Outcomes and prognosis of older patients with acute myeloid leukemia (AML) are fairly dismal and poor tolerance to regimens hinders treatment decision-making to expand to the greatest extent. Nevertheless, it is still indicated that a certain proportion of elder patients may benefit from intensive therapies [1], after which the insistent need for algorithms to select elder patients fit for intensive regimens has emerged. Based on the previous achievement, monitoring the peripheral blast clearance rate on the day 5 of induction chemotherapy (D5-PBCR) showed its promising value in younger patients [2]. Along with the increasingly important comprehensive geriatric assessment (CGA), we conducted this trial in fit elderly AML patients to confirm the non-inferior efficacy of modified intensive treatment on the basis of D5-PBCR. Materials and methods This multiple-center, single-arm, phase 2 trial of early intervention according to D5-PBCR results with modified "3+7" regimen was performed at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) and the other two hospitals in Shanghai. Patients aged 60-75 years were assessed via CGA and required to be fit for intensive chemotherapy. Eligible patients had newly diagnosed AML with more than 0·5% blasts detected in the peripheral blood and adequate end-organ function. The initial induction included idarubicin (6 mg/m² for 3 days) and cytarabine (100 mg/m² for 7 days). Peripheral blood specimens were collected before and on day 5 of induction and analyzed by multi-parameter flow cytometry to calculate the D5-PBCR. D5-PRCR (+) patients received extra IDA (6 mg/m² for 2 days) starting from induction day 6 with the absence of contraindications. Responders received another "2+5" regimens and at least two cycles of mediate dose cytarabine or even allogeneic stem cell transplantation, if eligible. The primary endpoint was composite complete remission (CR/CRi), and secondary endpoints were overall survival, event-free survival, early mortality, minimal residual disease after one cycle of induction, drug toxicity, and safety. The trial was registered in the Chinese Clinical Trial Register (ChiCTR-OPC-16008955). Results Between March 30, 2016, and June 30, 2021, a total of 120 eligible patients were enrolled in the trial (Fig.1). Fifty-nine (49.2%) patients were D5-PBCR (+), of which seventeen patients were ineligible for extra idarubicin due to severe infection or unstable hemodynamic parameters and one patient was lost to follow-up. None of the patients in the D5-PBCR (-) group discontinued induction due to adverse events, and three patients were lost to follow-up. The composite complete remission rate after one course of induction for all patients was 62.6% (62/99), with 65.5% (38/58) and 58.5% (24/41) for D5-PBCR (-) and D5-PBCR (+) groups, respectively (P=0.497). At a median follow-up of 24.3 months (95% CI 10.4-38.2), median overall survival (OS) was 20.0 months (95% CI 15.2-24.8) and 13.6 months (95% CI 9.8-17.4), and the median event-free survival (EFS) was 7.8 months (95% CI 2.5-13.1) and 6.6 months (95% CI 4.3-8.9), respectively (Fig.2). Neither the OS nor EFS showed significant differences between the two groups. The total 30-day mortality rate of the two cohorts was 6.8% (7/103). The median platelet recovery time (PLT>50×109/L) after induction therapy in CR/CRi was different between patients with D5-PBCR(-) and D5-PBCR(+) (22 days vs 26 days, P=0.000, Fig.2F). There was a trend but no significant difference in the recovery time of neutrophils (ANC>0.5×109/L) in two cohorts (21 days vs 23 days, P=0.025, Fig.2E). The incidence of adverse events during the first induction was comparable between the two groups and key adverse events of grade ≥3 included pneumonia(37%), sepsis (7%), and γ-glutamyl transpeptidase(GGT) increase (6%) in the entire cohort(Table.1). Conclusion: "3+7" regimen modified by the composition of D5-PBCR and CGA was safe and tolerable in fit older patients with AML. The efficacy and safety of induction were non-inferior compared with the results of existing trials, along with a relatively lower dose of IDA. We considered there may be reserved probability for combining other emerging drugs to challenge higher remission rate in fit AML with additional investigation. Keywords: acute myeloid leukemia; elderly; induction therapy; non-inferior; flow cytometry; D5-PBCR. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia

2018 ◽  
Vol 141 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Li Wang ◽  
Jun Xu ◽  
Xiaolong Tian ◽  
Tingting Lv ◽  
Guolin Yuan
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Remission Rate ◽  
Chinese Patients ◽  
Acute Myeloid

Background/Aims: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. Methods: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1–5), 2 g/m2/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5). The median follow-up duration was 10 months. Results: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 ± 6.0% and 3-year OS of 16.7 ± 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts ≥42.1% were correlated with an unfavorable CR. Secondary disease, age ≥60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). Conclusion: CLAG was effective and well tolerated for R/R AML. BM blasts ≥42.1%, age ≥60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis.

scholarly journals Effect of Diagnosis (Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, or Acute Myeloid Leukemia [AML]) on Outcome of AML-Type Chemotherapy

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 2969-2977 ◽  
Author(s):  
Elihu Estey ◽  
Peter Thall ◽  
Miloslav Beran ◽  
Hagop Kantarjian ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Multivariate Analyses ◽  
Patient Characteristics ◽  
Refractory Anemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Current Medical Practice ◽  
Acute Myeloid

Abstract In current medical practice, patients with refractory anemia with excess blasts in transformation (RAEB-t), and especially patients with RAEB, receive chemotherapy regimens (AML Rx) administered to patients with acute myeloid leukemia (AML) less often than do patients with AML. These entities are distinguished primarily by marrow blast percentage (5% to 19% RAEB, 20% to 29% RAEB-t, and ≥30% AML). The poor prognosis of many RAEB or RAEB-t patients, if untreated, led us to give them AML Rx using the same plan as for AML. The purpose of this analysis was to see if diagnosis (RAEB, RAEB-t, or AML) affected outcome. We treated 372 patients with AML (acute promyelocytic leukemia [APL] excluded), 106 with RAEB-t, and 52 with RAEB. AML Rx produced a 62% complete remission (CR) rate in RAEB, essentially identical to the rates in RAEB-t and AML, but event-free survival (EFS) from CR and from start of treatment (start of Rx), as well as overall survival, were poorer in RAEB than in AML or RAEB-t, with AML and RAEB-t being identical. However, patients with RAEB or RAEB-t were more likely to have poor prognostic characteristics, in particular complex abnormalities involving chromosomes 5 and/or 7. Multivariate analyses indicated that, when considered together with cytogenetics and other patient characteristics, a diagnosis of RAEB rather than AML or RAEB-t had no effect on EFS from start of Rx, EFS from CR, survival, or achievement of CR. These analyses suggested a trend for patients with RAEB-t to have better EFS from start of Rx than patients with AML or RAEB (P = .08; relative risk, 0.80; 95% confidence interval, 0.62 to 1.03), but there were no differences with respect to the other outcomes. Our data suggest that the propriety of administering AML Rx to patients with RAEB or RAEB-t who have poor prognosis without treatment is identical to the propriety of treating AML in this fashion. Deterrents to standard AML Rx in these patients could justifiably include cytogenetics, age, etc, but not a diagnosis of RAEB or RAEB-t per se.

scholarly journals Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

2017 ◽  
Vol 3 (6) ◽  
pp. 773-781 ◽  
Author(s):  
Abhijeet Ganapule ◽  
Sandeep Nemani ◽  
Anu Korula ◽  
Kavitha M. Lakshmi ◽  
Aby Abraham ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cost Effectiveness ◽  
Myeloid Leukemia ◽  
Cost Effective ◽  
Effective Strategy ◽  
Event Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Acute Myeloid

Purpose There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively ( P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% ( P = .003) and 63.8 ± 6.4% versus 32.3 ± 7.9% ( P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

scholarly journals MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

2017 ◽  
Vol 35 (35) ◽  
pp. 3964-3977 ◽  
Author(s):  
Emilia L. Lim ◽  
Diane L. Trinh ◽  
Rhonda E. Ries ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxidative Phosphorylation ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Outcome Prediction ◽  
Classification Scheme ◽  
Event Free Survival ◽  
Free Survival ◽  
Pediatric Aml ◽  
Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

scholarly journals Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia

Cancer ◽  
2008 ◽  
Vol 113 (6) ◽  
pp. 1370-1378 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Hagop M. Kantarjian ◽  
Sijin Wen ◽  
Michael J. Keating ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloid Sarcoma ◽  
Event Free Survival ◽  
Free Survival ◽  
Acute Myeloid

scholarly journals High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2570-2570
Author(s):  
George S. Laszlo ◽  
Todd A. Alonzo ◽  
Chelsea J. Gudgeon ◽  
Kimberly H. Harrington ◽  
Alex Kentsis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Event Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Acute Myeloid ◽  
Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

scholarly journals Acute Myeloid Leukemia Treatment Outcomes: First Report from Single Center Retrospective Study in Kazakhstan

2021 ◽  
Author(s):  
Jamilya Saparbay ◽  
Gulnara Kulkayeva ◽  
Vadim Kemaykin ◽  
Aset Kuttymuratov ◽  
Zhanna Burlaka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Good Prognosis ◽  
Event Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common hematological malignancy in adults. In the last decade, internationally approved AML treatment guidelines, including hematopoietic stem cell transplantation are widely used in Kazakhstan. The categorization of acute myeloid leukemia was done according to the French-American British classification. The prognosis of patients at the time of diagnosis was determined by cytogenetic tests following the guidelines of the European LeukemiaNet. The overall survival and event-free survival were analyzed using the Kaplan-Meier method, and hazard ratios were defined with Cox regression. Totally 398 patients with AML were treated in the National Research Oncology Center between 2010 and 2020. The mean age was 38.3 years. We have found the correlation between ethnicity, cytogenetic group, white blood cell count, and treatment approaches with overall and event-free survival. There was a significantly longer OS in a cytogenetic group with a good prognosis compared with intermediate and poor prognosis. The median survival time in the group with a good prognosis was 43 months, 23 months in the intermediate group (p=0.7), and 12 months in the poor prognosis group (p=0.016). There was a significantly longer OS for the group of patients who received hematopoietic stem cell transplantation (HSCT), 52 months versus 10 months in the group who received chemotherapy only, p-value < 0.0001. Prognostic factors, such as cytogenetic group, initial WBC count, and treatment approaches are significantly associated with patient survival. Our study data were consistent with previous reports.

scholarly journals Pathologic Features of Down Syndrome Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML0431

2019 ◽  
Vol 144 (4) ◽  
pp. 466-472 ◽  
Author(s):  
Kelley J. Mast ◽  
Jeffrey W. Taub ◽  
Todd A. Alonzo ◽  
Alan S. Gamis ◽  
Claudio A. Mosse ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Down Syndrome ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Event Free Survival ◽  
Diagnostic Features ◽  
Free Survival ◽  
Minimal Residual ◽  
Acute Myeloid

Context.— Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. Objective.— To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. Design.— Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, GATA1 mutation status, cytogenetics, and minimal residual disease results. Results.— Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. Conclusions.— Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome–related subtypes of acute myeloid leukemia and myelodysplastic syndrome.

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 257-270 ◽  
Author(s):  
Michael Lübbert ◽  
Olga Grishina ◽  
Claudia Schmoor ◽  
Richard F. Schlenk ◽  
Edgar Jost ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Histone Deacetylase ◽  
Odds Ratio ◽  
Myeloid Leukemia ◽  
Phase Ii Trial ◽  
Remission Rate ◽  
Free Survival ◽  
Acute Myeloid

PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses

2021 ◽  
Author(s):  
Kelly J. Norsworthy ◽  
Xin Gao ◽  
Chia-Wen Ko ◽  
E. Dianne Pulte ◽  
Jiaxi Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Strong Association ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Patient Level ◽  
Acute Myeloid

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

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