Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML

2010 ◽  
Vol 202 (2) ◽  
pp. 108-122 ◽  
Author(s):  
Birgitte S. Preiss ◽  
Olav J. Bergmann ◽  
Lone S. Friis ◽  
Anne G. Sørensen ◽  
Michael Frederiksen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Secondary Acute Myeloid Leukemia ◽  
De Novo Aml ◽  
Acute Myeloid

scholarly journals De Novo and Secondary Acute Myeloid Leukemia, Real World Data on Outcomes from the French Nord-Pas-De-Calais Picardie Acute Myeloid Leukemia Observatory

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4013-4013 ◽  
Author(s):  
Loïc Renaud ◽  
Olivier Nibourel ◽  
Celine Berthon ◽  
Christophe Roumier ◽  
Céline Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Supportive Care ◽  
Real World ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Secondary Aml ◽  
Secondary Acute Myeloid Leukemia ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background. Population-based registries may provide data complementary to that from clinical intervention studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations like secondary Acute Myeloid Leukemia (AML). Actually, secondary AML are frequently excluded from clinical trials so the registries constitute the only way to fine data for establishing recommendations for the management of these patients in the real world. Method. The French Nord-pas-de-calais Picardie AML observatory containing 1 582 AML patients diagnosed between 2000 and 2015. We compared 974 primary AML to 514 Secondary AML include AML arising from a pre-existing myelodysplastic (n=211), myeloproliferative (n=88) or myelodysplastic/myeloproliferative (n=57) disease and therapy related AML (t-AML) (n=158). Results. Median survival and 5 years overall survival were respectively 420 days [95%IC: 349-491] and 32% for patients with de novo AML; 157 days [95%IC: 118-196] and 7% for patients with secondary AML. 1101 patients were classified according to the MRC as favorable, intermediate and unfavorable, respectively 18(5.2%), 178(51.9%) and 147(42.9%) patients with secondary AML including 100(29.2%) complexes karyotypes and 117(15.4%), 468(61.7%) and 173(22.8%) patients with de novo AML including 121 (15.9%) complexes karyotypes. 987 patients were classified according to the ELN as favorable, intermediate-1, intermediate-2 and unfavorable for respectively 35(11.7%), 53(17.7%), 67(22.%) and 144(48.2%) patients with secondary AML and 219(31.8%), 167(24.%), 136(19.8%) and 166(24.1%) patients with de novo AML. The age at diagnosis was significantly different (p < 10-3) with a median of 72.6 years for secondary AML and 63.2 for de novo AML. 206 (40.4%) patients with secondary AML received demethylating agents versus 184 (19%) for de novo AML and 152(29%) received high dose chemotherapy (HDC) versus 619 (63.9%) patients with de novo AML. Best supportive care was the only treatment for 170 (17.5%) de novo AML and 164 (31.9%) secondary AML patients. For patients over than 60 years old, median survival and 5 years overall survival were respectively 182 days [95%IC: 136.5-127.4] and 12.9% for 559 patients with de novo AML; 128 days [95%IC: 95.0-161.0] and <4% for 413 patients with secondary AML. Conclusion. The poor prognosis of secondary and t- AML is confirmed by this registry study. Possible explanations for this worse outcome could be older age at diagnosis and increased frequency of complex karyotypes which lead to less intensive therapy or supportive care only. In this specific population, the choice of demethylating agent therapy was frequently made because of the weak efficacy of HDC and increased frequency of side effects in this vulnerable group. Disclosures No relevant conflicts of interest to declare.

Gene Mutations in Paired Initial Presentation and Relapse Samples From Acute Myeloid Leukemia Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3592-3592
Author(s):  
Satoshi Wakita ◽  
Hiroki Yamaguchi ◽  
Yoshio Mitamura ◽  
Fumiko Kosaka ◽  
Takashi Shimada ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
Gene Mutations ◽  
Initial Presentation ◽  
Paired Samples ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3592 Introductions: Gene mutationswere found in acute myeloid leukemia (AML) and their importance has been noted. Flt3, NPM1 and CEBPA were detected in “intermediate cytogenetic risk” group, and are becoming possible to distinguish subsets of patients with different outcomes. Moreover, several groups have reported that these mutations would be useful for not only predictive markers, but also minimal residual disease (MRD) markers in AML. Several recent studiesprovided compelling evidence that mutations in epigenetics modifying genes contribute to AML pathogenesis. DNMT3a mutations were common (about 20% frequency) in de novo AML and associated with poor prognosis. Furthermore, mutations of IDH1/2 and TET2 that also seem to be collaborating on DNA methylation modifying are detected, too. To clarify the importance and dynamics of these mutations in clinical course, we examined Flt3, NPM1, CEBPA, DNMT3a and IDH1/2 gene mutations in paired samples at initial presentation and relapse of AML patients. Materials and Methods: We analyzed the samples from adultpatients with de novo AML diagnosed at Nippon Medical School Hospital from 2000 to 2010. Mutation analyses were performed for Flt3 ITD by PCR amplification, Flt3 TKD by PCR-RFLP, and NPM1, CEBPA, IDH1/2 and DNMT3a mutations by direct sequence. Results: The 31 AML patients were enrolled. In chromosomal analysis at initial presentation, 19 with normal karyotype (NK-) AML, 2 with trisomy8, 4 with 11q23 associated, 1 with monosomy7, 2 with complex karyotypes and 3 with non-specific aberrations were observed. 15 cases were comparable for paired samples at diagnosis and relapse. 13 of them (86.7%) showed additional chromosomal aberrations at relapse. Gene mutations were detected more frequently in cytogenetic intermediate risk group (83.3%) than poor risk group (0%). There were 11 patients with Flt3 ITD at initial presentation, but 3 of them had no detectable mutation at relapse. Flt3 TKD were found in 3 patients at initial presentation, but all of them were lost at relapse. Among 12 patients with NPM1 mutation at initial presentation, 3 of them lost their mutation at relapse. CEBPA mutation was detected in only one paired sample at diagnosis and relapse. DNMT3a mutations were detected in 8 patients both at initial presentation and relapse. IDH2 mutations were detected in two patients at initial presentation, but 1 of them was lost at relapse. In summary, of the 37 gene mutations at initial presentation, 10 gene mutations were lost at relapse, and only 1 acquired gene mutation was detected at relapse. Flt3 ITD, NPM1, DNMT3a and IDH2 mutations frequently coexisted with another mutation. Discussion: This study is the first report of consecutive analyses on the major gene mutations in AML. Newly acquired gene mutations at relapse are rare compared to frequent additional chromosomal aberrations at relapse. Flt3 ITD mutations at initial presentation were detected also at relapse. This finding indicates that Flt3 ITD are responsible for relapse and refractoriness. On the other hand, all 3 cases with Flt3 TKD lost the mutation at relapse, suggesting that Flt3 TKD mutation does not contribute to their relapse. Some of Flt3 ITD, Flt3 TKD and NPM1 mutations could not be detected at relapse, indicating that these mutations should be used carefully for MRD marker. DNMT3a mutations were detected both at diagnosis and relapse in all 8 cases. This finding suggests that DNMT3a mutations might be a useful MRD marker. Disclosures: No relevant conflicts of interest to declare.

Acute Myeloid Leukemia With t(8;21)/RUNX1-RUNX1T1 demonstrate a High Number Of Secondary Genetic Lesions: Frequency and Impact On Clinical Outcome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2565-2565
Author(s):  
Maria Theresa Krauth ◽  
Christiane Eder ◽  
Tamara Alpermann ◽  
Wolfgang Kern ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Trisomy 8 ◽  
Employment Equity ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background Translocation t(8;21) with the resulting RUNX1-RUNX1T1 rearrangement is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). Although it is generally associated with a favourable prognosis, many additional genetic lesions may impact on outcome. Aim To assess the frequency and clinical impact of additional mutations and chromosomal aberrations in AML with t(8;21)/RUNX1-RUNX1T1. Methods We analyzed 139 patients (pts) who were referred to our laboratory for diagnosis of AML between 2005 and 2012 (65 females, 74 males; median age 53.3 years, range 18.6 - 83.8 years). All pts were proven to have t(8;21)/RUNX1-RUNX1T1 by a combination of chromosome banding analysis, fluorescence in situ hybridisation and RT-PCR. Analysis of mutations in ASXL1, FLT3-TKD, KIT (D816, exon8-11), NPM1, IDH1 and IDH2, KRAS, NRAS, CBL, and JAK2 as well as of MLL-PTD and FLT3-ITD was performed in all pts. Results 107/139 pts were classified according to FAB criteria (77.0%). 34/107 had AML M1 (31.8%) and 73/107 AML M2 (68.2%). 117/139 had de novo AML (84.2%), 22/139 had therapy-related AML (t-AML) (15.8%). 69/139 (49.6%) pts had at least one molecular alteration in addition to RUNX1-RUNX1T1, 23/69 (33.3%) had two or more additional mutations. Most common were mutations (mut) in KIT (23/139; 16.5%), followed by NRAS (18/139; 12.9%) and ASXL1 (16/139; 11.5%). FLT3-ITD and mutations in FLT3-TKD, CBL, and KRAS were found in 4.3% - 5.0% of all pts, whereas mutations in IDH2 and JAK2 were detectable in 3.6% and 2.9%, respectively. IDH1 mutations were found in only 0.7% (1/139). NPM1mut and MLL-PTD were mutually exclusive of RUNX1-RUNX1T1. FLT3-ITD as well as FLT3-TKD were exclusive of ASXL1 mutations. With exception of FLT3-ITD, which was only present in de novo AML, there was no difference in mutation frequencies between de novo AML and t-AML. 69.8% (97/139) pts had at least one chromosomal aberration in addition to t(8;21)(q22;q22). Most frequent was the loss of either X- or Y-chromosome (together 46.8%), followed by del(9q) (15.1%), and trisomy 8 (5.8%). FLT3-ITD, FLT3-TKD and trisomy 8 were found to be mutually exclusive. The number of secondary chromosomal aberrations did not differ significantly between pts with de novo AML and t-AML, showing only a trend towards higher frequency of -Y, del(9q), and trisomy 8 in pts with t-AML. Survival was calculated in pts who received intensive treatment (n=111/139, 79.9%; median follow-up 26.9 months; 2-year survival rate 73.4%). With exception of KITD816 mutation, which had a negative impact on overall survival in pts with de novo AML (2-year survival rate 64.2% vs. 82.3%, p=0.03), none of the other 13 mutations significantly influenced outcome, not even in case of 2 or more coexistent mutations. Also, no influence of additional chromosomal aberrations on survival was found. In selected cases (n=21/139), we compared dynamic changes in the patterns of genetic lesions at diagnosis and at relapse. In 14/21 (66.7%) pts the initial molecular mutation pattern changed at relapse. Mutations commonly gained at relapse were KIT mutations (6/21, 28.6%), followed by ASXL1 and IDH1R132 (each 2/21, 9.5%). FLT3-ITD, CBL, NRAS and JAK2 mutations emerged in 1/21 patients (4.8%) each. Loss of a mutation at relapse has been observed in KIT, ASXL1, and NRAS (each 2/21, 9.5%), as well as in KRAS, FLT3-ITD and FLT3-TKD (each 1/21, 4.8%). Concerning chromosomal alterations at relapse, 7/21 pts (33.3%) showed a change of their initial cytogenetic pattern, mostly shifting to a more complex karyotype (gain of chromosomal aberrations: 5/21, 23.8%; loss of chromosomal aberrations: 2/21, 9.5%). In all cases, t(8;21)(q22;q22)/RUNX1-RUNX1T1 remained stable at time of relapse. Conclusions 1) 50% of t(8;21)/RUNX1-RUNX1T1 positive pts had at least one additional molecular mutation and almost 70% showed additional chromosomal abnormalities. 2) KIT was the most frequent additional molecular mutation, followed by NRAS and ASXL1. 3) The only additional genetic marker with a significant adverse prognostic impact was KITD816 mutation. Disclosures: Krauth: MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Secondary Acute Myeloid Leukemia Is an Heterogeneous Subgroup of Elderly AML Where Patient’s Fitness Criteria and ELN Prognostic Stratification Can be Applied to Guide Treatment Decisions: An Analysis of 127 Patients By the Network Rete Ematologica Lombarda (REL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 953-953
Author(s):  
Erika Borlenghi ◽  
Chiara Pagani ◽  
Claudia Basilico ◽  
Massimo Bernardi ◽  
Matteo Carrabba ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Treatment Modalities ◽  
Secondary Acute Myeloid Leukemia ◽  
Elderly Aml ◽  
Prognostic Stratification ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: According to the WHO classification, secondary acute myeloid leukemia (s-AML) includes cases occurring in patients (pts) receiving prior antineoplastic treatments as well as cases developing in pts with a history of previous hematology disorders, such as a myelodysplastic syndrome (MDS) or a chronic myeloproliferative disease (MPD). Outcomes for this large group of pts, which has a high median age and a high frequency of unfavourable cytogenetics, has been traditionally considered very poor, compared to AML developing “de novo”, and treatment with intensive chemotherapy (iCT) is not standardized in elderly pts. Indeed pts with s-AML have been excluded from molecular and cytogenetic prognostic stratification defined by the ELN criteria. Aim: Since patients with s-AML actually represent an heterogeneous subgroup of pts a multicenter retrospective study was performed to analyse their outcome in relationship to age, fitness and ELN risk stratification, in order to potentially identify subgroups at different prognosis. Patients and Methods: We evaluated 127 pts, representing 35% of a population-based series of elderly AML, aged > 65 years (y), diagnosed at five Hematology Centers of the Hematological Network of Lombardy in Northern Italy from January 2008 to May 2014. Thirteen pts (10%) had t-AML and 114 (90%) had AML secondary to previous hematological disorders (89 MDS and 25 MPD). Median age was 74 y (range 65-94 y). Performance status (PS) was evaluable in 122 pts (96%) and PS ECOG was >3 in 32 pts (26%). According to “fitness criteria”, (Ferrara et al, Leukemia, 2013), 126 pts (99%) were evaluable: 54 pts (42.5%) were fit to i-CT (FIT), 55 (43.3%) unfit to i-CT (UNFIT), 17 (13.4%) unfit to ni-CT (FRAIL). Intensive CT was given to 34 (27%), ni-CT (low-dose arac, azacytidine or experimental non-myelotoxic drugs) to 26 (20%) and best supportive care (BSC) to 67 pts (53%). Overall concordance between the fitness and the treatment actually received was 78%.The ELN prognostic criteria were applicable in 69 pts (54%), because of lack of complete molecular and cytogenetic data in the others. Six pts (8.5%, all NPM1+) were at low, 14 (20%) at intermediate-1, 11 (16%) at intermediate-2 and 38 (55%) at high risk. Results: The median OS according to fitness was 9,6, 4 and 3 months (ms), in FIT, UNFIT and FRAIL pts, respectively (p=0.0021) (Figure 1). Both the treatment received (i-CT or ni-CT vs BSC) and the risk ELN classification were related to OS (p< 0.0001 and p=0.0089, respectively). In FIT pts the median OS was 8 ms in pts treated with i-CT, 11 ms with ni-CT, and 3 ms with BSC (p<0.0001) (i-CT vs ni-CT : p=0.6) (Figure2). The achievement of CR was related to outcome (median OS 12.7 ms vs 5 ms) (p= 0.0035). AML with antecedent hematological disorder (53.8%) or with t-AML (50%) had similar CR rate (53,8% vs 50%) as well as OS (median OS 11 ms vs 7 ms) (p =0.5). According to ELN risk, OS was better in LR/Int-1/int2 vs HR (median OS 11,4 vs 5 ms, p=0.0035) (Figure 2). Moreover, also the achievement of CR was related to ELN risk: 100% in LR, 57% in Int1/Int2, 14% in HR (p= 0.012), and percentages differed from de novo AML only in HR pts. Prognosis of the subgroup of 34 ELN low/Int1 risk pts treated with i-CT was fair with CR rate of 53%, and 2 y OS 40% compared to 10% in similarly treated Int2/HR pts (p=0.07). Conclusion: Elderly pts with s-AML are an heterogeneous subgroup both according to fitness and to ELN risk stratification and these parameters are significantly related to clinical outcome. Overall prognosis of elderly patients with s-AML is not exceedingly worse than in elderly with de novo AML. Outcome was better using i-CT or ni-CT compared to BSC, with no differences between the two treatment modalities. ELN risk stratification merits to be applied also to patients with s-AML and its integration with fitness criteria can identify a subgroup of patients which may benefit from intensive CT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

2021 ◽  
Author(s):  
Michael Heuser ◽  
B. Douglas Smith ◽  
Walter Fiedler ◽  
Mikkael A. Sekeres ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
De Novo ◽  
Secondary Acute Myeloid Leukemia ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

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