High Antileukemic Efficacy and Shortened Neutropenia of Dose-Dense Induction (Sequential-HAM Followed by Pegfilgrastim) in Primary Acute Myeloid Leukemia - Results of a Pilot Study of the German AML-CG.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 295-295
Author(s):  
Jan Braess ◽  
Karsten Spiekermann ◽  
Christian Buske ◽  
Peter Staib ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Hospital Costs ◽  
Early Death ◽  
Control Group ◽  
Favourable Safety ◽  
Favourable Safety Profile ◽  
Blast Count ◽  
De Novo Aml ◽  
Dose Dense

Abstract Dose density during early induction has been demonstrated to be one of the prime determinants for antileukemic efficacy. The German AML-CG therefore pilots a dose dense induction regimen S-HAM (sequential HD-AraC [3g/m2/12h d1,2,8,9] and Mitoxantrone 10mg/m2 [d3,4,10,11] followed by pegfilgrastim) in which two induction cycles are applied over 11 – 12 days as compared to conventional double induction, in which two cycles are applied over 25 – 29 days - thereby increasing dose density ca. two-fold in the critical first weeks of treatment. In the past 2,5 years 168 patients with de-novo AML (excluding APL) have been recruited into the trial with a median age of 53 years (range 18 – 78). Of 136 patients evaluable for response the following results were achieved: CR 62%, CRi 22%, PL 7%, ED 9% - resulting in an overall response rate (ORR) of 84%. The early death rate (ED) of 9% and the toxicity profile compared favourably with a historical control group of the AML-CG 1999 study (de-novo AML, < 60 years, HAM-HAM double induction) which demonstrated an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 89% of patients had a blast count of < 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. Whereas even for patients with unfavourable cytogenetics (including complex aberrations) a median overall survival of 13,5 months was reached (23% at 2 years), for patients with favourable karyotypes overall survival at 2 years was 81%and for patients with intermediate karyotypes 74% after S-HAM treatment. Importantly the compression of the two induction cycles into the first 11 – 12 days of treatment seems actually beneficial for normal hematopoesis as demonstrated by a significantly shortened duration of critical neutropenia of 30 days as compared to 45 days after conventionally timed double induction. This shortening of critical neutropenia by more than 2 weeks was highly relevant for the duration of hospital stay and hospital costs. In conclusion S-HAM with pegfilgrastim support is a highly effective regimen in primary de-novo AML with a very favourable safety profile and significantly shortened duration of neutropenia. This regimen will therefore constitute the (dose-dense) experimental arm for a randomized comparison with standard double induction in the next generation of the German AML-CG studies.

Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3903-3910 ◽  
Author(s):  
Jan Braess ◽  
Karsten Spiekermann ◽  
Peter Staib ◽  
Andreas Grüneisen ◽  
Bernhard Wörmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Early Death ◽  
High Dose ◽  
Kaplan Meier ◽  
De Novo Aml ◽  
Dose Dense ◽  
Acute Myeloid

AbstractDose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction. (European Leukemia Trial Registry LN_AMLINT_2004_230.)

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1977-1977
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Complete Remission ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Age Group ◽  
Risk Profiles ◽  
Age Related ◽  
De Novo Aml

Abstract After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 -< 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p<.001). The overall survival in the younger (60- < 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p<.001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60-<70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC > 20.000/ccm was found in 40% vs 39% (p=.52); LDH > 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- < 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.

Allogeneic Hematopoietic Cell Transplantation with FLAMSA-RIC Can Overcome the Poor Prognosis of Primary Refractory or Relapsed AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1938-1938
Author(s):  
Dominik Schneidawind ◽  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Free Survival ◽  
Secondary Aml ◽  
Off Label ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Refractory Aml

Abstract Abstract 1938 Introduction: Patients with relapsed or primary refractory AML have a dismal prognosis. Even salvage therapy with allogeneic hematopoietic cell transplantation (HCT) could not improve outcome due to high incidence of relapse and high non-relapse mortality (NRM). Recently, promising results in patients with unfavorable karyotype or treatment refractory AML have been reported using a sequential treatment with aplasia inducing chemotherapy consisting of Fludarabine, Ara-C and Amsacrine (FLAMSA) followed within 3 days by reduced intensity conditioning (RIC) for allogeneic HCT (Schmid et al., Blood 2006 Aug 1;108(3):1092–9). Methods: We report a retrospective analysis of our single center experience with FLAMSA-RIC in primary refractory or relapsed AML patients. We searched our database for patients receiving FLAMSA-RIC in the past 10 years. Details on characteristics and clinical course of the patients were confirmed by retrospective chart review. Results: We retrospectively identified and analyzed 51 consecutive patients (f=22, m=29) transplanted after FLAMSA-RIC at our institution from 2006–2011. At time of HCT patients were refractory after chemotherapy (n=22) or had an untreated relapse (n=29). Data on molecular and cytogenetic markers were available in 36 and 44 patients, respectively. 34 were initially high-risk because of unfavorable karyotype (n=25) or molecular genetic alterations (n=9). Median age of patients was 56 years (range, 20–72) and diagnosis of all patients was acute myeloid leukemia (de-novo AML, n=27, secondary AML, n=24). FLAMSA (Fludarabine 30 mg/m2 day −12 to −9, AraC 2000 mg/m2 day −12 to −11 and Amsacrine 100 mg/m2 day −12 to −9) was used as salvage therapy followed by RIC (Fludarabine 30 mg/m2 day −5 to −4/Busulfan 0.8 mg/kg day −6 to −4, n=10; TBI 4Gy on day −5/Cyclophosphamide 60 mg/kg on day −4 to −3, n=28; Busulfan 0.8 mg/kg day −6 to −4/Cyclophosphamide 60 mg/kg for matched and mismatched unrelated donors (MUD/MMUD) or 40 mg/kg for matched related donors (MRD) on day −3 to −2, n=13). As GVHD prophylaxis calcineurin inhibitor combined with mycophenolate mofetil and anti-thymocyte globuline (ATG-Fresenius®, 10 mg/kg for MRD and 20 mg/kg for MUD/MMUD) was used. 10 patients were transplanted from MRD, 16 from MUD, 21 from a MMUD and 4 from a MMRD. 14 patients received DLI (2 × 106 - 1 × 108 /kg after a median of 186 days, range 72–922) in absence of GVHD in case of mixed chimerism or relapse after HCT. Current overall survival (OS) was 18/51 patients with a median follow-up of 410 days (range, 179–1557) of patients alive resulting in a Kaplan-Meier estimated 2-year OS and event-free-survival (EFS) of 34% and 29%, respectively. There was no significant difference between the different RIC regimens with 50% Fludarabine / Busulfan vs. 26% TBI 4Gy / Cyclophosphamide and 40% Fludarabine / Busulfan (p=0.37). Causes of death were relapse (n=19), infections (n=5), GVHD (n=2), multi-organ-failure (n=5), cerebral hemorrhage (n=1) and progressive multifocal leukencephalopathy (n=1). Cumulative incidence of relapse at 2 years with death due to NRM as competing risk was 40% and cumulative incidence at 2 years of NRM with death due to relapse as competing risk was 27%. 2-year OS was inferior in patients with secondary AML compared to patients with de-novo AML (28% vs. 38% p=0.79). The outcome in the elderly subgroup defined by age ≥60 years (median age 67, n=22) was similar to the group of younger patients (median age 46, n=29) with 2-year OS of 31% vs. 37% (p=0.87). Patients with a blast count < 10% in the bone marrow at time of HCT had a better outcome with 64% vs. 25% OS (p=0.09). 2-year-OS was inferior in patients being refractory after chemotherapy (25% vs 38%, p=0.78). Incidence of acute GVHD (aGVHD) ≥II and chronic GVHD (cGVHD, limited, n=11, extensive, n=3) was 22% and 27%, respectively. Presence of aGVHD did not influence survival while presence of cGVHD was associated with an improved overall survival after HCT (58% vs 24%, p=0.009). Conclusion: FLAMSA-RIC followed by allogeneic HCT enables long-term disease free survival, even in primary refractory or relapsed AML patients. The sequential approach of this regimen seems to overcome the dismal prognosis of these patients. Its moderate toxicity allows the application of this curative salvage therapy option even in an elderly patient population. Disclosures: Off Label Use: The use of some agents in the conditioning is off-label.

Different Cytogenetic Patterns in Specified Categories of Secondary AML: Results of a Population-Based Registry Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3586-3586
Author(s):  
Jan M. Norgaard ◽  
Lene S.G. Oestgaard ◽  
Mette K. Andersen ◽  
Maria Kallenbach ◽  
Preben Johansen ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Risk Group ◽  
Prognostic Parameters ◽  
Cytotoxic Therapy ◽  
Cytogenetic Abnormalities ◽  
Secondary Aml ◽  
Hematological Neoplasm ◽  
Previously Treated ◽  
De Novo Aml

Abstract Abstract 3586 The prognosis of leukemia patients suffering from secondary AML (sAML) compared to that of patients with de novo AML is dismal. The group of sAMLs is heterogeneous and includes AML arising from an antecedent myelodysplastic (MDS) or myeloproliferative neoplasm (MPN), and AML caused by cytotoxic therapy (tAML). In the present retrospective population- and national registry-based analysis we identified 612 (27%) patients as having some form of sAML. Cytogenetic risk group patterns and clinical outcomes among the different categories of sAML were compared to those of 1635 de novo AML cases identified in a total population of 2261 patients (data missing in 14 cases). The cohort represents >90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The following groups of sAMLs were identified: A. Patients with an antecedent MDS or chronic myelomonocytic leukemia (324 cases), B. Patients with antecedent MPN (excluding chronic myeloid leukemia, 108 cases), C. Patients previously treated with chemo- and/or radiotherapy for another hematological neoplasm (113 cases), and D. Patients previously treated with chemo- and/or radiotherapy for another non-hematological neoplasm or disease (67 cases). For all 1168 curatively treated patients in the total cohort, presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs. de novo) were all prognostic parameters found to be highly statistically significant to probability of attainment of complete remission (CR) and to overall survival (OS) in univariate as well as multivariate analyses, data not shown. There were strikingly fewer patients showing favorable cytogenetic abnormalities among sAMLs. Focusing on the above defined 4 categories of sAML, patterns of cytogenetic risk group distribution were strikingly and statistically significantly different (nevaluable= 418, p-value, Chi-square <10−4), Table 1, with favorable cytogenetic abnormalities being relatively more frequent in sAML-category D.Table 1.Category of sAML and cytogenetic abnormalitiesCategory of sAMLCytogenetics, (revised MRC-categories)A (MDS and CMML) (%)B (MPN) (%)C (Cytotoxic therapy, hematological neoplasm) (%)D (Cytotoxic therapy, non-hematological neoplasm a.o.) (%)TotalFavorable1 (0.5)1 (1.3)2 (2.9)10 (18.5)14Intermediate157 (72)52 (68.4)49 (70)29 (53.7)287Unfavorable60 (27.5)23 (30.3)19 (27.1)15 (27.8)117Total218767054418 Additionally, in the sAMLs we found age, cytogenetic abnormalities, and white blood cell count (WBC) to be highly statistically significant to probability of attainment of CR and to duration of OS. By contrast, we did not find the specific sAML category to be of significance to probability of attainment of CR or to duration of OS, Table 2, Fig. 1.Table 2.Factors of significance to probability of attainment of CR and to OS in 246 cases of secondary AMLProbability of CR (Logistic regression, nevaluable= 246)Probability of overall survival (Cox regression, nevaluable= 246)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueAge1.071.03–1.11<10-41.021.01–1.040.006Cytogenetics3.291.71–6.34<10-42.021.46–2.78<10-4Male gender--NS--NSWBC1.011.003–1.0170.0061.0041.002–1.0070.001sAML-category--NS--NS In conclusion, from these analyses we confirm the prognostic significance of presence of sAML as well as other well established prognostic parameters in AML. We find cases of sAML-category D, i.e., patients previously treated with chemo- and/or radiotherapy for another non-hematological neoplasm or disease, to exhibit favorable cytogenetic abnormalities relatively frequently. Probability of attainment of CR and OS duration were similar in the four different specific categories of sAML. Well established prognostic parameters including age, cytogenetic abnormalities, and WBC are of significant prognostic value in sAML. Disclosures: No relevant conflicts of interest to declare.

Appropriate Dose Modification in Induction Therapy Is Essential for the Treatment of Infants with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2615-2615
Author(s):  
Daisuke Tomizawa ◽  
Akio Tawa ◽  
Tomoyuki Watanabe ◽  
Akiko Moriya Saito ◽  
Kazuko Kudo ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Induction Therapy ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Early Death ◽  
Risk Groups ◽  
Pulmonary Complications ◽  
Pediatric Leukemia ◽  
Dose Modification ◽  
De Novo Aml

Abstract Abstract 2615 Background: Infants (age <1 year) with AML are naturally vulnerable to intensive cytotoxic therapy, and we have previously reported unacceptably high early death rate mainly due to pulmonary complications among the first 32 infants (28 eligible) enrolled in the JPLSG AML-05 study, which prompted us to suspension of patient accrual and protocol amendment (Tomizawa D. 52ndASH abstract #2146). Seventeen additional infants were enrolled after the amendment, and here we report the final outcome of total 45 infants with AML treated on AML-05 study. Patients & Methods: JPLSG AML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient's request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. For patients <2 years old, drug dosages were reduced by calculating on body weight basis, and after the study amendment, additional dose reduction by 33% in initial induction course was made for infants <1 year old. Results: The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years). Although, there was no difference in 3-year probability of event-free survival (pEFS) between infants and patients ≥1 year old [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (49.8 – 60.2%) (p = 0.63)], 3-year probability of overall survival (pOS) in infants was inferior; 56.0% (95%CI, 37.9 – 70.7%) vs. 75.0% (70.0 – 79.4%) (p = 0.011). When the outcome of infants were compared with patients 1 - <2 years old (N=58) and ≥2 year old (N=341), again, there was no difference in 3y-pEFS [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (40.6 – 67.6%) vs. 55.3% (49.5 – 60.7%) (p = 0.83)], but worse 3y-pOS was observed in infants [56.0% (95%CI, 37.9 – 70.7%) vs. 77.0% (62.8 – 86.4%) vs. 74.8% (69.2 – 79.5%) (p= 0.037)]. The inferiority of pOS in infants compared to the patients 1 - <2 years old and ≥2 year old was because of higher early death and non-relapse death observed in infants: 11.1% (5/45) vs. 1.7% (1/58) vs. 0.3% (1/341) (p < 0.001) and 22.2% (10/45) vs. 6.9% (4/58) vs. 9.4% (32/341) (p = 0.033), respectively. However, reduction of both early death and non-relapse death was observed after the study amendment, although not statistically significant because of small numbers; 17.9% (5/28) to 0.0% (0/17) (p = 0.14) and 32.1% (9/28) to 5.9% (1/17) (p = 0.064). Notably, in spite of dose reduction in the first induction course, CR rate [pre-amendment vs. post-amendment; 67.9% (19/28) vs. 82.4% (14/17) (p = 0.28)], 2y-pEFS [58.6% (35.1 – 76.1%) vs. 49.0% (22.0 – 71.4%) (p = 0.56)], and 2y-pOS [67.8% (47.3 – 81.8%) vs. 74.1% (44.0 – 89.6%) (p= 0.41)] did not deteriorate. Conclusions: Our experience suggests that appropriate chemotherapeutic dose modification in induction therapy to avoid early deaths is essential in treating infants with de novo AML. As dose intensification approach is difficult to apply for this age subgroup, incorporation of less toxic targeted agents based on biological features is needed to attain better outcome for infants with AML. Disclosures: No relevant conflicts of interest to declare.

Clinical Outcome of Therapy-Related Acute Myeloid Leukemia Is Strongly Related to Cytogenetic Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1401-1401
Author(s):  
Croix Fossum ◽  
Rhett P. Ketterling ◽  
Lindsey E. Roeker ◽  
Ajoy L. Dias ◽  
Michelle Elliott ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Alkylating Agent ◽  
De Novo ◽  
Disease Course ◽  
Primary Malignancy ◽  
Non Hodgkin Lymphoma ◽  
Cytogenetic Profile ◽  
De Novo Aml

Abstract Background: Treatment-related AML (t-AML) accounts for 10 to 20% of all AML cases and carries an especially poor prognosis (Kayser et al. 2011, Godley et al. 2008). Patients diagnosed with t-AML are likely to have abnormal cytogenetic profiles with chromosome changes that are predictive of an aggressive malignancy, poor response to therapy, and decreased overall survival(Smith et al. 2003). The simultaneous use of multiple chemotherapeutic agents of different classes makes it increasingly difficult to predict risk for developing t-AML and determining disease course. An updated analysis of predictive factors for t-AML is needed so clinicians can more accurately inform patients of their prognosis. The aim of this study was to classify t-AML according to primary malignancy, previous chemotherapy exposure, and cytogenetic profile. Methods: A retrospective chart review of patients that were diagnosed with AML at Mayo Clinic from 7/1/1990 to 5/13/2015 was performed following IRB approval. AML patients found to have a previous malignancy treated with chemotherapy were classified as t-AML. Chemotherapeutics were classified as alkylating agents, antimetabolites, anti-tubulin agents, and topoisomerase II inhibitors. Patients diagnosed with a myelodysplastic or myeloproliferative disorder prior to development of AML were excluded from this study. Previous chemotherapy exposures, duration of chemotherapy exposure, complete blood count, chromosome abnormalities, and survival data were collected for t-AML cases. Cytogenetic changes were classified as favorable, intermediate, and adverse according to the system used by Kayser et al. 2011. JMP 10.0 was used for statistical analysis. Results: Out of 584 patients, 64 patients (11%) had a primary malignancy that was treated with chemotherapy prior to being diagnosed with AML. The most common primary malignancies were breast cancer (31%), non-Hodgkin lymphoma (27%), colorectal cancer (8%), and Hodgkin lymphoma (8%). Laboratory findings showed median hemoglobin 9.6 g/dL (4.7-13.8), median white blood cells 3.2 x109 (0.6-126), median platelets 50x109 (3-320), median peripheral blood blasts of 8% (0-91), and median bone marrow blasts 38% (1-94). 95% of patients diagnosed with t-AML had been previously treated with an alkylating agent. Additional exposure to an anti-metabolite trended towards a more adverse cytogenetic profile (χ2=5.0, p=0.08) but there was not a statistically significant decrease in overall survival (KM analysis, p=0.31). The median overall survival for patients diagnosed with t-AML was 10.2 months compared to 19.2 months for patients with de-novo AML (KM analysis, p=0.04). Adverse cytogenetic profiles were associated with decreased survival (KM analysis, p <0.0001). However, there was no difference in overall survival between patients with t-AML that had intermediate cytogenetics and those with de-novo AML (KM analysis, p=0.36). None of the chemotherapy classes other than antimetabolites were associated with poor cytogenetics or survival when combined with an alkylating agent. Conclusion: Over half of all patients classified as having t-AML in this study received prior chemotherapy for breast cancer or non-Hodgkin lymphoma. Cytogenetic classification of t-AML into favorable, intermediate and adverse groups is useful in predicting disease course. Interestingly, t-AML patients with intermediate risk cytogenetics had similar overall survival to patients with de-novo AML. This suggests that the poor outcomes observed in patients with t-AML is predominantly due to the subset with adverse cytogenetics. Thus, cytogenetic analysis remains the best indicator of overall survival regardless of chemotherapy exposure. Additional work is needed to delineate the risk associated with the aforementioned chemotherapy classes. Disclosures Al-Kali: Celgene: Research Funding.

Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6512-6512 ◽  
Author(s):  
J. E. Karp ◽  
D. Rizzieri ◽  
N. Vey ◽  
G. Mufti ◽  
R. Geller ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Early Death ◽  
Hematologic Malignancies ◽  
Hematologic Toxicity ◽  
Nccn Guidelines ◽  
Poor Risk ◽  
De Novo Aml

6512 Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m2) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML. [Table: see text]

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

Phase 2 Trial of the Histone Deacetylase Inhibitor Valproic Acid as a Monotherapy or in Combination with All-Trans Retinoic Acid in 24 Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1808-1808
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Barbara Hildebrandt ◽  
Sabine Knipp ◽  
Baerbel Junge ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Valproic Acid ◽  
Side Effects ◽  
De Novo ◽  
Intensive Chemotherapy ◽  
Bone Marrow Blast ◽  
Blast Count ◽  
De Novo Aml ◽  
A Minor ◽  
To Receive

Abstract Valproic acid (VPA) has been shown to inhibit histone deacetylase activity, and to synergize with ATRA in the differentiation induction of leukemic myeloid blast cells in vitro. We applied VPA to 20 patients (16 sAML/MDS, 2 de-novo-AML, 2 sAML/OMF) too old or physically unfit to receive intensive chemotherapy. VPA monotherapy was targeted to reach serum concentrations of 50–100mg/ml. ATRA was added (80mg/m2/d in two divided doses, every other week) in some of the patients who did not respond or who relapsed. To enhance responses, we treated an additional 4 patients (2 sAML/MDS, 1 sAML/ET, 1 de novo AML) with VPA+ATRA from the start. Median age was 70 years (51–84). Median bone marrow blast count was 30% (10–80). 5 patients had only 10–15% marrow blasts but were included because they showed treatment failure or relapse after chemotherapy and were unable to receive further cytotoxic treatment. Median treatment duration was 99 days (20–396) for VPA and 79 days (18–339) for ATRA. Responses according to international working group (IWG, Cheson et al., 2003) criteria were observed in 5 patients (25%) on VPA monotherapy (4PR, 1CR). Of the responding patients two have ongoing responses (CR, PR) for 12 and 13 months, respectively. 1 patient reaching PR discontinued VPA when her physical condition had improved sufficiently to allow further chemotherapy. 1 patient relapsed after 2 months and was switched to VPA+ATRA, without response. 1 patient died of infectious complications. 8 additional patients showed stable disease without increases in peripheral blast count. Responses lasted for a median of 4 months (2–13). Among the 4 patients receiving VPA+ATRA from the start, 1 (25%) achieved PR. When he stopped VPA after 3 months because of side effects, he continued on ATRA, achieving a CRi (CR with incomplete recovery of platelets) lasting for 8 months. 4 of 14 nonresponders were switched to VPA+ATRA, but none of them showed a response. Response to VPA treatment was not associated with FAB subtype or karyotype. Median bone marrow blast count was 28 (13–45)% in responders, 30 (10–75)% in patients with stable and 41 (25–80)% in patients with progressive disease. Since our patients mainly had secondary AML, we also analyzed our results according to the proposals of the IWG for MDS (Cheson et al., 2000). Among patients receiving VPA monotherapy 1 patient had a major trilineage response. 2 patients showed a minor erythroid and one a minor neutrophil response. In the second group of patients one had a major erythroid response. Concerning side effects, VPA caused tremor in four cases, leading to cessation of treatment in two. Regarding ATRA, grade 1–2 skin toxicity was observed in 4, grade 1–2 gastrointestinal toxicity in 2, and pleural effusion in 1 patient. In summary, we observed responses according to IWG criteria in 25% of our patients (6/24). The best responses to VPA or VPA+ATRA in AML patients occurred in patients with low blast count, mainly in patients who showed relapsed or refractory disease shortly after intensive chemotherapy. These data indicate that VPA might be most effectively applied after or in addition to intensive chemotherapy.

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