Prognostic Implications of CD14 Positivity in Acute Myeloid Leukemia Arising From Myleodysplastic Syndrome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3523-3523
Author(s):  
Yunsuk Choi ◽  
Sungdoo Kim ◽  
Young-Hun Park ◽  
Jae Seok Lee ◽  
Dae-Young Kim ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Free Survival ◽  
Secondary Aml ◽  
Hla Dr ◽  
Prognostic Implications ◽  
De Novo Aml

Abstract Abstract 3523 Introduction: Secondary AML that has evolved from MDS shows different clinical features and outcomes compared to de novo AML. Prognostic implications of immunophenotypes have been studied in de novo AML, whereas those have not well been defined in secondary AML from MDS. Methods: This retrospective study involved analysis of data from 65 adult patients, 37 males and 28 females, who were diagnosed with AML arising from MDS at a single institute. Data for baseline clinico-pathological features, treatments, and outcomes were collected from medical records of each patient. Immunophenotyping was performed for the markers including TdT, CD34, CD13, CD33, CD117, CD14, CD56, HLA-DR, CD3, CD7, CD10, and CD19 using flow cytometry. Results: At the time of MDS diagnosis, the WHO subtype was RA/RARS in 5, RCMD in 10, RAEB-1 in 17, RAEB-2 in 29, and unknown in 4. For the treatment of MDS, hypomethylating agents were given to 17 patients and 2 patients underwent allogeneic hematopoietic cell transplantation (HCT). Median duration of MDS prior to diagnosis of AML was 4.9 months (range, 0.3–91.1). At the time of AML evolution, median age was 50.7 years (range, 18–80), and cytogenetic risk group was good-risk in 1, intermediate-risk in 45, and poor-risk in 18. Proportion of positivity of each immunophenotype marker was as follows: TdT (5%), CD34 (65%), CD13 (98%), CD33 (97%), CD117 (90%), CD14 (22%), CD56 (10%), HLA-DR (93%), CD3 (2%), CD7 (35%), CD10 (8%), and CD19 (2%). After the evolution to AML, 52 patients received induction chemotherapy consisted of cytarabine plus idarubicin or daunorubicin and 8 patients underwent allogeneic HCT as initial treatment of AML. Complete remission (CR) was induced in 27 patients after treatment. At a median follow-up time of 29.2 months (range, 2.6–116.2) among surviving patients, 49 patients died, 13 relapsed, and 53 died or relapsed. Median overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 7.6, 26.1, and 5.4 months, respectively. Of immunophenotype markers, CD14 positivity only showed prognostic implications at the univariate analyses: lower CR rate after induction chemotherapy (P=0.034) and shorter survivals (OS, P<0.001; RFS, P=0.078, and EFS, P<0.001). Differences in OS and EFS remained significant after adjustment for other variables (OS, HR, 4.49, 95% CI, 2.16–9.87, P<0.001; EFS, HR, 4.06, 95% CI, 2.03–8.13, P<0.001). Other prognostic variables included age of 60 years or older (shorter OS [P=0.003] and EFS [P=0.020]), WBC over 60,000/mcl (shorter OS [P<0.001] and EFS [P=0.001]), and poor cytogenetic risk group (shorter OS [P=0.005]). Conclusions: Surface expression of CD14 on leukemic blasts was an independent prognostic factor for survivals in the patients with AML arising from MDS. Disclosures: No relevant conflicts of interest to declare.

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.

Poor Outcome in Secondary Acute Myeloid Leukemia (AML): A First Report From the Population-Based Swedish Acute Leukemia Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Soren Lehmann ◽  
Vladimir Lazarevic ◽  
Ann-Sofi Hörstedt ◽  
Erik Hulegårdh ◽  
Christer Nilsson ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Population Based ◽  
Induction Treatment ◽  
Secondary Aml ◽  
Male Predominance ◽  
Hematological Disorder ◽  
De Novo Aml

Abstract Abstract 130 Secondary AML comprises AML patients with an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML; tAML). Population-based data on this patient group are scarce. Here, we report for the first time, data on secondary AML from the Swedish Acute Leukemia Registry covering 98% of all AML cases diagnosed in Sweden between 1997 and 2006. In total, 3372 AML patients were registered during this period. Of these, 949 (28%) had secondary AML; 655 (19%) had a history of AHD and 294 (8.7%) had tAML. The proportion of secondary AML increased from 8% in patients below the age of 40 years to 36% in patients between 70–79 years. Of patients with AHD, 423 (65%) had previously been diagnosed with myelodysplastic syndrome (MDS) and 227 (35%) with various types of myeloproliferative disorders (MPN). AML with AHD showed male predominance (57%), whereas tAML showed female predominance (64%). This distribution was significantly different (p<0.001) compared to de novo AML with an equal gender distribution. Median and mean ages for patients with AML with antecedent hematological disorder were 73 and 71 years, which differed significantly from de novo AML with 70 and 66 years, respectively (p<10−11). For tAML, median and mean ages were 71 and 67 years, respectively, not significantly different from de novo AML. Patients with secondary AML had slightly worse WHO/ECOG performance status (WHO PS) with lower incidence of WHO PS 0 (10%: 14%: 18% for AML with AHD:tAML:de novo AML) and a higher incidence of WHO PS 3–4 (27%: 24%: 20%). The proportion of patients with PS 1 and PS2 was similar for secondary AML and de novo AML. Intensive induction treatment was given to 45% of all patients with AHD, to 57% of patients with tAML compared to 68% for patients with de novo AML. In patients below the age of 65, the proportion of intensively treated patients was 76, 85 and 98%, respectively. CR rates for in patients including all ages were 40% for AML with AHD, 54% for tAML and 72 % for de novo AML (p-values<0.0001 for all calculations). CR rates were lower in all cytogenetic risk groups in both AML with AHD and tAML compared to de novo AML (Low risk NA: 70%: 91%; intermediate risk 53%: 56%: 89%; high risk 30%: 43%: 76%). CR rates were lower for both secondary leukemia types within all WHO PS groups, despite similar early death rates in secondary and de novo AML. Median survival for all patients regardless of age or type of treatment was 4 mo, 4 mo and 9 mo respectively for patients with AML with AHD, tAML and de novo AML, respectively. For all patients receiving intensive induction treatment, corresponding figures were 7 mo, 9 mo and 17 mo, and for patients below 65 years of age 7 mo, 9 mo and 38 mo. We conclude that secondary AML is less common in younger patients and that the proportion increases to a third of patients above 70. Patients with AHD and tAML less often receive intensive induction treatment than those with de novo AML and treatment responses are poor regardless of cytogenetic risk group or performance status also in intensively treated patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic Transplantation in First Remission Improves Outcome in Secondary Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 281-281
Author(s):  
Christer Nilsson ◽  
Erik Hulegårdh ◽  
Vladimir Lazarevic ◽  
Hege Garelius ◽  
Asa Rangert Derolf ◽  
...  
Keyword(s):  
De Novo ◽  
Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Exact Test ◽  
Secondary Aml ◽  
Fisher's Exact Test ◽  
Fisher’S Exact Test ◽  
First Remission ◽  
De Novo Aml

Abstract Allogeneic stem cell transplantation (SCT) is widely used as post-remission treatment in younger patients with poor or intermediate risk AML. Transplant decisions are mainly based on cytogenetic and molecular risk group, age, comorbidity and on the availability of a suitable donor. Secondary AML, including therapy-related AML (t-AML) and AML after an antecedent hematological disorder (AHD-AML), constitutes more than one fourth of the AML cases and is a predictor of a poor outcome. However, the extent to which SCT improves outcome of this patient group is poorly studied. In this study, we set out to investigate the role of SCT for the survival of secondary AML patients within the population-based Swedish Adult Acute Leukemia Registry. In total, 5881 patients with AML diagnosed during the period 1997 – 2013 were included in the study. Of these, 4233 (72%) were de novo AML, 1098 (19%) AHD-AML and 550 (9%) t-AML. The median age at diagnosis was 70 in de novo AML, 73 in AHD-AML and 70 in t-AML. The gender distribution was equal in de novo AML (51% males). In AHD-AML, there was a male predominance of 57% whereas in t-AML, there was a female predominance of 56%. The proportion of patients who underwent SCT in first remission (CR1) was 10% in de novo AML, 5% in AHD-AML and 8% in t-AML (de novo vs AHD-AML p < 0.001, de novo vs t-AML p = 0.068, AHD-AML vs t-AML p = 0.081; Fisher's exact test). In patients aged 65 or below, the proportion of SCT in CR1 was 24%, 21% and 20%, respectively. The median age of SCT patients was 48 (range 17 – 71) in de novo AML, 57 (27 – 76) in AHD-AML and 49.5 (18 – 68) in t-AML. In de novo AML, the distribution of genetic risk groups among SCT patients was 3% low risk, 55% intermediate risk and 42% high risk. Corresponding figures for AHD-AML was 0%, 34% and 66% and for t-AML 5%, 45% and 50% respectively (de novo vs AHD-AML p = 0.004, de novo vs t-AML p = 0.299, AHD-AML vs t-AML p = 0.124; Fisher's exact test). The estimated median survival after the date of SCT in CR1 was 15 months in AHD-AML and 22 months in t-AML but not reached in de novo AML (95% lower confidence limit 107 months). Among patients <65 years who had been in CR for 3 months (genetic low risk excluded), those with secondary AML had a greater benefit from consolidation with SCT than those with de novo AML (Figure 1). The projected 7-year survival in de novo AML was 60% with SCT and 44% with conventional post remission therapy (CPRT) as compared to 46% and 21%, respectively, in secondary AML. The survival hazard with SCT was 0.45 in secondary AML (95% CI 0.28-0.72) as compared to 0.66 in de novo AML (CI 0.53 – 0.82), by multivariable Cox regression adjusting for type of secondary AML, age, sex, and cytogenetic risk group. To refine the analysis correcting for major confounding factors, a matched pair analysis was performed in patients with CR longer than 3 months. Matching criteria were type of secondary AML (AHD or t-AML), cytogenetic risk group and age (+/- 3 years). Remission of the patient with CPRT was at least as long as the time between CR1 and transplantation for the matched patient undergoing SCT. The projected 7-year survival rate was 43% in the SCT and 8% in the CPRT group (p = 0.01; log-rank test, Figure 2) further indicating a benefit for SCT as post remission therapy in secondary AML. We conclude that SCT improves survival in patients with secondary AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Comparison of Prognostic Factors and Outcomes of Patients with Secondary Acute Myeloid Leukemia (AML) Following Myelodysplastic Syndromes (MDS), Myeloproliferative Disorders (MPD), or Therapy-Related AML (t-AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4292-4292 ◽  
Author(s):  
Sanjay Mohan ◽  
Paul Elson ◽  
Cristina Rodriguez ◽  
Rachid Baz ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Risk Group ◽  
Myeloproliferative Disorders ◽  
Remission Induction ◽  
Secondary Aml ◽  
Secondary Acute Myeloid Leukemia ◽  
Significant Difference ◽  
Multivariable Analyses

Abstract Background: Response rates to induction chemotherapy and survival are poorer for patients (pts) with secondary AML compared to those with de novo AML. Within the category of secondary AML, no studies have compared the outcomes of induction chemotherapy in pts with AML arising from antecedent MDS vs. from MPD vs. t-AML. Methods: We conducted a retrospective review of all pts with newly diagnosed, pathologically-confirmed AML at a single institution between 1997 and 2005 and identified pts who also were diagnosed with an antecedent MDS, MPD, or t-AML. Data were collected on baseline characteristics and outcome, and controlled for in stepwise multivariable analyses. All pts were treated with anthracycline-based induction regimens. The primary endpoints were: complete remission (CR) rate (as defined by the IWG criteria) and survival from time of AML diagnosis, to determine whether those with AML arising from MDS, from MPD, or t-AML had different outcomes; and to define predictors of outcome among pts with secondary AML. Results: Of 457 AML patients, 281 were treated with remission induction therapy, of whom 66 had AML arising from MDS, MPD, or t-AML. Thirty-one (47%) had antecedent MDS, 20 (30%) an MPD, and 15 (23%) had t-AML. Twenty-six pts (39%) were female. The median age at the time of AML diagnosis for those with MDS, MPD, and t-AML was 67, 61, and 57 years, respectively (range 36–82, p=0.03 for all). Time from antecedent diagnosis/event was 7, 42, and 38 months, respectively (p=0.001). Cytogenetic risk categories (per CALGB 8461) were favorable in 3 pts (5%), intermediate in 30 (45%), unfavorable in 22 (33%), and unknown in 11 (17%). Neither cytogenetics (p=0.19) nor FAB/WHO AML classification (p=0.43) differed among groups. Median WBC at AML diagnosis was lower for pts with AML from MDS (3.7k/uL, vs. 9.9 k/uL for AML from MPD and 7.2 k/uL for t-AML, p=0.04), as were the percentage of peripheral blasts (6%, vs. 30% for AML from MPD and 23% for t-AML, p=0.005) and incidence of splenomegaly (6%, vs. 50% for AML from MPD and 0% for t-AML, p<0.001). CR rate was not significantly lower for patients with AML from MDS (35%) than for those with AML from MPD (55%) or t-AML (53%, p=0.33). Overall median survival was 8.0 months, with no significant difference among the 3 groups (7.7 months for AML from MDS, 11.1 months for AML from MPD, and 5.2 months for t-AML, p=0.23). Gender, interval from diagnosis of the antecedent disorder to diagnosis of AML, and marrow blast count did not correlate with CR rate or survival. In multivariable analyses, the antecedent diagnosis remained non-predictive of response rate or survival. Favorable- or intermediate-risk cytogenetics, however, compared to poor-risk, were significant predictors of higher CR rates (p= .005) and longer survival (p<.001). Lower peripheral blast percentage and age <60 years were favorable prognostic factors for CR. Conclusions: Contrary to expectations, pts with AML from MDS, from MPD, or t-AML had similar outcomes. The most important predictors of response to induction chemotherapy were cytogenetic risk group, age, and peripheral blast percentage. Only cytogenetic risk group was predictive of survival.

CPX-351 Is Effective in Newly Diagnosed Older Patients with AML and with Multiple Risk Factors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3626-3626 ◽  
Author(s):  
Jeffrey E Lancet ◽  
Jorge E Cortes ◽  
Tibor Kovacsovics ◽  
Donna E. Hogge ◽  
Jonathan E. Kolitz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Older Patients ◽  
Research Funding ◽  
De Novo ◽  
Risk Group ◽  
High Risk Group ◽  
Free Survival ◽  
Secondary Aml ◽  
Multiple Risk Factors ◽  
Standard Risk

Abstract Abstract 3626 Background: CPX-351 is a liposomal formulation of cytarabine (Ara-C) and daunorubicin (DNR) in a 5:1 molar ratio designed to maximize anti-tumor synergy. CPX-351 accumulates within bone marrow with preferential uptake of liposomes by leukemia cells followed by intracellular release of encapsulated drug. A Phase 2b study randomized untreated older patients with AML 2:1 to CPX-351 or standard 7+3. At entry patients were stratified by age, cytogenetics, and presence or absence of antecedent hematologic disorder (AHD)/prior cytotoxic treatment that evolved into AML (sAML) into a high-risk group (age ≥70 or adverse cytogenetics or sAML) or standard-risk group (age 60–69 and non-adverse cytogenetics and de novo AML). The standard-risk group was relatively homogeneous, while the high-risk group gathered together patients with one, two or all three risk factors. Response after CPX-351 was increased in all patients (66.7% vs. 51.2%). Patients with secondary AML had coherent improvement in survival (HR=0.40, p=0.01), EFS (HR=0.51, p=0.04), and CR + CRi rate (57.6% vs. 31.6%). This report presents the results of uni/multivariate analyses for survival and event free survival. Methods: Untreated de novo or sAML patients, aged 60–75, PS= 0–2, serum creatinine < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 × ULN, and LVEF ≥50% were eligible. Patients with history of treatment for their AHD were eligible. Patients received up to 2 induction and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or 7+3 (Ara-C= 100 mg/m2/d and DNR= 60 mg/m2). Consolidation with hematopoietic stem cell transplantation (HSCT) was permitted. The primary endpoint was CR + CRi rate. Event free survival was calculated from randomization to the date of documentation of persistent leukemia after induction, relapse after achievement of response, or death, whichever occurred first. Allogeneic transplants were permitted for post remission treatment. The association between baseline characteristics and survival was assessed by univariate and multivariate Cox regression analyses. Response was included as a time-dependent variable. The multivariate model used stepwise selection to identify prognostic factors after accounting for potential treatment effects. Results: Significant factors affecting overall survival (OS) in the univariate analysis included: response (p=0.01), ≥2 risk factors (p=0.013), secondary AML (p=0.021), and adverse cytogenetics (p=0.038). After accounting for treatment, response (p=0.003) and ≥2 risk factors (p=0.005) were strongly associated with OS in the multivariate model. Response and 60-day deaths were similar in both study arms for patients with 0 or 1 risk factor. Patients with 2 or 3 risk factors treated with CPX-351 had rates of response and 60-day death rates that were similar to those with only 0 or 1 risk factor. Control arm patients with multiple risk factors did much worse, with fewer CRs, no CRi's, and a substantially higher rate of early deaths. Conclusions: CPX-351 is highly active in every subgroup of older patients with newly diagnosed AML. This analysis demonstrates that CPX-351 minimizes the loss of response and increase in 60-day mortality that occurs with 7+3 treatment among patients with secondary AML and adverse cytogenetics. The relative benefit of CPX-351 is greatest among patients with ≥ 2 risk factors. Disclosures: Lancet: Celator Pharmaceuticals: Research Funding. Cortes:Celator Pharmaceuticals: Research Funding. Kovacsovics:Celator Pharmaceuticals: Research Funding. Hogge:Celator Pharmaceuticals: Research Funding. Kolitz:Celator Pharmaceuticals: Research Funding. Hoering:Celator Pharmaceuticals: Consultancy. Chiarella:Celator Pharmaceuticals: Employment. Louie:Celator Pharmaceuticals: Employment. Feldman:Celator Pharmaceuticals: Research Funding.

Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group

2009 ◽  
Vol 27 (24) ◽  
pp. 4007-4013 ◽  
Author(s):  
Ichiro Tsukimoto ◽  
Akio Tawa ◽  
Keizo Horibe ◽  
Ken Tabuchi ◽  
Hisato Kigasawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Death Rate ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
Intermediate Risk ◽  
Free Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with De Novo and Secondary Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 149-149 ◽  
Author(s):  
Boglarka Gyurkocza ◽  
Rainer F. Storb ◽  
Barry Storer ◽  
Thomas Chauncey ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Progression Free Survival ◽  
Disease Status ◽  
Progression Rate ◽  
Free Survival ◽  
Secondary Aml ◽  
Allogeneic Hct ◽  
Donor Type ◽  
Unrelated Donors

Abstract We report the results of 256 patients (median age = 59; range, 5–74 years) with de novo AML in first complete remission (CR1; n=100), beyond CR1 (n=79) and with treatment-related or secondary AML (n=77) who underwent allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related (n=109) or from unrelated donors (n=147). Indications of allogeneic HCT in CR1 were persistent cytogenetic or molecular evidence of disease, poor-risk cytogenetics at diagnosis, treatment-related or secondary AML and age more than 60 years. Younger patients were included if they had comorbid conditions that excluded them from conventional allogeneic HCT. Sixteen patients were mismatched with their donors for ≥ one HLA antigen, while the remainder were matched 10/10 at the antigen level. Conditioning consisted of low-dose total body irradiation (TBI; 2 Gy) on day 0 either alone (n=28) or combined with fludarabine, 30 mg/m2/day on days −4 to −2 (n=228). Calcineurin inhibitors (cyclosporine or tacrolimus) and mycophenolate mofetil were used for postgrafting immunosuppression. Durable engraftment was observed in 94% of patients. With a median follow-up of 35 (range, 3 – 111) months in surviving patients, the estimated progression-free and overall survivals at 5 years were 32% (95% CI: 25–38%) and 32% (95% CI: 25–38%), respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 40% (95% CI: 33–46%) and 29% (95% CI: 22–35%), respectively. Estimated 5-year survival rates, progression-free survival, relapse/progression rate, and non-relapse mortality according to disease status are shown in Table 1; Table 2 shows the same indices according to donor type. The cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) in patients with related donors were 40% and 13%, and in those with unrelated donors were 58% and 14%, respectively. The cumulative incidence of chronic extensive GVHD at 5 years was 44% in patients with related donors, and 42% in patients with unrelated donors. Age &gt; 60 years at the time of HCT did not have an impact on the outcome (univariate analysis). Additional analyses regarding the impact of HCT comorbidity scores and minimal residual disease at the time of HCT are in progress. Based on this multicenter analysis, we conclude that allogeneic HCT from related or unrelated donors, utilizing a conditioning regimen of low dose TBI (2 Gy) with fludarabine provides long term remission in elderly and/or medically infirm patients with AML, who were not considered candidates for conventional HCT. Table 1. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to disease status. CR1: 1st remission; &gt;CR1: subsequent remission, induction failure/persistent disease; sAML: treatment-related and secondary AML. Disease Status n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) CR1 100 33 (20–46) 34 (23–46) 36 (26–47) 30 (19–40) &gt;CR1 79 38 (26–49) 35 (23–46) 40 (29–52) 25 (15–35) sAML 77 20 (8–32) 23 (11–35) 45 (32–57) 32 (20–45) Table 2. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to donor type. Donor Type n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) HLA-identical related 109 34 (23–44) 34 (24–45) 47 (37–58) 18 (10–26) HLA-matched unrelated 131 31 (22–40) 30 (21–39) 37 (29–46) 33 (24–72) HLA mismatched unrelated 16 24 (0–50) 24 (0–50) 6 (0–18) 70 (43–97)

Flow Cytometric Assessment of Post Induction Response In Patients with Sub-Optimal Morphologic Response to Induction Chemotherapy- A Report From the Children's Oncology Group AML Protocol AAML0531

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2740-2740
Author(s):  
Michael R. Loken ◽  
Todd A. Alonzo ◽  
Laura Pardo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Initial Response ◽  
Risk Groups ◽  
Phase Iii ◽  
Response Data ◽  
Remission Status ◽  
Extramedullary Relapse ◽  
De Novo Aml

Abstract Abstract 2740 Initial response to induction chemotherapy is a significant predictor of outcome in leukemias. Data from MRC10 AML trial demonstrated that patients (pts) with ≤15% blasts at the end of induction I (EOI1), as determined by morphologic analysis, had a similar outcome as those in morphologic complete remission (mCR, <5% blasts), whereas those with >15% blasts have a significantly diminished survival. The COG Phase III AML protocol AAML0531 has enrolled 968 eligible pts with de novo AML as of March 31, 2010. Those with >15% blasts by morphologic assessment (persistent disease, mPD) at EOI1 are considered a high-risk cohort; those with 5% to 15% blasts (partial remission, mPR) were included in the standard-risk group. As part of AAML0531, pts choose to enroll on a biology study to evaluate treatment response by multidimensional flow cytometry (MDF) after 2 courses of therapy (EOI1 and EOI2). Here we directly compared the morphologic bone marrow (BM) response at EOI1 in pts with mPR or mPD with that assessed by MDF and correlated the remission status at EOI1 to the mCR rate at EOI2. Of the 900 pts with evaluable response data at EOI1, 628 (70%) entered mCR; 104 (12%) had mPR; 126 (14%) had mPD; and 42 (5%) either died (n=19) or had refractory CNS AML (n=23). All pts, regardless of their blast %, were eligible to receive the second course of induction chemotherapy per protocol. Of those with mPD at EOI1 and evaluable data by EOI2, 65 (59%) entered mCR; 1 died; and 44 (40%) had mPD. At EOI1, 180 pts did not enter mCR (80 had mPR, and 100 had mPD). MDF evaluation of those 180 BM specimens showed that 74 (41%) had no evidence of disease by MDF at EOI1. Of those 74 pts, 69 (93%) entered mCR at EOI2. In contrast, mCR at EOI2 for those with any level of disease by MDF at EOI1 was 49% (p<0.001). When a blast threshold of 5% by MDF at EOI1 was used to correlate with EOI2 response, those with 0.5% to 4.9% blasts at EOI1 had an EOI2 mCR rate of 68% compared to 41% in those with >5% blasts by MDF (p=0.013). Because they are in different risk groups, pts with mPR and those with mPD were evaluated separately for the presence of disease by MDF. Median blast % in pts with mPR was 7% (range 5%-15%). Of the 76 pts with mPR at EOI1 with an evaluable EOI2 response, 19 (25%) did not enter mCR at EOI2. At EOI1, morphologic BM response was compared to that by MDF. Of the 80 pts in mPR at EOI1, 43 (54%) had no evidence of AML by MDF; 17 (21%) had <5% blasts; and 7 (9%) in mPR had >15%. In pts in mPR who did not have AML by MDF (n=43), 39 had remission status available by EOI2: 34 (87%) entered mCR, and 5 (13%) had refractory disease (>5% blasts). Of the latter 5 patients, 4 had no evidence of disease by MDF. We subsequently evaluated BM status of the pts with PD by MDF at EOI1 and EOI2. Of those with mPD at EOI1, 62% entered mCR at EOI2. Of the 100 pts with mPD at EOI1 and MDF data for response evaluation, 31 had no evidence of disease by MDF, and all 25 with evaluable response by EOI2 entered mCR. In the remaining 69 pts, the presence of AML by MDF ranged from 0.05% to 95% (median 22%). Patients with mPD at EOI1 with any level of disease by MDF had a mCR rate of 41% at EOI2. Of the 16 pts with mPD and 0.5% to 4.9% blasts by MDF at EOI1, 14 had an evaluable EOI2 response: 11 (79%) entered mCR; 2 (18%) experienced treatment failure at EOI1; and 1 suffered extramedullary relapse. When the EOI1 evaluation was limited to the 53 patients with '5% blasts by MDF, the mCR rate at EOI2 was 30%. This study demonstrates a substantial discrepancy between morphologic and MDF assessments of induction BM specimens and highlights the need to implement MDF for accurate evaluation of remission status. We further demonstrate that a blast threshold of 5% by MDF at EOI1 may be an accurate predictor of response to the second course of therapy. Disclosures: No relevant conflicts of interest to declare.

Comparing Outcomes of Patients with Secondary AML: Treatment-Related MDS/AML, AML Secondary to Myeloproliferative Neoplasms (t-MPN), and AML with Prior Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3557-3557 ◽  
Author(s):  
Cecilia Y Arana Yi ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
William G. Wierda ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Molecular Markers ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Secondary Aml ◽  
Flt3 Mutations ◽  
History Of ◽  
De Novo Aml

Abstract Abstract 3557 Background: Secondary Acute Myeloid Leukemia (AML) accounts for approximately 10% of AML's and are often associated with adverse outcomes compared to de novo AML. In addition to cytogenetics, multiple gene mutations have been incorporated in the de novo AML risk stratification as independent prognostic and predictive factors. Little is known about these molecular markers in secondary AML. We analyzed the characteristics and outcomes of AML patients arising from myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), treatment-related AML (t-AML), or with prior history of cancer not treated with chemotherapy or radiation compared to de novo AML, and investigated the frequency and prognostic relevance of molecular markers among those groups. Patients and Methods: We analyzed the outcomes of adult patients with AML receiving induction chemotherapy at MDACC (n= 248) from 2010 to 2012. Median age was 67 years (range 17–82) and 142 (57.2 %) patients were >60 yrs. 108 (44%) were female. 146 (59 %) had de novo AML, 43 (17%) had t-AML, 23 (9%) had post-MDS, 16 (7%) post-MPN, and 20 (8%) AML with antecedent cancer not treated with chemotherapy and/or radiation therapy. Median white blood cell count (WBC) at diagnosis was 4.45 × 109/L (r: 0.4–186.5), and 82 (33%) pts had WBC >10 x109/L. Cytogenetics were diploid in 91 (37%), inv 16 in 16 (7%), t(8;21) in 12 (5%), trisomy 8 in 10 (4%), chromosome −5 and/or −7 in 60 (24%), 11q in 11 (4%), miscellaneous in 30 (12%), and insufficient metaphases on 18 (7%). 43(17%) had FLT3 mutations including 26 (10%) with FLT3-ITD, 14 (6%) FLT3-D835, and 3 (1%) double mutant. 32 (13 %) had NPM 1, 15 (6%) CBFb-MYH1, 10 (4%) ABL1/ETO, 6 (2%) JAK2, 34 (14 %) RAS, 1 (0.4%) cKIT, 18 (7%) CEBPA, 10 (4%) IDH1, and 8 (3.2%) IDH2. The pts were treated with several different induction chemotherapies. Idarubicin and cytarabine (IA)-based were more frequent in de novo and in 2nd cancer groups, while hypomethylating agents were more common in post-MDS and post-MPN groups. CR rates were higher in de novo AML than the rest of the groups, and early deaths were more common in the post-MPN group. The frequency of mutations was similar among groups with the exception of JAK 2 mutation, which was more frequent in post-MPN (Table 1). In pts with secondary AML, FLT3 mutations do not seem to further worsen their outcome (median survival 6.2 months for FLT3 wt and 6.4 for FLT3 ITD in 2nd AML; corresponding values for de novo AML are not reached and 13.3 months, respectively). (Figure 1) EFS and OS was worse in the post-MDS and post-MPN groups compared to de novo AML and second cancer group (p>0.001). Conclusion: In patients with secondary AML, antecedent of MDS or MPN are associated with unique molecular signatures (eg, rare FLT3-ITD in post MDS, frequent JAK2 in post-MPN) and have an inferior outcome. In contrast AML in pts with history of previous cancers not previously exposed to chemotherapy or radiation therapy survival outcomes are similar to de novo AML. Mutational status may not be as predictive of outcome among patients with secondary AML as it is for de novo AML. Disclosures: No relevant conflicts of interest to declare.

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