Karyotype Plus NPM1 Mutation Status Defines a Group of Elderly Patients with AML (≥60 Years) Who Benefit From Intensive Post-Induction Consolidation Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2504-2504
Author(s):  
Wolfgang R. Sperr ◽  
Otto Zach ◽  
Iris Poell ◽  
Michael Kundi ◽  
Susanne Herndlhofer ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Hematologic Toxicity ◽  
Wild Type ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Predictive Variables ◽  
Monosomal Karyotype

Abstract Abstract 2504 Whereas treatment strategies for AML patients (pts) aged <60 years are well established, therapy in the elderly deserves special consideration. In the present study, we analysed survival and risk factors predicting outcome in 192 consecutive patients (pts) with de novo AML aged ≥60 years (median age: 70.5 years, range 60–89 years). Pts were treated at a single center (Medical University of Vienna) between November 1994 and January 2011, and received conventional induction chemotherapy with DAV (daunorubicin, 45 mg/m2/day, days 1–3; etoposide, 100 mg/m2/day, days 1–5; ARA-C, 2 × 100 mg/m2/day, days 1–7; between 1994 and 2008). Pts achieving a complete hematologic remission (CR) were scheduled to receive a full consolidation program with up to 4 cycles of IDAC (ARA-C, 2 × 1 g/m2/day i.v. on days 1, 3, and 5). Of the 192 pts, 115 (60%) achieved a CR following induction therapy, 57 pts (30%) did not achieve a CR, and 20 pts (10%) died within 40 days after start of induction therapy. Among several parameter including the leukocyte count, hemoglobin, platelet count, LDH, and fibrinogen, only the karyotype according the the Breems-Score was an independent predictor for achieving CR in our multivariate analyses. CR rates in pts with core binding factor (CBF) AML, cytogenetically normal (CN) AML, non-monosomal karyotype (Mkneg) AML, and monosomal karyotype (Mkpos) AML, were 100% (8/8), 66% (57/87), 56% (33/59), and 44% (11/25), respectively (p<0.05). Of the 115 pts in CR, 106 (92%) received up to 4 cycles of IDAC (4 cycles, n=53 pts [50%]; 3 cycles, n=20 pts [19%]; 2 cycles, n=20 [19%]; and 1 cycle, n=13 [12%]). Treatment was well tolerated without grade 3 or 4 neurotoxicity. The most frequent non hematologic toxicity was febrile neutropenia requiring antibiotics (1st consolidation: 50.5%; 2nd consolidation: 58.4%, 3rd consolidation: 55.6%, 4th consolidation: 51.0%). A remarkable finding was that the median time of absolute neutropenia in all IDAC cylces (8–9 days/consolidation) was relatively short when compared to induction chemotherapy or other consolidation regimens. Only two patients died during consolidation with IDAC (cardiac failure, n=1, severe sepsis, n=1). The median overall survival (OS) for all pts was 9.7 months, and for pts achieving a CR, the OS amounted to 24.2 months. The most important predictive variables for continuous complete remission (CCR) were the karyotype and the presence of an NPM1 mutation determined by PCR and melting point analysis. As assessed by uni- and multivariate analysis, both parameters were found to be independent predictive variables (p<0.05), whereas the other markers examined, i.e. FLT3 ITD, overexpression of ERG, MN1, or BAALC, as well as the number of induction cycles required to achieve CR, showed no predictive value. The median CCR and CCR after 5 years were 17.9 and 31.3%, respectively in pts with CN/Mkneg-NPM1 mutated AML, and 11.3 months and 25% for pts with CBF AML (p<0.001; see figure). In pts with CN/Mkneg and wild type NPM1 AML and Mkpos AML, the median CCR rates were 10.8 and 6.0 months, respectively. Together, our data show that elderly patients with CN/Mkneg-NPM1 mutated AML or CBF AML can achieve long term CCR when treated with intensive chemotherapy and up to 4 consolidation cycles of IDAC, whereas pts with CN/Mkneg-NPM1 wild type AML and Mkpos AML did not achieve long term CCR despite intensive consolidation. These results are in favour of individualized chemotherapy in elderly pts with AML and suggest that patient-selection in advanced age should not only be based on patient-related factors and the karyotype but also on the NPM1 mutation status. Disclosures: No relevant conflicts of interest to declare.

Role of Etoposide in Combination with All-Trans Retinoic Acid in the Treatment of Elderly Patients with Acute Myeloid Leukemia and NPM1 Mutation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 559-559 ◽  
Author(s):  
Marie-Luise Hütter ◽  
Konstanze Döhner ◽  
Ingo G.H. Schmidt-Wolf ◽  
Francisco Del Valle ◽  
Björn Heydrich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Elderly Patients ◽  
Induction Therapy ◽  
De Novo ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
The Impact

Abstract Rationale: In a previous randomized trial (AML HD98B) in elderly (&gt;60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive induction therapy with idarubicin, cytarabine and etoposide significantly improved outcome; this beneficial effect appeared to be restricted to patients having NPM1 mutation without concomitant FLT3-ITD (NPM1mut/FLT3-ITDneg). In our subsequent trial in elderly patients (AMLSG 06-04), all patients received ATRA with a similar backbone of chemotherapy, except that for induction therapy idarubicin was intensified and etoposide was omitted. NPM1mut AML is associated with myelomonocytic/monocytic differentiation, and etoposide is believed to have a particular effect in these morphologic subtypes of AML. Aims: To evaluate the impact of etoposide in combination with ATRA in elderly patients with AML exhibiting NPM1 mutation enrolled into two consecutive AMLSG protocols. Methods: 171 patients with NPM1mut AML were included in this retrospective analysis; 78 patients from trial AML HD98B (trial A; accrual from 1998 to 2004); and 95 patients from trial AMLSG 06-04 (trial B, 2004–2008). Twenty-nine of 78 (37%) patients and 87 of 93 (94%) received ATRA in trials A and B, respectively. Results: Initial patient characteristics, such as median age (67.8 and 67.9 years for trial A and B, respectively), type of AML (de novo, secondary or therapy-associated), white blood cell count (WBC), LDH, and FLT3-ITD mutation status (41% and 47%), were not significantly different between the two cohorts. The rates of complete remission (CR) were 68% and 71% for NPM1mut patients in trial A and B, respectively. Lower age and lower WBC counts were significantly associated with achievement of CR; study, treatment with ATRA, type of AML, and FLT3-ITD mutation status had no impact. Univariable survival analyses revealed no significant difference for the end points event-free (EFS), relapse-free (RFS) and overall survival (OS) between the two patient cohorts from trial A and B. However, when restricting the analysis to patients who had received ATRA, a significant better EFS (p=0.05) and RFS (p=0.03) was found for patients with the genotype NPM1mut/FLT3-ITDneg in trial A (that included etoposide) compared to trial B (in which etoposide was omitted); there was no difference in EFS (p=0.18) and RFS (p=0.09) for patients with the genotype NPM1mut/FLT3-ITDpos. In addition, no difference was seen either in patients with the genotype NPM1mut/FLT3-ITDpos or in patients with the genotype NPM1mut/FLT3-ITDneg in terms of OS mainly due to a high second CR rate in patients with the genotype NPM1mut/FLT3-ITDneg. Conclusion: The data from this retrospective subgroup analysis suggest that etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3-ITD.

Imatinib and Interferon-Alpha Maintenance Therapy for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Ineligible for Allogeneic Stem Cell Transplantation (SCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2042-2042
Author(s):  
Heike Pfeifer ◽  
Barbara Wassmann ◽  
Andreas Käbisch ◽  
Michael Lübbert ◽  
Lothar Leimer ◽  
...  
Keyword(s):  
Side Effects ◽  
Elderly Patients ◽  
Maintenance Therapy ◽  
Low Dose ◽  
Front Line ◽  
Consolidation Chemotherapy ◽  
Mutation Status ◽  
Line Therapy ◽  
Remission Duration

Abstract Abstract 2042 Poster Board II-19 Introduction: The tyrosine kinase inhibitor imatinib (IM), alone or in combination with chemotherapy, has become the mainstay of front-line treatment for Ph+ ALL. We recently demonstrated that IM in combination with intensive consolidation chemotherapy of approximately one year duration is feasible in elderly patients with de novo Ph+ ALL, but is associated with a high relapse rate. Allogeneic SCT (alloSCT) is potentially curative but may not be feasible in most elderly or comorbid patients. Maintenance therapy (MT) in such patients is conceptually attractive, but data on whether any type of MT facilitates long-term leukemia-free survival of patients with Ph+ALL in first CR is lacking. Based on data suggesting that interferon-alpha (IFN-a) possesses anti-leukemic activity in patients with Ph+ALL, we conducted a phase II study to determine the feasibility and efficacy of MT consisting of imatinib in combination with low-dose (LD) IFN-a in elderly patients with Ph+ALL who were not eligible for SCT. In addition, we examined whether bcr-abl transcript levels and mutation status were predictive of relapse and remission duration. Methods: Nineteen elderly patients (median age 66 yrs; [60-75 yrs.]) who had received IM-based remission induction and consolidation therapy as reported previously (Ottmann et al., Cancer 109:2068-76, 2007) were enrolled in a clinical trial of IM 400 mg daily in combination with LD-IFNa with a target dose of 3 Mio IU/week. At the time of enrollment, the majority of patients (n=12) had received five (n=3) or six (n=9) consolidation cycles, the remaining patients had discontinued intensive front-line therapy after four (n=2), three (n=1), two (n=1), and one (n=1) consolidation cycles, 2 patients were switched to MT after induction. The median number of cycles of consolidation chemotherapy given concurrently with IM was six. Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing. Results: The median overall duration of MT is 26 mos. (range 3-92 mos.). Seven of 19 pts. (37 %) are in ongoing CR, with a median remission duration from start of maintenance of 76.7 mos. (54-91 mos.). Median overall survival of all pts. is 61 mos. (range: 20-99 mos.). Eleven of 18 evaluable pts. experienced side effects which lead to a dose reduction of IFN. 9 pts. suffered from moderate depressions or fatigue. Hematologic toxicity was mild: only 2 pts. developed grade 3 cytopenia during MT. Remission duration was independent of the number of previous cycles of intensive chemotherapy, of the MRD response during the first 6 mos. of intensive front-line therapy (16 mos. vs. 26 mos.) and of achievement of PCR negativity at any time during intial therapy. Surprisingly, the bcr-abl transcript level at the start of MT likewise had no impact on time to disease recurrence. Conclusions: In elderly Ph+ALL pts. ineligible for allogeneic SCT, maintenance with imatinib in combination with low-dose IFN-a results in long-term sustained remissions in a substantial proportion of patients, with acceptable side effects. Surprisingly, the MRD response and mutation status prior to MT were not significantly predictive of remission duration. Likewise, greater intensity of prior chemotherapy as determined by the number of administered consolidation cycles had no significant benefit with respect to remission duration during MT. More extensive evaluation of tyrosine kinase inhibitors in combination with LD IFNa as MT for Ph+ALL is warrented. Disclosures: Ottmann: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.

Cost Burden Analysis of Ineffective Induction Chemotherapy in Elderly Patients with AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4531-4531
Author(s):  
Aileen Cleary Cohen ◽  
Nancy Davidson ◽  
Jason Scharf ◽  
Derek Middlebrook
Keyword(s):  
Elderly Patients ◽  
Incremental Cost ◽  
Induction Chemotherapy ◽  
Health Plan ◽  
National Health ◽  
Induction Therapy ◽  
Patient Population ◽  
Complete Response ◽  
Cost Burden ◽  
National Health Plan

Abstract Abstract 4531 Introduction According to the Surveillance, Epidemiology, and End Results (SEER) database 12,810 patients will be diagnosed with acute myeloid leukemia (AML) in 2009 with an incidence rate of 3.5 per 100,000 persons in the United States. The SEER data estimates that 55% of those diagnosed are 65 years or older. Standard first line therapy for the treatment of AML consists of at least one round of chemotherapy commonly referred to as induction. A significant portion of those patients who receive standard induction chemotherapy will have leukemia that fails to show a complete response as defined by less than 5% leukemia blasts in the bone marrow with normal tri-lineage hematopoiesis and peripheral blood count recovery (Mueller S, et al. BMC Cancer 2006, 6:143). Age, patient performance status, the presence of secondary AML, cytogenetics, and molecular markers are prognostic for particular cohorts of patients, however, there is currently no means to predict whether an individual's leukemia will or will not undergo a complete response (CR) after the administration of standard AML induction chemotherapy. Methods A budget impact model was designed to assess the incremental societal cost and incremental cost to a typical national health plan of treating patients who will fail induction therapy. The analysis only evaluated elderly patients over the age of sixty five. Data were gathered from the peer reviewed literature. All costs have been updated to 2009 dollars using the medical care component of the consumer price index. The patient population was determined to be 6,981 patients in 2009 with 30% receiving induction therapy (Menzin J, et al. Arch Intern Med. 2002; 162:1597-1603) and only 38% demonstrating a CR (Appelbaum FR, et al. Blood 2006 107:3481-5) resulting in 1,303 patients failing during induction therapy. The costs were taken from Menzin et al., which used Medicare claims data to determine the associated costs of AML patients during the first two years post diagnosis. In the model Medicare payments are used as a proxy for direct costs to society and a national health plan. These reimbursements are able to capture the costs of the initial hospital visit, lab/diagnostic/radiology, supportive care, drugs, and adverse events through the observation of payments across all appropriate settings of care (inpatient hospitalization, skilled nursing facility, outpatient hospital/clinical, physician's office, home health, and hospice). A patient undergoing chemotherapy incurred costs of $120,468 over two years, while a patient avoiding chemotherapy only incurred costs of $40,720. Results The incremental cost of a patient receiving induction therapy was calculated to be $79,748. For a national health care plan with an assumed average of one million members results in a cost of $283,856 to treat patients whose leukemia would not respond to induction chemotherapy. The overall societal impact of treating this patient population with ineffective therapy is $104 million. Conclusions Patients who are subjected to ineffective chemotherapy face the cytotoxic effects of the treatment, none of the benefits of treatment response, and impose a significant cost burden to themselves and the healthcare payment system. Diagnostics currently in development that can identify patients at the time of diagnosis with disease unresponsive to therapy may have the ability to alleviate unnecessary costs, while steering patients to better tailored and more effective therapies. Disclosures: Cleary Cohen: Nodality, Inc: Employment. Middlebrook:Nodality Inc: Employment.

Characterization of Extramedullary Acute Myeloid Leukemia – Results of the AML96 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2154-2154
Author(s):  
Friedrich Stölzel ◽  
Christoph Röllig ◽  
Michael Kramer ◽  
Brigitte Mohr ◽  
Uta Oelschlägel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
The Body ◽  
Hematopoietic Stem ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 2154 Background: Myeloid Sarcoma (MS) is defined as an extramedullary mass composed of myeloid blasts occurring at an anatomical site other than the bone marrow. Furthermore, the term extramedullary manifestation (EM) is applied if it accompanies overt acute myeloid leukemia (AML) and represents non-effacing tissue infiltration. EM is reported to correspond often to the skin but can affect almost every site of the body. The prognosis of MS or EM has been discussed controversially in the past. EM at diagnosis of AML is generally thought to be a rare event. However, data defining the prevalence of EM at diagnosis of AML and its prognostic value are missing. The aim of this analysis was to provide data for estimating the prevalence of EM at diagnosis of AML and to determine its relevance by including clinical and laboratory data from patients being treated in the prospective AML96 trial of the Study Alliance Leukemia (SAL) study group. Patients and Methods: A total of 326 patients with AML (age 17 – 83 years) and EM were treated within the AML96 trial with a median follow up of 8.8 years (95% CI, 8.4 to 9.3 years). All patients received double induction chemotherapy. Consolidation therapy contained high-dose cytosine arabinoside and for patients ≤ 60 years of age the option of autologous or allogeneic hematopoietic stem cell transplantation (HSCT). Logistic regression analyses were used to identify prognostic variables for CR rates. The method of Kaplan-Meier was used to estimate OS and EFS. Confidence interval (CI) estimation for the survival curves was based on the cumulative hazard function using the Greenwood's formula for the SE estimation. Survival distributions were compared using the log rank test. Results: 17% of the AML patients entered into the AML96 trial were diagnosed with EM. In 313 of the 326 patients (96%) EM was evident at diagnosis. The majority of patients with EM were diagnosed with de novo AML (84%, n=273), whereas gingival infiltration (51%, n=166) displayed the main EM of AML with CNS involvement being less common (4%, n=14). The majority of patients had a cytogenetic intermediate risk profile (71%, n=221) with a total of 172 patients (56%) harboring a normal karyotype. Patients with EM had a statistically significant lower median CD34-positivity of bone marrow blasts, higher percentage of FAB subtypes M4 and M5, higher WBC counts and LDH at diagnosis and higher percentage of NPM1 mutations compared to those patients without EM (all p<.001). When comparing achievement of CR between patients with EM to patients without EM, no statistical difference between these two groups was observed. Analysis according to the NPM1/FLT3-ITD mutation status revealed highest 5-year-OS (37%, 95% CI: .24 - .508) and 5-year-EFS (36%, 95% CI: .224 - .448) in the NPM1-mut/FLT3-wt group and lowest 5-year-OS (12%, 95% CI: 0 - .261) and 5-year-EFS (4%, 95% CI: 0 - .124) in the NPM1-wt/FLT3-ITD group, p=.007 and p=.001, respectively. Of the 49 relapsed patients with EM who had a NPM1-mutation at diagnosis 48 deceased despite of intensified relapse therapies. Conclusions: This analysis represents the largest study so far investigating the impact of EM AML. Patients with EM AML have distinct differences from AML patients without EM regarding their clinical and molecular characteristics at diagnosis. However these differences do not translate into differences in response to induction chemotherapy. Compared to patients without EM, survival analysis revealed differences according to the NPM1/FLT3-ITD mutation status which is also described for patients without EM AML. However, the prognosis for patients with EM who harbor a mutated NPM1 the prognosis at relapse seems to be dismal. Disclosures: No relevant conflicts of interest to declare.

Impact of High Body Surface Area on AML Outcome in Younger Patients: A Goelams Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 973-973 ◽  
Author(s):  
Xavier Cahu ◽  
Martin Carre ◽  
Christian Recher ◽  
Emmanuel Gyan ◽  
Jean-Francois Hamel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Long Term Results ◽  
Younger Patients ◽  
Full Dose ◽  
Related Donor ◽  
Very High

Abstract In younger patients with acute myeloid leukemia (AML), standard intensive induction chemotherapy combines anthracyclins and cytarabine (Ara-C). While dosage is usually determined according to body-surface area (BSA), various chemotherapy adjustments are empirically performed in patients with high BSA from full dose administration to capping doses. The aim of the present study is to determine the outcome of younger AML patients with high BSA at diagnosis. Between November 2001 and April 2005, the prospective GOELAMS 2001 trial enrolled patients between 18 and 60 affected with non promyelocytic AML.1,2 Briefly, patients randomly received either daunorubicin or idarubicin in association with standard dose Ara-C during induction therapy. Height, weight and induction chemotherapy doses were registered at diagnosis. BSA was evaluated using the formula of Dubois and Dubois. BSA was categorized in low (BSA ≤1.5m2), intermediate (1.5<BSA<2), high (2<BSA<2.15) or very high BSA (BSA ≥2.15). In the course of consolidation therapy, patients with a matched related donor received an allogeneic stem cell transplantation. Patients without a matched related donor received either a single or tandem autologous bone marrow transplantation. Patients who did not achieve sufficient stem cell mobilization received chemotherapy-only consolidation. 823 patients were eligible to induction therapy. 43 (5%), 638 (77%), 91 (11%) and 51 (6%) patients displayed low, intermediate, high or very high BSA at diagnosis, respectively. Median age, performance status, karyotype group were similar in all BSA groups. On the contrary, male gender was enriched in high and very high BSA groups (86% and 88%, respectively). During induction therapy, 20 patients (39%) with very high BSA were administered reduced dose (decrease of > 10% in anthracyclin or Ara-C dosing compared to full dose) versus 8%, 4% and 7% in low, intermediate or high BSA subgroups (p <10-5). Type of consolidation therapy - chemotherapy, autologous or allogeneic stem cell transplantation - was not significantly different in BSA groups. Compared to patients with intermediate BSA, patients with a low or high BSA displayed a similar OS and EFS. On the contrary, patients with a very high BSA displayed a decreased 5-year OS (27% (95% CI, 18-43) vs 47% (95% CI, 44-51), p= 0.006, figure 1A) and LFS (22% (95% CI, 13-36) vs 41% (95% CI, 37-45), p=0.004). Non-relapse mortality was similar in the very high or intermediate BSA groups, suggesting that intensive therapy was similarly tolerated in intermediate or very high BSA patients. Meanwhile, relapse incidence was increased in patients with a very high BSA compared to intermediate BSA patients (61% (95% CI, 46-73) vs 44% (95% CI, 40-48), p = 0.02, figure 1B). Conclusion: patients with a very high BSA display an adverse outcome, due to an increased relapse incidence. Meanwhile, non-relapse mortality is not significantly increased in very high BSA patients. These data suggest that patients with very high BSA should receive full dose induction chemotherapy. Bibliography; 1. Recher C , Bene MC, Lioure B et al. Leukemia, Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. Leukemia 2014; 28:440-3. 2. Lioure B, Bene MC, Pigneux A et al. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood 2012; 119: 2943–2948. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (≥60 years) who benefit from intensive post‐induction consolidation therapy

2016 ◽  
Vol 91 (12) ◽  
pp. 1239-1245 ◽  
Author(s):  
Wolfgang R. Sperr ◽  
Otto Zach ◽  
Iris Pöll ◽  
Susanne Herndlhofer ◽  
Paul Knoebl ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Consolidation Therapy ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Post Induction

Tolerability of An Effective Two Day Induction Regimen for Newly Diagnosed AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4035-4035
Author(s):  
Melissa L. Larson ◽  
Nitin Goyal ◽  
Ann M. Thomas ◽  
Jamile M. Shammo ◽  
John J. Maciejewski ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Induction Therapy ◽  
Dose Intensity ◽  
Remission Induction ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Refractory Disease ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Background: The standard remission induction regimen for treating Acute Myeloid Leukemia consists of seven days of continuous infusion cytarabine and three days of an anthracycline, the “7 + 3” regimen. We present a single institution, retrospective analysis of toxicity associated with a regimen that requires only two days of chemotherapy using high dose cytarabine and mitoxantrone. The regimen is based on the timed sequential therapy concept where two pulses of chemotherapy are given. The first pulse recruits cells into the cell cycle, while the second pulse is given at the time of peak recruitment. Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day of chemotherapy consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Each patient’s chart and electronic record were thoroughly reviewed, and toxicities associated with induction therapy were analyzed and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v3.0. Responses were defined per the Revised IWG Recommendations (Cheson, J Clin Onc21: 4642, 2003). Results: One hundred four patients were eligible for toxicity evaluation. Hematologic toxicities were the most common toxicities seen with this induction therapy. Overall, all patients experienced hematologic toxicity of some grade with 98% of patients having one or more Grade 3/4 hematologic toxicity. The incidences of grade 3/4 hematologic toxicities are the following: Hemoglobin 65.3% (Gr 3 59.6%, Gr 4 5.7%), thrombocytopenia 93.2% (Gr 3 9.6%, Gr 4 83.6%), and neutropenia 89.4% (Gr 3 1.9%, Gr 4 87.5%). Febrile neutropenia occurred in 64% of the patients, and grade 3 and 4 infections occurred in 25%. Common non-hematologic toxicities included fatigue, nausea, vomiting, diarrhea, and electrolyte abnormalities. The vast majority of non-hematologic toxicities were grade 1 and 2. Three patients (2.9%) died within the first 30 days of induction therapy. One patient died before completing therapy due to massive hemoptysis. One died from complications of refractory disease, and the third patient died from disseminated fungal infection. An additional 10 patients (6 TF-RD, 1 TF-aplasia, 1 CR, 1 CRi, 1 CRp) died within the first 60 days. Of the 6 patients with refractory disease, 4 received re-induction therapy to which 3 did not have a response and the fourth died of sepsis while aplastic. Two patients had intracerebral hemorrhage (TF-aplasia and CRp). One patient died suddenly in CR of unknown causes and one patient (CRi) died from complications of pneumonia/ARDS. Conclusion: Although this regimen incorporating high dose cytarabine into remission induction presents a significantly higher dose intensity of cytarabine and mitoxantrone compared to that of the “7+3” regimen, the toxicity profile and 30-day mortality rate compare favorably to the “7 + 3” regimen. This regimen has been shown to produce a CR rate comparable to that of the “7+3” regimen with equal efficacy and better tolerance in elderly patients with AML. We conclude that this regimen effectively administers a high yet apt dosage of chemotherapy, and it can even be used for remission induction in elderly patients. This induction regimen could serve as a platform for future studies of maintenance and biologic therapies in the elderly AML patients.

Single-Cell Network Profiling (SCNP)-Based Classifier to Predict Response to Induction Therapy in Elderly Patients with Acute Myeloid Leukemia (AML): Validation in Two Independent Sample Sets From ECOG and SWOG Trials.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2489-2489
Author(s):  
Alessandra Cesano ◽  
Cheryl L Willman ◽  
Kenneth J. Kopecky ◽  
Urte Gayko ◽  
Santosh Putta ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Single Cell ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
De Novo ◽  
Training Set ◽  
Employment Equity ◽  
Cell Network ◽  
Disease Characteristics ◽  
Equity Ownership

Abstract Abstract 2489 Purpose: Standard Induction chemotherapy (Ara-C/daunorubicin, 3+7 regimen) in elderly patients (pts) with AML results in approximately 35–45% complete remission (CR) rate, and pts with resistant disease (RD) have a median survival of only 1–3 months. Developing a test for accurate prediction of response to standard induction therapy at the time of diagnosis may help inform treatment selection and improve clinical trial design. Methods: Single cell network profiling (SCNP) is a multi-parameter flow cytometry based approach for simultaneous interrogation of intracellular signaling pathways at a single cell level. SCNP was used to evaluate signaling profiles in leukemic blasts and to develop a classifier (DXSCNP) of response to induction therapy (CR/CRi, i=incomplete) in a Training Set of cryopreserved diagnostic samples (57 PB and 43 BM) collected from 74 non-M3 AML pts, aged 56+ treated with 3+7-based regimens on 4 SWOG clinical trials. SCNP intracellular readouts quantifying apoptotic response after 24 hrs in vitro treatment with Ara-C/Daunorubicin formed the inputs for DXSCNP. Pt and disease characteristics available either at diagnosis, i.e. relevant to induction therapy choices (e.g., age, WBC counts, FAB class, secondary AML, performance status – CLINICAL1), or available after start of induction therapy (CLINICAL2) were used to develop 2 clinical predictors (DXCLINICAL1 and DXCLINICAL2) of CR/CRi in the Training Set. The performance characteristics of these 3 classifiers were then tested separately in BM and PB sample sets. Specifically, classifier validation was performed in 2 independent BM sample sets (A: n=24 BM samples from ECOG E3999 trial; B: n=42 independent BM samples from the same 4 SWOG trials from which the Training samples were derived) and in 1 PB sample set (C: n=53, from the 4 SWOG trials; notably only 24 patients were shared between Set B and C)). The area under the receiver operating characteristic curve (AUROC) was used to measure each classifier's ability to predict response to 3+7 induction therapy. Out of bag estimates (OOB) of AUROC were calculated using the Training Set, and H0:AUROC=0.5 was tested against HA:AUROC>0.5 for each classifier in the Validation Sets. Results: As shown in Table 1, DXSCNP was a significant predictor of CR/CRi in BM samples. The AUROC for the DXSCNP classifier was 0.81 in the Training Set and 0.76 (p=0.01) and 0.72 (p=0.02) in Validation Sets A and B, respectively. No significant DXCLINICAL1 was identified from the 74 pts in the Training Set(OOB AUROC∼0.5). By contrast the AUROC of DXCLINICAL2 (which included inputs for cytogenetics, Flt3ITD, and NPM1 mutational status) was 0.63 (OOB) in the Training Set, and 0.61 (p=0.18) and 0.53 (p=0.38) in Validation Sets A and B, respectively. Of note, DXSCNP remained significant (p=0.03 and 0.04) when controlling for DXCLINICAL2 in both sample sets. Similar performance of DXSCNPwas observed in different pre-specified subgroups (although of small sample sizes) defined by pt, sample or disease characteristics. Using PB samples, the AUROCs for the DXSCNP classifier were, 0.87 (OOB) in the Training Set and 0.53 (p=ns) in the Validation Set C. However, the performance of DXSCNP in PB samples differed significantly between secondary vs. De novo AML i.e. AUROC= 0.24 vs 0.8 respectively. Of note, DXSCNPperformed similarly for the subset of de novo patients for whom paired BM with PB samples were tested (AUC=0.78 (PB) and 0.74 (BM)). Conclusion: This is the first study describing the successful validation of an SCNP-based classifier to predict response to standard induction chemotherapy in elderly AML pts with performance superior to clinical variables available at diagnosis. A similar SCNP classifier with overlapping cellular biology inputs was previously validated for pediatric AML. These results confirm the ability of quantitative SCNP readouts to provide independent and actionable information on disease biology and pt treatment choices. Independent validation in prospective studies is warranted. Disclosures: Cesano: Nodality, Inc: Employment, Equity Ownership. Gayko:Nodality, Inc.: Employment, Equity Ownership. Putta:Nodality, Inc.: Employment, Equity Ownership. Louie:Nodality, Inc.: Employment, Equity Ownership. Westfall:Nodality, Inc.: Employment, Equity Ownership. Purvis:Nodality, Inc.: Employment, Equity Ownership. Spellmeyer:Nodality, Inc.: Employment, Equity Ownership. Marimpietri:Nodality, Inc.: Employment, Equity Ownership. Hackett:Nodality, Inc.: Employment, Equity Ownership. Shi:Nodality, Inc.: Employment, Equity Ownership.

Prognostic Impact of Mutations in the Nucleophosmin (NPM1) and of the FMS-Related Tyrosine Kinase 3 (FLT3) Genes in Elderly Patients with Acute Myeloid Leukemia (AML) Treated with Intensive Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2542-2542 ◽  
Author(s):  
Anne Etienne ◽  
Cecile Borel ◽  
Sarah Reutenauer ◽  
Sylviane Olschwang ◽  
Marie-Joelle Mozziconacci ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Young Patients ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Wild Type ◽  
Old Patients ◽  
Npm1 Mutation ◽  
Female Patients ◽  
Cell Counts ◽  
Significant Difference

Abstract AML is a heterogeneous disease and the actual most reliable prognostic factor is the karyotype. Mutations of NPM1 and FLT3 constitute the most frequent molecular genetic alterations in patients with AML. Their prognostic impact is now well recognized, especially in young patients with intermediate prognosis karyotype. However few studies have focused on elderly patients. We retrospectively studied the prevalence of NPM1 mutation and FLT3 internal tandem duplications (ITD) and its association with complete remission (CR) and survival in 86 patients aged 61 years or older treated between 1996 and 2007 for acute non promyelocytic leukemia with intermediate karyotype in the Institut Paoli-Calmettes, Marseille, and the university hospital of Toulouse. All patients received intensive induction chemotherapy (“3+7” regimen). Median age was 70 years (range, 61–79). The median follow-up of surviving patients was 34 months. 44 patients (51%) had NPM1 mutation and 21 had FLT3-ITD (24%). In the NPM1 mutated group, there were significantly more: female patients, absence of antecedent hematologic disorder, de novo AML, and low CD34 expression. In the FLT3-ITD group, there were significantly more: female patients, increased white blood cell counts and peripheral blood blasts. Overall CR rate was 67%; median disease free survival (DFS) and overall survival (OS) were 11 and 10 months, respectively. CR rate was negatively associated with a poor performans status and a high score previously described including assessment of comorbidities (Etienne et al., Cancer2007; 109(7):1376–83). CR rate was 57% versus 72% for patients with FLT3-ITD compared to patients with wild-type FLT3 (p 0.2), and 64% versus 71% for the NPM1 mutated group compared with the NPM1 non-mutated group (p 0.5). Median OS was 6 months versus 12 months for patients with FLT3-ITD mutation versus wild type patients (p = 0.04). Median OS was 9 months for patients with NPM1 mutation and did not differ from non-mutated patients. No significant difference in term of CR rate and OS was found between the 29 patients carrying NPM1 mutation without FLT3-ITD and the 57 other patients without NPM1 mutation or with FLT3-ITD. Median DFS was 21 months versus 9 months for these two groups, respectively (p 0.2). These results confirm the prognostic impact of FLT3-ITD in our series of old patients with AML. Unlike young patients, NPM1 mutated elderly patients have a similar outcome than NPM1 wild type patients. The absence of prognostic impact of NPM1 mutation without FLT3-ITD has to be validated on larger prospective cohort. FLT3 status should be taken into account for treatment choices in elderly patients.

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