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

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.

scholarly journals Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Maël Heiblig ◽  
Hélène Labussière ◽  
Marie Virginie Larcher ◽  
Gaelle Fossard ◽  
Marie Balsat ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Predictive Value ◽  
Scoring System ◽  
Research Funding ◽  
Risk Group ◽  
Advisory Committees ◽  
Post Induction ◽  
Mutational Status ◽  
Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p&lt;0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p&lt;0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P &lt;0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P &lt;0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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.

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.

Quantitative Monitoring of NPM1 Mutation A Minimal Residual Disease Identifies Patients At High Risk for Relapse within the ELN Favorable Risk Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1404-1404
Author(s):  
Max Hubmann ◽  
Marion Subklewe ◽  
Thomas Köhnke ◽  
Stephanie Schneider ◽  
Annika Dufour ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Residual Disease ◽  
Risk Group ◽  
Disease Recurrence ◽  
Consolidation Therapy ◽  
Rt Pcr ◽  
Npm1 Mutation ◽  
Minimal Residual

Abstract Abstract 1404 Introduction: Molecular analyses of leukemia-specific markers has led to an improvement of the prognosis evaluation in patients (pts) with acute myeloid leukemia (AML). The European Leukemia Net (ELN) has published a classification which separates different subgroups by cytogenetic and molecular genetic analyses. Nevertheless, there are still pts suffering from disease recurrence within the ELN favorable risk group. To identify these pts at high risk for relapse the monitoring of minimal residual disease (MRD) of leukemia-specific markers could become an important diagnostic tool. In this study the potential of MRD monitoring by quantitative real-time PCR (RT-PCR) of NPM1 A mutation (NPM1 A) at different checkpoints within the ELN favorable risk group of pts with NPM1 A and without FLT3-ITD was investigated. Methods: Pts participating in the AMLCG99, AMLCG2004, and AMLCG2008 trial were prospectively or retrospectively screened for NPM1 mutation and FLT3-ITD by melting curve analyses. 334 pts were screened positive for NPM1 mutation and 262 pts showed a NPM1 A, 78.4 % of all NPM1 mutations. For MRD monitoring a relative RT-PCR was performed in 538 samples of 178 NPM1 A positive pts with a sensitivity of 10-6. MRD was monitored at diagnosis, in aplasia, after induction therapy, after consolidation therapy, and during the follow-up. MRD levels were normalized to the housekeeping gene ABL1 and expressed as a ratio to an internal control of known concentration. Results: In the analysis of the NPM1 A positive and FLT3-ITD negative pts (ELN favorable risk group) 82.5% (n=85) achieved complete remission (CR) after induction therapy. With a median follow-up of 26 (range 1–118) months, 36 (42.9%) pts relapsed within this subgroup. In aplasia, and after induction therapy, pts with a long-lasting remission showed significantly lower NPM1 A ratios in contrast to pts who relapsed during the follow-up. Via Receiver-Operating Curves (ROC) we analyzed the diagnostic power to identify pts at high risk for relapse and determined clinical useable cut-offs at the different checkpoints. ROC were significantly associated with disease recurrence at the checkpoints in aplasia and after induction therapy, but not after consolidation therapy. After induction therapy, a cut-off with a ratio of 0.01 was determined. This cut-off separates the patient cohort into two prognostic groups. NPM1 A MRD levels above the cut-offs result in an increased risk of relapse compared to pts with MRD level below this cut-off. This is reflected in a significantly lower 2-year relapse free survival (RFS) of 18% versus 72% (Figure 1). In 25 pts of this favorable risk group follow-up samples in CR were available for analysis of an upcoming relapse within 100 days of sampling. Only 2 of these pts developed relapse within of the next 100 days, but both pts showed increasing MRD levels prior to relapse. 18 relapse samples were available in this subgroup and interestingly, one patient (5.5%) was NPM1 A negative at relapse. When we further enrolled the FLT3-ITD positive pts into our analyses, not surprisingly we found a negative impact on the RFS of MRD positive and MRD negative pts. Conclusions: Our results confirm the observations of other studies that showed the prognostic impact of NPM1 MRD monitoring by RT-PCR. With the MRD monitoring we could identify pts at high risk for relapse within the ELN favorable risk group. Particularly high MRD levels after the induction therapy were strongly associated with a worse RFS. This and previously published data of others demonstrate that in addition to pre-therapeutic factors, the individual MRD course should be used as prognostic factor for the guidance of treatment and pts with high or increasing levels of MRD should undergo allogeneic stem cell transplantation, if eligible. Disclosures: No relevant conflicts of interest to declare.

Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
B. C. Medeiros ◽  
J. R. Gotlib ◽  
S. E. Coutre ◽  
C. Jones ◽  
S. A. Khan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Low Doses ◽  
Npm1 Mutation ◽  
Acute Myeloid

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

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