High-dose Cytarabine-based Consolidation Research Articles

'CARMEN': is less, more? Lessons from trials in human immunodeficiency virus-Burkitt lymphoma (HIV-BL).

'CARMEN': is less, more? Lessons from trials in human immunodeficiency virus-Burkitt lymphoma (HIV-BL).

A dose‐dense short‐term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high‐risk Burkitt lymphoma or high‐grade B‐cell lymphoma: safety and efficacy results of the “CARMEN” phase II trial

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n=16), HGBL (n=3) or double-hit lymphoma (n=1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate=90%; 95% confidence interval (CI)=77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI=60-80%) and 75% (95% CI=66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.

Classifying AML Patients with Inv(16) into High-Risk and Low-Risk Relapsed Patients Based on Peritransplantation Minimal Residual Disease Determined By CBFβ/MYH11 Gene Expression

A subtype of patients with core binding factor acute myeloid leukemia (AML) is characterized by the presence of the presence of inv(16)(p13q22) and rarely by a translocation t(16;16)(p13;q22). The final genetic product is the fusion of the CBFβ gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) at 16p13, which is termed as CBFβ/MYH11 fusion gene. Although this type of AML is considered a favorable cytogenetic subgroup both in NCCN guideline or ELN classification, in particular with the application of high-dose cytarabine-based consolidation chemotherapy regimens, disease relapse remains one of the most important causes leading to death, occurring in around 35% of patients. Thus, for this cohort of patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is needed to as salvage treatment to improve the overall survival.It has been reported that when patients achieved hematological remission, the MRD prior to transplantation (pre-MRD) has been demonstrated to be a useful parameter to predict leukemia relapse after allo-HSCT. Evaluating minimal residual disease (MRD) by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) can quantify the expression level of fusion transcript at different time points along with the treatment. More recently, CBFβ/MYH11 fusion gene has been confirmed to be a good MRD marker and further screening out the patients in high-risk of relapse either during the treatment or after transplantation. However, due to the limit number of patients, there has been no studies about predictive value of CBFβ/MYH11expression after allo-HSCT.Therefore, in this study, we attempted to investigate the impact of pre-MRD determined by RQ-PCR-based CBFβ/MYH11 gene expression on transplant outcomes of AML patients with inv(16)(p13q22) or t(16;16)(p13;q22). Besides, our previous studies has demonstrated that in compared to HLA-identical transplantation, haplo-identical allo-HSCT had superior graft-versus-leukemia (GVL) effect in AML patients with standard-risk. Thus, here we also wanted to know whether the level of CBFβ/MYH11 pretransplant could further divide this form of AML into high-risk and low-risk relapse patients before allo-HSCT.Ninety AML patients with inv(16) in complete remission (CR) were monitored CBFβ/MYH11 transcript before and after allo-HSCT as MRD. A total of 23 patients received HLA-matched sibling donor transplantation (MSDT) and 67 patients received unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were analyzed in this study. Patients were divided into four groups based on the value of CBFβ/MYH11 prior to transplantation (pre-MRD): with negative (group 1)/positive (group 2) pre-MRD before MSDT; with negative (group 3)/positive (group 4) pre-MRD before haplo-HSCT. The results showed that patients in group 2 had the highest cumulative incidence of relapse (2-year CIR, 40.7%), the lowest leukemia-free survival (2-year LFS, 50.8%) and the overall survival (2-year OS, 62.5%) among all four groups. The other three groups of patients had comparable CIR, TRM and OS (P>0.05). The patients were also classified into the other three groups according to CBFβ/MYH11 value of +1 month after transplantation: group 5: pre- and post-transplant MRD were both negative; group 6: the value of post-transplant MRD was lower than 0.2%; group 7: the value of post-transplant MRD was higher than 0.2%. Group 7 had the highest CIR compared to group 5 and 6 (P=0.217 & P=0.001, respectively) and the lowest LFS (P=0.072 & P=0.002, respectively), though the TRM and OS of these three groups were comparable (P>0.05). These results indicated that AML patients with inv(16) were able to be separated into high-risk and low-risk relapse groups based on peritransplant MRD determined by RQ-PCR-based CBFβ/MYH11. Haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT. DisclosuresNo relevant conflicts of interest to declare.

KIT Mutation Versus MRD, Which Is More Important To Predict Relapse Of Acute Myeloid Leukemia With t (8; 21)?

BackgroundAlthough acute myeloid leukemia (AML) with t (8; 21) translocation generally belongs to the favorable-risk AML subtypes, relapse occurs in about 40% of cases and long-term (>5years) survival less than 50%. KIT-mutation (KIT+) and minimal residual disease (MRD) levels have been demonstrated as two most important risk factors in several retrospective studies. Until now, only two prospective studies (Our AML05 trial; French CBF-2006 trial) have assessed their respective prognostic values (Zhu HH, et al. Blood 2013; 121:4056; Jourdan E, et al. Blood 2013; 121:2213). We found both KIT+ and MRD were independent risk factors for relapse, but Joundan et al found only MRD rather than KIT+ was sole prognostic factor for relapse in multivariate anaysis. Both studies did not perform a comprehensive subgroup analysis combining the two factors, and risk-adopt postremission treatment might also affect this assessment. Therefore, we performed a subgroup analysis combining KIT mutation and MRD in a prospective protocol AML05 to answer which is more important to predict outcomes of t(8;21)AML. MethodsFrom July, 2005, to Jan, 2013, 114 patients with t (8; 21) AML after achieving complete remission were included in this analysis. KIT mutations in exons 17 and 8 were screened using the direct sequencing method. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. MRD-positive (MRD+) was defined as < 3 log reduction of RUNX1/RUNX1T1 transcript from baseline after second consolidation therapy. Sixty-two patients received high-dose cytarabine-based consolidation chemotherapy (CT) or autologous hematopoietic stem-cell transplantation (auto-HSCT), and 52 patients received allogeneic HSCT (allo-HSCT). ResultsWhen receiving CT/auto-HSCT as postremission treatment, KIT+ patients (n=19) had a higher 3 year cumulative incidence of relapse (CIR) than KIT-patients (n=43) (94.4% vs. 38.2%, p<0.0001). Similar results also found in MRD+ (n=19) and MRD- (n=43) patients (CIR 92.9% vs. 46.6%, p<0.0001). Among KIT+ patients, a very high relapse rate was found in both MRD+ and MRD-patients (CIR, 100% vs.88.9%). However, among KIT-patients, MRD+ patients had a significant higher relapse rate than MRD-patients (CIR, 84.4% vs.26.3%, p=0.0006). When pooling KIT+ and or MRD+ into one group (KIT+/MRD+), this group had a significant higher relapse rate than KIT-MRD- group ( 94.4% vs. 26.3%, p<0.0001), However, the prognostic values of KIT and MRD was lost when patients received allo-HSCT (CIR of KIT+/MRD+ and KIT-MRD-, 23.8% vs. 15.6%, p=0.47). Similar results were also been found in disease-free survival (DFS) and overall-survival (OS). Multivariate analysis revealed that KIT+, MRD+, and treatment (allo-HSCT or CT/auto-HSCT) were three independent prognostic factors for relapse (all p<0.0001), DFS (all p<0.0001) and OS (p<0.0001, p<0.0001, p=0.007). ConclusionsBoth KIT status and MRD level were important to predict relapse of t (8;21) AML. KIT+ patients hold a very high relapse risk.▪▪ [Display omitted] Disclosures:No relevant conflicts of interest to declare.

High-dose cytarabine-based consolidation shows superior results for older AML patients with intermediate risk cytogenetics in first complete remission

We evaluated outcomes in two consecutive groups of AML patients age>60 years in CR after 7+3 induction therapy. Group 1 received consolidation with cytarabine 1.5g/m2 q12h×6+daunorubicin for two cycles, while group 2 received consolidation with 7+3 followed by mitoxantrone+etoposide. For patients with intermediate-risk cytogenetics, group 1 had a significantly superior DFS (p=0.046), and a trend toward better OS (p=0.087). The treatment group remained a significant predictor of DFS on multivariate analysis. The results indicate that a high-dose cytarabine-containing consolidation regimen produces superior outcomes in AML patients age>60 years with intermediate-risk cytogenetics.

High-Dose Cytarabine-Based Consolidation Shows Superior Results for Elderly AML Patients with Intermediate Risk Cytogenetics in First Complete Remission

AbstractAbstract ▪3574▪This icon denotes a clinically relevant abstract Introduction:In elderly patients with acute myeloid leukemia (AML) treated intensively, the optimal post-remission strategy is unclear. High dose cytarabine (HiDAC) 3 g/m2 is the standard consolidation dose for younger adults with AML with favorable and intermediate risk disease, but is associated with high rates of severe toxicity and early death in older adults that counteract any improvement in efficacy when compared to standard dose cytarabine. We have used a modified high-dose cytarabine consolidation regimen, and compared this to a similar cohort receiving a conventional-dose regimen. Methods:164 patients with AML age 60 years and over, who achieved complete remission after standard induction therapy consisting of cytarabine 100 mg/m2/day continuous IV infusion × 7 days and dauorubicin 60 mg/m2 IV daily × 3 (7+3) from 1998 – 2008, received two different types of post-remission therapy in sequential cohorts. Group 1 (n=55), treated from 1998–2002, received 2 consolidation cycles, each consisting of cytarabine 1.5 g/m2 q12h × 6 doses + daunorubicin 45 mg/m2/day × 2, while group 2 (n=109), treated from 2003–2008, received a first consolidation using 7+3 followed by a second cycle consisting of mitoxantrone 10 mg/m2 IV daily × 5 plus etoposide 100 mg/m2 IV daily × 5 (NOVE). Results:The two groups did not differ with respect to median age (68 vs. 69 years), mean baseline WBC, gender, prior malignancy/AHD and proportion of patients undergoing allogeneic HSCT in CR-1 (9.1 vs.8.3%). 40 patients (72.7%) in the first group, and 86 patients (78.9%) in the second group received the intended consolidation regimen (p=0.38). Among the entire cohort (n=164), and in the subgroup with adverse risk cytogenetics, there was no significant difference in OS or DFS between the two groups. For patients with intermediate risk cytogenetics, on an intention-to-treat basis, the disease-free survival (DFS) was significantly higher for group 1 vs. group 2 (Table 1).Table 1Outcome for patients with intermediate risk cytogenetics.Group1 (N=38)Group 2 (N=84)P (log-rank)DFS (median), mos.13.48.50.0462 year DFS37%24%5 year DFS18%7%OS (median), mos.25.614.70.0872 year OS53%37%5 year OS27%17% Conclusion:Older patients with intermediate-risk cytogenetics, who received a modified high-dose cytarabine-based consolidation regimen combined with anthracycline, had a superior DFS and a trend toward superior OS, as compared to those who received conventional-dose consolidation therapy. These findings require further evaluation in a prospective randomized study but, if confirmed, suggest that older fit patients with intermediate risk cytogenetics should receive more intensified post-remission therapy with modified high-dose cytarabine. Disclosures:No relevant conflicts of interest to declare.

Risk-Stratification Treatment Directed by Minimal Residual Disease Improves the Outcome of Acute Myeloid Leukemia with t(8;21) in First Complete Remission: Results of the AML05 Multicentre Trial

AbstractAbstract 139▪▪This icon denotes a clinically relevant abstract BackgroundAlthough patients with acute myeloid leukemia (AML) and the t(8;21) translocation generally have a favorable prognosis, relapse occurs in about 40% of cases and long-term (>5years) survival less than 50%. Patients with a KIT-mutation had an even higher relapse rate up to 70% and dismal survial. Once relapse, the outcome is extremely poor, even receiving allogeneic hematopoietic stem-cell transplantation (allo-HSCT).Therefore, rapidly identifying high-risk relapse patients and preemptively treating them with more aggressive therapy, such as HSCT, may decrease the chance of relapse and improve patient survival. We sought to improve outcome in patients with t(8;21) acute myeloid leukemia(AML) in first complete remission (CR) by applying risk-directed therapy that was based on measurements of minimal residual disease (MRD) by quantitative PCR during treatment. MethodsFrom June 1,2005, to Dec 31, 2011, 137 patients with t(8;21) AML were enrolled at three centres. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. High-risk was defined by not achieving major molecular remission (MMR,> 3 log reduction of RUNX1/RUNX1T1 transcript from baseline) after second consolidation therapy or loss of MMR within 6 months since achieving MMR. Low-risk was defined by achieving MMR after second consolidation therapy and maintenance of MMR within 6 months thereafter. High-risk patients were recommended to receive allogeneic hematopoietic stem-cell transplantation (allo-HSCT) and low-risk patients to high-dose cytarabine-based consolidation chemotherapy. 116 patients who achieved CR and completed second consolidation were assigned to risk-directed therapy. Finally, sixty-nine patients actually received risk-directed therapy and 47 patients received a non risk-directed treatment for patients¡ bias. FindingsWith a median follow-time of 36 months in patients alive, risk-directed therapy and non risk-directed therapy achieved 5 year cumulative incidence of relapse(CIR) of 15.0%±4.7% and 57.5%±8.0%(p<0.0001), disease-free survival(DFS) of 74.7%±5.8% and 37.1%±7.4%(p<0.0001) and overall survival (OS) of 82.7%±5.1% and 49.8%±8.5% (p=0.002) (Figure 1). Allo-HSCT benefited high-risk as well as KIT-mutated but impaired low-risk patients’ DFS and OS (all p<0.05) (Figure 2). Multivariate analysis revealed that MRD status (high-risk vs. low-risk) and treatment (risk-directed vs. no risk-directed) were independent prognostic factor for relapse(hazard ratio 8.85, 95% CI 2.05–38.13, p=0.003; 0.26, 95% CI 0.12–0.61, p=0.002), DFS(hazard ratio 9.32, 95% CI 2.21–39.3; p=0.002; 0.36, 95% CI 0.17–0.75, p=0.007) and OS (hazard ratio10.53, 95% CI 1.41–78.83; p=0.022; 0.37, 95% CI 0.15–0.93, p=0.035).KIT-mutation was an independent prognostic factor for relapse(hazard ratio 2.12, 95% CI 1.01–4.48, p=0.049) but not for DFS and OS. InterpretationRisk-stratification treatment directed by MRD could improve the outcome of AML with t(8;21) in first complete remission. Allo-HSCT benefits high-risk as well as KIT-mutated but impairs low-risk patients¡ survival. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation Confers a Favorable Outcome in Patients with NPM1 Positive Acute Myeloid Leukemia: Results From a Donor Vs. No-Donor Analysis of 309 Patients Treated in the SAL AML-2003 Trial

Abstract 493 Background:According to retrospective analyses, the presence of a mutated Nucleophosmin-1 gene (NPM1+) in acute myeloid leukemia (AML) is associated with a favorable prognosis, particularly in the absence of an FLT3-ITD mutation (FLT3-ITD-). Therefore, AML with NPM1+/FLT3-ITD- and normal karyotype has been classified as favorable risk in current prognostic classifications. In order to assess the predictive value with regard to allogeneic stem cell transplantation (allo SCT), we compared the clinical course of 309 NPM1+ AML patients eligible for allo SCT in a donor versus no-donor analysis. Patients and Methods:Patients diagnosed with AML, aged 18–60 years, and treated in the AML 2003 trial of the Study Alliance Leukemia (SAL) were analyzed. According to the risk-adapted treatment strategy of the trial, cytogenetically intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-identical-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. Patients with no available donor received high-dose cytarabine-based consolidation or autologous SCT. In order to avoid selection bias in an as-treated analysis of transplanted versus non-transplanted patients, we compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor in a donor-no-donor analysis. Survival analyses were performed using the Kaplan-Meier method including log-rank tests for significance testing. Cox regression models and Wald tests were used for multivariate analyses on the influence of potential prognostic variables on the outcomes. Results:Of 1182 patients enrolled in the AML 2003 trial between December 2003 and November 2009, 375 were NPM1+ (32%), and 309 patients were eligible for evaluation for the donor vs. no-donor analysis. Their median age was 49 years, 304 patients had an intermediate-risk karyotype according to MRC criteria (98%), and amongst them there were 277 patients with a normal karyotype (90%). The FLT3-ITD mutation was present in 144 patients (37%). A donor was identified for 77 patients (25%), of whom 57 actually received allo SCT as first consolidation (74%). The no-donor group consisted of 232 patients. Age, disease status, cytogenetic profile, and FLT3-ITD incidence were equally distributed between the two groups. Median follow up was 41 months (3.4 years). The 3-year RFS in the donor and no-donor groups was 72% (95%–CI 61%–82%) and 47% (95%–CI 40%–55%), respectively. (p=0.007). The OS in the donor and no-donor groups were 70% (95%–CI 59%–81%) versus 60% (95%–CI 54%–67%) after 3 years, and 70% (95%–CI 59%–81%) versus 53% (95%–CI 45%–61%) after 5 years (p=0.138). In multivariate analyses, the presence of a donor as a prerequisite for allo SCT retained its statistically significant favorable influence on RFS (HR=0.56) even after adjustment for established risk factors such as FLT3-ITD, cytogenetic risk, WBC, LDH, age, and disease status. In patients with normal karyotype and NPM1+/FLT3-ITD- (n=152), the 3-year RFS in the donor and no-donor groups was 87% (95%–CI 77%–97%) and 53% (95%–CI 42%–63%), respectively (p=0.001). Conclusions:According to our results, allo SCT leads to a significantly prolonged RFS in NPM1+ AML patients with a pronounced effect even in NPM1+/FLT3-ITD- patients. The absence of a statistically significant difference in OS is most likely due to the fact that relapsed NPM1+ patients responded well to salvage treatment, particularly to allo SCT from an unrelated donor. Our data suggest that patients with NPM1+ AML who have a well-matched donor benefit from allo SCT in first remission. This hypothesis is currently being tested prospectively in a randomized controlled trial (“ETAL-1”, NCT01246752) evaluating allo SCT in all intermediate-risk AML patients with a well-matched sibling or unrelated donor identified until the achievement of first CR. Disclosures:No relevant conflicts of interest to declare.

A Strong Immune Effect by Allogeneic Stem Cell Transplantation May Improve Survival in AML Patients with a High Ratio of the FLT3-ITD Mutation to the Wt-FLT3 Allele: Results from an Analysis of 257 Patients Treated in the SAL AML-2003 Trial

Abstract 497 Background:The ratio of the FLT3-ITD mutation to the wt-FLT3 allele has significant prognostic importance in FLT3-ITD mutated acute myeloid leukemia (AML). Patients with a high mutant/wt ratio above 0.78 have significantly shorter overall (OS) and disease-free survival (DFS), whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations (Thiede C et al, Blood 2002).There is still uncertainty about the role of allogeneic transplantation (allo-SCT) in the treatment of patients with FLT-ITD mutations (FLT3-ITD+). In order to prove the presence of an allogeneic effect, we compared the survival after allo-SCT in first remission in patients with a mutant rate < 0.8 with those ≥ 0.8. For comparison, the results in patient cohorts treated with chemotherapy alone were analyzed. Patients and Methods:Patients diagnosed with AML, aged 18–60 years, and treated in the AML-2003 trial of the SAL Study Alliance Leukemia were analyzed. According to the risk-adapted treatment strategy of the trial, cytogenetically intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-matched-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. Patients with no available donor received high-dose cytarabine-based consolidation or autologous SCT. Survival analyses were performed using the Kaplan-Meier method including log-rank tests for significance testing. Results:Of 1182 patients enrolled in the AML-2003 trial between December 2003 and November 2009, 257 were FLT3-ITD+ (22%). The ratio of the FLT3-ITD mutation to the wt-FLT3 allele was < 0.8 in 182 patients (low-ratio) and ≥ 0.8 in 75 patients (high-ratio). 47 (26%) of the low-ratio group and 30 (40%) of the high-ratio group received an allogeneic transplantation.In the cohorts having received an allogeneic transplantation, the 3-year DFS in the low- and high-ratio groups was 58% and 50%, respectively (p=0.53). The 3-year OS was 61% and 59%, respectively (p=0.47).In the cohorts having chemotherapy as consolidation, the 3-year DFS in the low- and high-ratio groups was 36% and 10%, respectively (p<0.001). The 3-year OS was 43% and 11%, respectively (p<0.001). Conclusions:According to our results, allo-SCT in patients with a high allelic ratio of FLT3-ITD mutation led to an overall and event-free survival comparable with those with a low allelic ratio. In patients who received chemotherapy as consolidation and no allogeneic transplantation significant differences in DFS and OS could be shown between patients with a high vs. low ratio confirming our results obeserved in the previous AML96 study. These data point towards a strong graft versus leukemia effect after transplantation thus abrogating the negative impact of a high allelic ratio seen after conventional therapeutic appoaches. Disclosures:No relevant conflicts of interest to declare.

Isolated Mediastinal Myeloid Sarcoma Successfully Treated with Chemoradiotherapy Followed by Unrelated Allogeneic Stem Cell Transplantation

A 22-year-old man was diagnosed with isolated mediastinal myeloid sarcoma which radiologically mimicked primary mediastinal lymphoma. Despite administration of standard remission induction chemotherapy with daunorubicin and cytarabine, and three cycles of intensive high-dose cytarabine-based consolidation, chemo-resistant hypermetabolic lesions were persistently detected in the highest mediastinum and in the supraclavicular area. However, complete remission and long-term survival were achieved by curative radiotherapy followed by unrelated allogeneic stem cell transplantation.

Identification of Clinically Relevant Predictive MRD Checkpoints in AML Patients with NPM1 Mutations: A Study of the AML Study Group (AMLSG).

Abstract 1586▪▪This icon denotes an abstract that is clinically relevant.Poster Board I-612 BackgroundMutations in the nucleophosmin 1 (NPM1) gene represent the most frequent gene mutations in acute myeloid leukemia (AML), with highest frequency (50-60%) in cytogenetically normal (CN)-AML. Several studies have shown the applicability and prognostic value of an NPM1 mutation (NPM1mut)-based assay for detection of minimal residual disease (MRD). So far, there are no studies evaluating the prognostic value of NPM1mut MRD levels in a large controlled cohort of AML patients (pts) enrolled on prospective clinical trials. AimsTo evaluate the prognostic value of NPM1mut MRD levels in younger (16 to 60 years) AML pts harbouring NPM1 mutations type A, B or D, and to assess the influence of concurrent FLT3 internal tandem duplications (ITD). MethodsAll pts were enrolled in the prospective AMLSG 07-04 and AML HD98A treatment trials. Treatment comprised double induction therapy with ICE (idarubicin, cytarabine, etoposide) followed by high-dose cytarabine-based consolidation, autologous or allogeneic stem cell transplantation. Levels of NPM1mut expression ratios, defined as NPM1mut copies per 104ABL copies, were determined by RQ-PCR using TaqMan technology. Dilution series showed a maximum sensitivity of 10-6 and high specificity as no wildtype NPM1 could be detected. ResultsA total of 1079 samples, [bone marrow (BM), n=1062; peripheral blood, n= 17) from 212 pts were analyzed at diagnosis, after each treatment cycle, during follow-up and at relapse (median number of samples per pt, n=4; range, 1-16). NPM1mut expression ratios at diagnosis varied between 1.1×104 and 10.4×106 (median, 6.9×105). Pretreatment transcript levels were not associated with clinical characteristics (e.g., age, white cell counts, BM blasts) and did not impact on relapse-free (RFS) and overall survival (OS). Following the first induction cycle, the median decrease of the MRD level ratio normalized to pretreatment levels was 4.21×10-3, independent of the presence of concurrent FLT3-ITD (p=0.39). After the 2nd induction cycle, the median reduction of MRD levels was significantly stronger in the FLT3-ITDneg group (6.75×10-5) compared with the FLT3-ITDpos group (4.19×10-4) (p=0.003) and this differential effect was observed throughout consolidation therapy.For evaluation of the prognostic impact of NPM1mut MRD levels, we compared patients achieving PCR-negativity with those with positive values at different checkpoints. The first reliable checkpoint was after double-induction therapy: the cumulative incidence of relapse (CIR) at 4 years of PCR-negative patients (n=27) was 0% compared with 48% (SE, 4.4%, p<0.00001) for PCR-positive patients (n=105). This translated into a significant better OS (p=0.0005). The second checkpoint was after completion of consolidation therapy (first measurement during follow-up period). Again, 4-year CIR was significantly (p<.00001) lower in the PCR-negative group with 11% (SE, 6.5%) compared with 51% (SE, 4.8%) in PCR-positive patients, again translating in a significantly better OS (p<.00001). In addition, the level of NPM1mut expression ratio at any time point examined after completion of therapy correlated with the risk of relapse, since 20 of 22 pts with a value above 1000 NPM1mut/104ABL copies relapsed after a median interval of 90 days (range, 11-709 days). The remaining 2 pts had increasing levels at last follow-up but are still in continuous complete remission (CR). In a few cases relapse prediction appeared to be limited due to inadequate increase of NPM1mut expression levels or to loss of NPM1 mutation at the time of relapse (n=5). On the other hand, we observed a number of pts (n=17) in continuous CR who had intermittent low (<1000 NPM1mut/104ABL copies) NPM1mut expression ratios. ConclusionsThe levels of NPM1mut expression at two distinct checkpoints, after double induction therapy and after completion of consolidation therapy, can be used as a prognostic factor in NPM1mut AML pts. The adverse outcome of pts carrying a concurrent FLT3-ITD is reflected by a significant lower reduction of tumor burden. DisclosuresGöhring:Celgene Corp.:. Schlegelberger:Celgene Corp.:.

Prognostic Value of Molecular Markers for Guiding Post-Remission Therapy in Patients with De Novo Acute Myeloid Leukemia (AML) and Intermediate-Risk Cytogenetics

The heterogeneous prognosis of patients with intermediate-risk cytogenetics AML (AML-IR) can be partially clarified by screening of NPM1 mutations (NPMmut) and internal tandem duplication of FLT3 (FLT3-ITD). Nonetheless, additional factors might influence the prognostic effect of these molecular lesions, such as the FLT3-ITD mutant level. Moreover, the optimal post-remission strategy might differ depending on the underlying molecular lesion. In this regard, we analyzed the outcome, according to NPM1 and FLT3 mutations and post-remission therapy given, of a series of patients diagnosed with de novo AML-IR in a single institution who received intensive chemotherapy. Patients were treated following 4 sequential protocols of CETLAM group during the period 1994–2006, consisting of 1 or 2 cycles of standard induction chemotherapy and 1 course of high-dose cytarabine-based consolidation therapy. Thereafter, patients underwent hematopoietic stem cell transplantation (HSCT) according to donor availability and presumed risk (protocols LAM 99 & 2003). NPM1 mutations and FLT3-ITD were screened in diagnostic DNA by PCR amplification followed by Genescan analysis. The ratio between FLT3-ITD and wildtype FLT3 alleles (ITD/wt ratio) was calculated using the area under the peak of corresponding alleles. Overall, 134 patients (51% male; median age, 53; range: 17–70) with AML-IR (normal karyotype, 66%) were studied. NPM1mut and FLT3-ITD were found in 45% and 37% of patients, respectively, with a median ITD/wt ratio of 0.59 (0.045–5.5). After induction regimen, 109 patients (81%) achieved complete response (CR). The only variables predictive of a favorable response were NPMmut (90% vs. 75%; p=0.01) and age <60 (85% vs. 72.5%; p=0.05). After a median follow-up of 69 months, relapse risk (RR) at 5 years was 54% (±5%). RR was higher in patients presenting with hyperleukocytosis (>50 × 109/L), NPMwt, and FLT3-ITD. Interestingly, the prognostic value of FLT3-ITD depended on the relative mutant level, and detection of FLT3-ITD with a low ITD/wt ratio (i.e.,<0.3) did not increase the risk conferred by underlying NPM1 mutational status. In accordance, a composite variable based on NPMmut and quantitative FLT3-ITD was created defining 2 prognostic categories: a low-risk group (LOWmol), constituted by patients with NPMmut and either absence of FLT3-ITD or low ITD/wt ratio, and a high-risk subset (HIGHmol), defined by the absence of NPMmut and/or high ITD/wt ratio. This molecular stratification showed independent prognostic value for RR (5-year RR: 24%±10% vs. 81%±7 in LOWmol vs. HIGHmol patients, respectively; p<0.001), and survival (OS; relative risk: 2.8, 95% CI:1.6-5, p<0.001; figureMoreover, the effect of post-remission therapy varied in both molecular-defined subgroups. Thus, among patients with an age ≤60, 5-year survival in LOWmol patients with a planned autologous HSCT (autoHSCT) was 83%±9%, not differing significantly from that of patients undergoing allogeneic HSCT (intention-to-treat analysis; figureOn the other hand, 5-year OS of HIGHmol patients who underwent allogeneic HSCT in first CR was 73%±13, which compared favorably with other post-remission strategies (5-yr OS: 27%±7%; p=0.019).In conclusion, in patients with intermediate-risk AML, the combined assessment of NPM1 mutations and quantitative estimation of FLT3-ITD allows the distinction of 2 categories of patients with different prognosis. Thus, whereas autoHSCT arises as an effective postremission therapy in patients harboring low-risk molecular features, allogeneic HSCT in first CR seems to overcome adverse prognosis of patients with high-risk disease.Nonetheless, the validity of this molecularly-based therapeutic algorithm warrants confirmation in other studies. [Display omitted]

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission.

In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.

Transplantation of Autologous Peripheral Blood Progenitor Cells Procured after High-Dose Cytarabine-Based Consolidation Chemotherapy for Adults with Secondary Acute Myelogenous Leukemia in first Remission

Patients with acute myelogenous leukemia secondary to an antecedent hematologic disturbance or cytotoxic chemotherapy are considered to have a very low likelihood of leukemia-free survival regardless of the form of post-remission therapy. The purpose of this study is to evaluate, on the basis of intention to treat, the feasibility and efficacy of high-dose cyt-arabine/anthracycline consolidation chemotherapy followed by autologous transplantation of chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for seventeen adult patients (median age 63, range 27 to 68) with secondary acute myelogenous leukemia in first remission. Ten eligible patients underwent autologous transplantation of peripheral blood progenitor cells procured following high-dose cytarabine/mitoxantrone consolidation chemotherapy used as a method of in vivo purging. A median of 5 collections (range 2 to 13) were reuired to procure a median of 9.27 × 108 total mononuclear cells/kg (range 2.35 to 21.44 × 108 per kg). The median number of CD34-positive progenitor cells was 1.18 × 106 kg (range 0.34 to 30.9 × 106 kg). After preparative conditioning with 11.25 Gy total body radiation and cyclophosphamide (120 mg/kg) and autologous transplantation, the median time to neutrophil and platelet recovery were 18 days (range 12 to 29 days) and 25 days (range 8 to 158+ days), respectively. After a median follow-up for surviving patients of 33.4 months (range 7.5 to 54 months), 9 of 17 patients (53%) remain alive with 7 in continued first remission. The median remission duration is 13 months (3 to 53 months) and actuarial leukemia-free survival at 3 years is 51+25%. Toxicity of autologous peripheral blood progenitor cell transplant included serious liver and pulmonary toxicity in 2 and 1 patient, respectively. Our results demonstrate that a postremission program of high-dose cytarabine-based consolidation chemotherapy followed by autologous transplantation of chemotherapy-mobilized peripheral blood progenitor cells is feasible for patients with secondary acute myelogenous leukemia producing prolonged leukemia-free survival with minimal toxicity.

Long-Term Outcome of High-Dose Cytarabine-Based Consolidation Chemotherapy for Older Patients with Acute Myelogenous Leukemia

Despite reports of improved response and leukemia-free survival for adults with acute myelogenous leukemia, advanced age remains a significant adverse prognostic factor for both response to induction therapy and prolonged leukemia-free survival. In addition to a high incidence of treatment-related complications, older patients may have other disease characteristics which predict for brief remission duration despite intensive consolidation chemotherapy. We analyzed the long-term results of high-dose cytarabine-anthracycline consolidation chemotherapy in older patients and examined the effect of major prognostic factors including a history of myelodysplasia, increased age, and cytogenetics. One hundred and ten patients age ± 60 with newly diagnosed acute myelogenous leukemia were enrolled on three sequential studies conducted from 1982 to 1996. Fifty-six patients (51%) achieved a complete remission and were eligible for high-dose cytarabine-based consolidation chemotherapy administered in two to three courses.After a median follow-up of surviving patients for seventeen months, twelve patients remain alive with eleven in continued remission. Median remission duration for all eligible patients is nine months and the actuarial leukemia-free survival is 14 ± 10%. Toxicity of consolidation therapy included treatment-related death in six patients and serious neurotoxicity in five. When compared to younger patients, patients over age 60 sustained a much higher risk of relapse despite successfully completing intensive consolidation therapy, regardless of whether other adverse prognostic features were present.Advanced age in acute myelogenous leukemia is associated with a significantly higher risk of relapse unmodified by the presence or absence of other adverse disease characteristics. Although older patients tolerated intensive therapy designed to address the high risk of relapse, there was no apparent benefit of high-dose cytarabine consolidation alone as post-remission treatment for acute myelogenous leukemia in this population.

Long-Term Outcome of High-Dose Cytarabine-Based Consolidation Chemotherapy for Adults With Acute Myelogenous Leukemia

Modern induction chemotherapy produces 60% to 80% complete remissions in adults with newly diagnosed acute myelogenous leukemia. A major challenge is to eradicate subclinical disease in remission and prevent leukemic relapse. We analyzed the long-term results of high-dose cytarabine-anthracycline consolidation chemotherapy without maintenance treatment and examined the effect of major prognostic factors, including age, sex, history of preleukemia, and cytogenetics. Two hundred twenty-seven patients with newly diagnosed acute leukemia were enrolled on two sequential studies conducted from 1982 to 1991. One hundred fifty-one patients (67%) achieved a complete remission. One hundred twenty-three patients were eligible for high-dose cytarabine-based consolidation administered in two to three courses. After a median follow-up of 4.8 years, 40 patients remain alive, with 28 in continued remission. Median remission duration for all eligible patients is 12.8 months, and actuarial leukemia-free survival (LFS) at 5 years is 26% +/- 8%. Advanced age and male sex were negative prognostic indicators for LFS. For patients < or = 45 years of age, 5-year LFS was 35% +/- 13%, as compared with 18% +/- 11% for patients greater than age 45 (P = .03). Toxicity of consolidation chemotherapy included treatment-related death in nine patients and serious neurotoxicity in five. Our results show an improved LFS for younger patients treated with high-dose cytarabine-based consolidation. There was no apparent benefit for older patients compared with reported data with less intensive regimens.

Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia

Modern induction chemotherapy produces 60% to 80% complete remissions in adults with newly diagnosed acute myelogenous leukemia. A major challenge is to eradicate subclinical disease in remission and prevent leukemic relapse. We analyzed the long-term results of high-dose cytarabine-anthracycline consolidation chemotherapy without maintenance treatment and examined the effect of major prognostic factors, including age, sex, history of preleukemia, and cytogenetics. Two hundred twenty-seven patients with newly diagnosed acute leukemia were enrolled on two sequential studies conducted from 1982 to 1991. One hundred fifty-one patients (67%) achieved a complete remission. One hundred twenty-three patients were eligible for high-dose cytarabine- based consolidation administered in two to three courses. After a median follow-up of 4.8 years, 40 patients remain alive, with 28 in continued remission. Median remission duration for all eligible patients is 12.8 months, and actuarial leukemia-free survival (LFS) at 5 years is 26% +/- 8%. Advanced age and male sex were negative prognostic indicators for LFS. For patients &lt; or = 45 years of age, 5- year LFS was 35% +/- 13%, as compared with 18% +/- 11% for patients greater than age 45 (P = .03). Toxicity of consolidation chemotherapy included treatment-related death in nine patients and serious neurotoxicity in five. Our results show an improved LFS for younger patients treated with high-dose cytarabine-based consolidation. There was no apparent benefit for older patients compared with reported data with less intensive regimens.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.