Allogeneic Stem Cell Transplantation In First Complete Remission Research Articles

Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study

▪Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study.Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT.Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (> 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (< 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53).Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. [Display omitted] DisclosuresHuguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.

Early Detection of WT1 minimal Residual Disease Predicts Outcome in Acute Myeloid Leukemia and Identify Patients with High Risk of Relapse Independently of Allogeneic Stem Cell Transplantation

Background:WT1 overexpression is frequently identified in acute myeloid leukemia (AML) andhas been reported as a potential marker for minimal residual disease (MRD) monitoring. However, the role of WT1 MRD response as prognostic and/or treatment stratifying factor is still under debate.Aims: In this work, we evaluated the prognostic value of post-induction WT1 MRD level, as well as the interaction between post-induction WT1 MRD response and the effect of allogeneic stem cell transplantation (SCT) in first complete remission (CR), in a cohort of AML patients aged 18 to 59 years old treated in the Acute Leukemia French Association (ALFA)-0702 trial.Methods: Among the 713 patients enrolled in ALFA-0702 study (X. Thomas et al, JCO 2017), 539 had an overexpression of WT1 at diagnosis (75.6%) defined as a ratio WT1 transcript/100 ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples (WT1+). After induction, MRD levels were assessed using cDNA-based real-time quantitative PCR. Occurrence of a WT1 MRD ratio >2.5% in BM or >0.5% in PB was defined here as positive MRD (MRDpos), while ratio under these threshold was defined as negative MRD (MRDneg). The prognostic value of MRD was assessed by comparing cumulative incidence of relapse (CIR) with death in remission as competing event, relapse-free survival (RFS) and overall survival (OS) among patients who achieved first CR. As patients with favorable-risk AML according to European LeukemiaNet (ELN)-2010 classification were not eligible for SCT in first CR, interaction between MRD response and SCT effect was evaluated in patients with intermediate/unfavorable-risk AML by comparing the influence of SCT, considered as a time-dependent covariate, on the outcomes of MRDneg and MRDpos patients.Results: Among the 539 WT1+ patients at diagnosis, 473 achieved CR (87.7%). Post-induction WT1 MRD evaluation was available in 339/473 patients (71.7%), 279 patients were MRDneg and 60 were MRDpos. At this early time point, MRD was predictive of relapse: 4-year CIR was 36.5% in MRDneg patients versus 69.2% in MRDpos patients (Cause-Specific Hazard Ratio, 2.88 [1.93-4.29]; p<0.001). When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRD remained independently associated with relapse incidence (CSHR, 2.15 [1.41-3.29]; p<0.001). This translated into longer survival in MRDneg patients. At 4 years, RFS was 60.9% versus 24.9% (HR, 2.69 [1.89-3.83]; p<0.001) and OS was 71.6% versus 43.3% (HR, 2.34 [1.56-3.51]; p<0.001) in MRDneg and MRDpos patients, respectively. When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRDneg remained independently associated with longer RFS (HR, 2.12 [1.47-3.07]; p=0.001) and OS (HR, 1.79 [1.18-2.73]; p<0.001).We then analyzed the role of SCT in 254 patients with intermediate/unfavorable-risk AML and available post-induction WT1 MRD evaluation (199 MRDneg, 55 MRDpos). SCT was performed in 155 patients. Overall, both MRD and SCT were independent prognostic factors. Post-induction MRD response remained of strong prognostic value, since MRDpos patients had a higher CIR (CSHR, 2.33 [1.54-3.53]; p<0.001) and a shorter RFS (HR, 2.25 [1.55-3.26]; p<0.001). In this population, SCT was beneficial and significantly improved CIR (CSHR, 0.33 [0.22-0.51]; p<0.001) and RFS (HR, 0.53 [0.37-0.76]; p=0.001). Despite a higher effect of SCT in MRDneg patients (Figure 1), the interaction between MRD status and SCT effect was not statistically significant (p= 0.3).Conclusions: Our study confirms the prognostic value of post-induction WT1 MRD in younger adults with AML treated in the prospective ALFA-0702 study. The observation that early WT1 MRD response retains its prognostic value among patients independently of allogeneic SCT in first CR might help selecting these patients more accurately in the next future. [Display omitted] DisclosuresRenneville:CELGENE: Research Funding. Recher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Rousselot:BMS: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study

▪Purpose: The use of rituximab, a chimeric monoclonal antibody to CD20, has led to significant improvement in the treatment of B-cell non-Hodgkin's lymphoma and mature B-cell ALL. CD20 is expressed in 30 to 50% of adult BCP-ALL patients. Although some single arm studies suggested that adding rituximab to chemotherapy could improve the outcome of these patients, no randomized study has been reported so far.Methods: To evaluate the potential benefit of adding rituximab, we conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab, in patients aged 18-59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts. Rituximab (375 mg/m2) was given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7) and first year of maintenance (6 infusions) for a total of 16 to 18 infusions. Allogeneic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The primary study objective was event-free survival (EFS). A study sample size of 220 patients was estimated in order to detect a 20% gain in EFS at 2 years (two-sided test, power 85%, type 1 error 5%). A sensitivity analysis was performed after censoring patients allografted in first CR at transplant time. This trial was registered at http://www.clinicaltrials.gov as #NCT00327678.Results: From 2005 to 2014, 220 patients from 56 centers were randomized. Eleven patients had non-eligibility criteria (n=5 Ph+ ALL; n=3 CD20-negative ALL; n=1 HIV infection) or withdrew their consent (n=2) and were accordingly excluded from this modified ITT analysis that dealt with 209 patients (105 in the rituximab arm and 104 in the control arm). Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics including age, ECOG status, WBC, and central nervous system (CNS) involvement (6% of the whole cohort). After induction ± salvage reinduction, CR rate was 92% and 91% in rituximab and control arm, respectively. In patients who reached CR after first induction and were evaluated for Ig/TCR minimal residual disease level (MRD), the rates of patients with MRD<10-4 in the rituximab vs control arm were 65% vs 61% (p=0.82) and 91% vs 82% (p=0.31), after induction and first 3 consolidation blocks respectively. A higher proportion of patients received allogeneic SCT in first CR in the rituximab arm (34% vs 20% in the control arm; p=0.029). With a median follow-up of 30 months, patients treated in the rituximab arm had a lower cumulative incidence of relapse (CIR) (2-year CIR, 18% [95% CI, 10-26] vs 30.5% [95% CI, 21-40] in control arm; p=0.02), while no significant difference was observed regarding non-relapse mortality (NRM) between both arms (2-year NRM, 12% [95%CI, 5-18] vs 12% [95%CI, 5-18] in control arm; p=0.80). This translated into longer EFS in patients treated in the rituximab arm (2-year EFS, 65% [95% CI, 56-75] vs 52% [95% CI, 43-63] in control arm; HR= 0.66 [0.45-0.98]; p=0.038; Figure 1) but no longer overall survival (OS) (2-year OS, 71% [95% CI, 62-80] vs 64% [95%CI, 55-74] in control arm; HR= 0.70 [0.46-1.07]; p=0.095). Other factors impacting EFS were age, CNS involvement and WBC at diagnosis. Together with the randomization arm, all these factors remained significantly associated with EFS in multivariate analysis, even when adjusting on allogeneic SCT in first CR as a time-dependent covariate. When censoring patients who received allogeneic SCT in first CR at transplant time, EFS and OS were longer in the rituximab arm (2-year EFS, 66% [95% CI, 56-78] vs 53% [95% CI, 44-65] and 2-year OS, 74% [95% CI, 65-85] vs 63% [95%CI, 54-74]; HR= 0.59 [0.37-0.93] and 0.55 [0.34-0.91] and p=0.021 and 0.018, respectively). Finally, 71 and 55 infection-related SAEs were reported in non-transplanted patients in the rituximab and control arm, respectively, without significantly higher incidence in the rituximab arm, at any treatment phase.Conclusions: In adults with CD20-positive, Ph-negative, BCP-ALL, the addition of rituximab to the pediatric-inspired GRAALL protocol improves EFS; it also prolongs OS when ignoring patient's outcome after transplantation in first CR. [Display omitted] DisclosuresOff Label Use: Rituximab is not currently approved for this indication.. Chalandon:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Minimal Residual Disease At 3 Months, Combined to the Presence of IKZF1 Deletion in B-Lineage or Absence of NOTCH1 pathway Mutation in T-Lineage, Recapitulates the Disease Risk Assessment in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia - A GRAALL Study

Abstract 572 Aim.In recent series of adults with acute lymphoblastic leukemia (ALL), the GRAALL (ASH 2009, abstract 577) and other cooperative groups have confirmed the strong prognostic value of Ig/TCR minimal residual disease (MRD) on patient outcome. Despite this, age, WBC, CNS involvement, recurrent chromosomal translocations, and early response to steroids and chemotherapy remain frequently used to tailor post-remission therapy and envision allogeneic stem cell transplantation (SCT) in most adult ALL trials. We updated our MRD study, now with 262 patients who all achieved complete remission (CR) after the first induction and were assessed for MRD after induction (MRD1, at 6 weeks) and consolidation (MRD2, at 12 weeks). One hundred and fifty-eight patients had Philadelphia chromosome (Ph)-negative B-cell precursor ALL (BCP-ALL), while 104 had T-cell ALL (T-ALL). Since 107 of the BCP-ALL (68%) were studied for IKZF1 deletion and 90 of the T-ALL patients (87%) for NOTCH1/FBXW7 mutations, we were able to reassess the MRD significance according to these newly described oncogenic markers. These two covariates (i.e. MRD and IKZF1/NOTCH1/FBXW7 genetics) allowed us to redefine a much simpler yet more powerful stratification of disease risk in both BCP- ALL and T-ALL subsets. Methods.All 262 patients studied (median age, 31.5 years) were treated in the GRAALL-2003 and GRAALL-2005 trials. Although they were younger and had more frequently circulating blasts, other characteristics and outcome did not differ from patients treated in the same trials but not assessed for MRD. Ig/TCR MRD levels were determined according to Euro-MRD guidelines (Leukemia 2007;21:604). IKZF1 deletions were assessed by multiplex multi-fluorescent PCR. NOTCH1/FBXW7 mutations were assessed as previously described (Blood 2009;113:3918). Multivariate backward stepwise selection Cox models were used for the cumulative incidence of relapse (CIR), disease-free (DFS) and overall survival (OS) endpoints, after censoring transplanted patients at SCT. Models were always adjusted on age (35-year cutoff), WBC (30 and 100 G/L cutoff for BCP- and T-ALL, respectively), CNS involvement, and trial. Additional BCP-specific covariates included CD20 expression, t(4;11) and t(1;19) translocations, and IKZF1 deletion. Additional T-specific covariates included cortical immunophenotype according to the EGIL classification, TLX1 overexpression, and NOTCH1/FBXW7 mutation. Finally, allogeneic SCT was re-evaluated in the newly defined risk subsets, as a time-dependent covariate. Results.An initial multivariate analysis revealed that among blood response after 1 week of steroid, bone marrow response after 2 weeks of therapy, and molecular response at both MRD1 and MRD2 time-points, the MRD2 level was the main and sole independent predictor of relapse (P=0.003). In BCP-ALL patients, persistent MRD2 and IKZF1 deletion were the only two independent factors identified, the presence of at least one factor defining 51% high-risk patients with 52% versus 15% CIR (HR, 3.8; P= 0.008), 41% versus 81% DFS (HR, 3.6; P= 0.005), and 54% versus 80% OS (HR, 3.9; P= 0.015) at 4 years. Allogeneic SCT in first CR significantly decreased relapse incidence and prolonged DFS in these new high-risk BCP-ALL patients (HR, 0.23 and 0.40; P= 0.016 and 0.05, respectively). In T-ALL patients, persistent MRD2 and lack of NOTCH1/FBXW7 mutation were the only two independent factors identified, the presence of at least one factor defining 49% high-risk patients with 64% versus 12% CIR (HR, 6.4; P= 0.002), 36% versus 88% DFS (HR, 6.4; P= 0.002), and 41% versus 95% OS (HR, 7.3; P= 0.015) at 4 years. SCT had no significant effect on relapse incidence and DFS in these new high-risk T-ALL patients. Conclusion.In adult patients with Ph-negative ALL treated with the pediatric-inspired GRAALL regimen, IKZF1 deletion in BCP-ALL, NOTCH1/FBXW7 mutation in T-ALL, and MRD at 3 months in both subsets replace all classical risk factors, leading to a new simplified prognostic scoring system based only on IKZF1 and NOTCH1/FBXW7 genetics and MRD clearance. This new risk score identifies approximately half of the patients as good-risk, with a relapse incidence as low as 10–15%. It will be validated and used prospectively in the next generation of GRAALL trials, to stratify both new drug evaluation and SCT in first CR. Disclosures:No relevant conflicts of interest to declare.

Long-Term Results of the Imatinib GRAAPH-2003 Study in Newly-Diagnosed Patients with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia..

Abstract 3080Poster Board III-17 IntroductionThe combination of imatinib with high-dose chemotherapy has been shown as very promising in patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by several groups. Reported studies all demonstrated a higher response rate and an improved outcome as compared to the pre-imatinib era, but generally with a short follow-up. This was also observed in our GRAAPH-2003 study with complete remission (CR) rate, 18-month disease-free survival (DFS), and 18-month overall survival (OS) of 96%, 51%, and 65%, respectively (de Labarthe et al. Blood 2007). We report here the long-term results of this study with a longer median follow-up of 46 months. Patients & MethodsFrom 2004 to 2005, 45 patients with newly-diagnosed Ph+ ALL (median age, 45 years; range, 16-59 years; 25 males and 20 female) were included in the GRAAPH-2003 study. Briefly, imatinib was started with HAM consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders. Imatinib was administered until allogeneic (if a matched familial donor or an unrelated donor matched at 9 or 10 of 10 HLA antigens) or autologous (if no donor and a good molecular response) stem cell transplantation (SCT). Results were compared with the results of the previous pre-imatinib LALA-94 trial (Dombret et al. Blood 2002). ResultsWhen compared to the former LALA-94 study, 4-year OS and DFS were estimated at 52% (36-66) versus 20% (14-26) (p=0.0001) and 43% (27-58) versus 20% (14-28) (p=0.002) in the GRAAPH versus LALA cohorts, respectively. In the GRAAPH-2003, all the 22 CR patients with a donor may receive allogeneic SCT in first CR. In addition, 10 CR patients without a donor but low post-HAM BCR-ABL level received autologous SCT. No significant differences were observed between the donor and the no-donor groups in terms of OS (55% versus 54% at 4 years; p=0.80) and DFS (47% versus 39% at 4 years; p=0.40). This result was partly explained by the good outcome observed in patients who received autologous SCT. The 4-year OS in the allogeneic SCT, autologous SCT, and no SCT groups were 55%, 80%, and 25%, respectively (auto versus allo, p=0.16; auto versus no SCT, p=0.008; allo versus no SCT, p=0.05). The 4-year DFS in the allogeneic SCT, autologous SCT, and no SCT groups were 47%, 50%, and 25%, respectively (auto versus allo, p=0.91; auto versus no SCT, p=0.27; allo versus no SCT, p=0.17). Overall, 4-year cumulative incidences of relapse and death in CR were estimated at 24% (14-40) and 32% (20-49), respectively, underlying the toxicity of the whole GRAAPH-2003 strategy. Notably, 7 of the 22 allografted patients died in CR, as compared to only 1 of the 10 autografted patients. ConclusionWe show here that the beneficial impact of the combination of imatinib with chemotherapy is not transient and is preserved in the long term. Taking into account the good outcome of patients receiving autologous SCT and the toxicity of allogeneic SCT, the place and timing of SCT, as well as the optimal chemotherapy to be delivered with imatinib prior to SCT, must be carefully re-evaluated in further prospective trials. DisclosuresDombret:cejgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Post-Induction Minimal Residual Disease (MRD) Defines a Large Subset of Adults with Favorable Ph-Negative Acute Lymphoblastic Leukemia (ALL), Who Do Not Benefit From Allogeneic Stem Cell Transplantation (SCT) in First Complete Remission: A GRAALL Study.

Abstract 577▪▪This icon denotes an abstract that is clinically relevant. Introduction:Allogeneic SCT is currently the preferred therapeutic option for most younger adults with ALL in first complete remission (CR), as recently confirmed by the large ECOG-UKALL Intergroup study (Goldstone, Blood 2008). In this study, however, early response to therapy was not taken into account. As Ig/TCR MRD is one of the main determinants for outcome in childhood ALL, we analyzed its impact on outcome and SCT results in adults treated within pediatric-inspired GRAALL trials. For that purpose, we focused on early MRD evaluations (MRD1: at CR achievement; MDR2: after the first consolidation). Patients & Methods:Among 507 patients aged 15-60 years with Ph-negative ALL in first CR after induction included in the GRAALL-2003 (Huguet, JCO 2009) or in the ongoing GRAALL-2005 trial until the first planned interim analysis, 212 patients (B/T lineage, 137/75; median age, 31 years) had an Ig/TCR MDR1 evaluation (with MRD2 evaluation for 77% of them) by CDR3 RQ-PCR or fluorescent competitive Genescan associated with a sensitivity allowing the classification into the following levels: negative (0); positive <10-4 (1); positive 10-4 to 10-3 (2); positive 10-3 to 10-2 (3); positive ≥10-2 (4) (Table 1). Allogeneic SCT was indicated in patients aged 55y or less with a donor (sibling or 10/10 HLA-matched unrelated) and high-risk ALL, as defined on baseline (WBC in B-lineage ALL, CNS involvement, cytogenetics) and response-related risk criteria (steroid- and chemo-sensitivity). Patient characteristics and outcome were identical according to trial, as well as in MRD-tested and non-tested patients. [Display omitted] Results:Cumulative incidence of relapse (CIR) was strongly predicted by 5-level MRD1 (P<0.0001). As CIR were similar in both levels 0-1 and in both levels 3-4, patients were eventually classified as MRD1-fav (level 0-1, N = 124 (59%); 3y-CIR, 13%), MRD1-int (level 2, N = 32 (15%); 3y-CIR, 38%), and MRD1-unfav (level 3-4, N = 56 (26%); 3y-CIR, 56%). Thirty-four of 62 patients at risk reached level 0 or 1 at MRD2 only, 22 of them from the MRD1-int subgroup. However, CIR was not different in these ‘slow responders‘ than in MRD2-int/unfav patients (P=0.27), suggesting that MRD1 alone may be used to stratify further therapy. Median age and baseline characteristics did not differ between MRD1-fav and MRD1-int/unfav patients, while MRD1-fav was associated with higher rates of steroid- and chemo-sensitivity (P=0.05 and P<0.001, respectively). In MDR1-fav patients, 3y-DFS and 3y-OS were 80% (95% CI, 70-87) and 82% (95% CI, 71-90), respectively. After SCT censoring, their 3y-CIR, 3y-DFS, and 3y-OS were 12% (95% CI, 6-24), 84% (95% CI, 72-91), and 86% (95% CI, 72-93), respectively. In multivariate analysis adjusted on protocol, MRD1-fav was the best predictor of lower CIR (RR = 0.22; P<0.001), prolonged DFS (RR = 0.25; P<0.001), and longer OS (RR = 0.20; P<0.001). Low WBC (for CIR, DFS, and OS) and steroid-sensitivity (for CIR only) remained independent risk factors. Similar results were observed in patients with B-lineage ALL, while the number of T-ALL patients was too small to allow a separate analysis. In 127/132 evaluable patients with high-risk ALL eligible for SCT, 3y-CIR was 4% in MRD1-fav and no-donor (N=27), 14% in MRD1-fav and donor (N=33; 30 actually grafted in CR1), 42% in MRD1-int/unfav and donor (N=41; 38 actually grafted in CR1), and 66% in MRD1-int/unfav and no-donor patients (N=26). The difference between donor and no-donor groups tended to be significant in MRD1-int/unfav patients (P=0.14), while not in MRD1-fav patients (P=0.60). Conclusion:Younger adults with ALL may be classified in a favorable subset with a low relapse rate, only based on post-induction MRD level. At least when treated with a pediatric-inspired protocol, this subset represents more than half patients with Ph-negative ALL. In GRAALL studies, those favorable patients, even when presenting initial bad-risk factors, do not seem to draw any benefit from allogeneic SCT in first CR. Disclosures:No relevant conflicts of interest to declare.

Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome–positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study

AbstractThe combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

Gene Mutations as Predicitive Markers for Postremission Therapy in Younger Adults with Normal Karyotype AML.

Background: Mutations in the genes encoding NPM1, FLT3 (FLT3 ITD, FLT3 TKD), CEBPA, MLL (PTD) and NRAS have been identified as molecular markers in acute myeloid leukemia (AML) exhibiting a normal karyotype. Most recent studies focused on the prognostic value of single markers not taking into account their potential interactions. In addition, little is known about the predictive value of these markers on postremission therapy.Aims: To evaluate the prognostic impact of NPM1, FLT3, CEBPA, MLL and NRAS gene mutations on response to induction therapy, relapse-free (RFS) and overall survival (OS) as well as the predictive impact of these mutations on RFS and OS following different postremission therapies.Methods: Patients [16 to 60 years of age] were entered on four AMLSG treatment trials [AML-2/95, AML-1/99, AML HD93, AML HD98A]. As a consistent feature, in all four trials a genetic randomization was performed assigning all patients with an HLA-matched family donor (MRD) to allogeneic stem cell transplantation (SCT) in first complete remission (CR). Leukemia cells were analyzed for mutations in the above genes as previously described.Results: Between 1993 and 2004, 872 patients exhibiting a normal karyotype were registered. Median age was 48 years; median follow-up time was 49 months. Mutations were identified as follows (total number of samples analyzed; incidence of mutations): NPM1 (n=526; 53%), FLT3-ITD (n=531; 31%), FLT3-TKD (n=617; 11%), CEBPA (n=509; 14%), MLL-PTD (640; 8%), and NRAS (641; 13%). CR rate was 76%. In a logistic regression model, the NPM1+/FLT3-ITD- (p<.0001) and the CEBPA+ genotypes (p=0.05) were associated with induction success. Of 666 patients achieving a CR after induction therapy, 171 had a MRD and 143 (84%) of these received an allogeneic SCT in first CR. In survival analyses, the variable “availability of a MRD” was included on a strict intent-to-treat basis. Cox proportional hazard models for RFS and OS revealed age <48 years (hazard ratio (HR) 0.72 and 0.62, respectively), availability of a MRD (HR 0.62 and 0.75), the CEBPA+ (HR 0.42 and 0.36) and the NPM1+/FLT3-ITD- (HR 0.34 and 0.43) genotype as prognostic factors. To better define the role of allogeneic SCT in first CR, subgroup analyses were performed according to the combined FLT3-ITD and NPM1 mutation status (NPM1+/FLT3-ITD- versus all other combinations). These analyses revealed a marked difference in HR estimation for the variable “availability of a MRD”. In the NPM1+/FLT3-ITD- subgroup, HR for RFS and OS were 0.89 (95%-CI 0.49–1.64) and 0.93 (95%-CI 0.51–1.67) translating into a nearly equivalent RFS after 4 years of 61% (MRD) and 57% (no MRD). In contrast, in the subgroup defined by all other combinations of FLT3-ITD and NPM1 mutations, HR for RFS and OS were 0.56 (95%-CI 0.39–0.81) and 0.69 (95%-CI 0.48–0.98) translating into a marked difference in 4 years RFS of 47% (MRD) and 23% (no MRD).Conclusions: Specific genotypes emerge as highly significant prognostic factors for response to induction therapy and for survival in AML patients exhibiting a normal karyotype. The genotypic marker constellation NPM1+/FLT3-ITD- also fulfils the criteria of a predictive marker indicating a strong beneficial effect of allogeneic SCT in first CR only in the subgroup of patients without the NPM1+/FLT3-ITD- marker constellation.

Outcome of treatment in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial

From 1994 to 2000, 154 adults with Philadelphia chromosome-positive (Ph(+)) and/or BCR-ABL(+) acute lymphoblastic leukemia (ALL) were treated according to a prospective trial (median follow-up, 4.5 years) with the aim to study the prognostic value of early response to therapy and the role of stem cell transplantation (SCT) in first complete remission (CR). All patients received a standard induction course followed by a course of mitoxantrone and intermediate-dose cytarabine (HAM). After each course, minimal residual disease was tested by specific reverse transcriptase-polymerase chain reaction (RT-PCR) (median sensitivity, 10(-5)). Allogeneic SCT (if a donor) or autologous SCT (if not) was planned at 3 months in all patients in CR after HAM. CR rates after induction, after HAM, and at 3 months were 53%, 67%, and 62%, respectively. High leukocyte count and m-bcr subtype were the 2 identified bad-prognosis factors for CR at 3 months, both superseded by a poor early response assessed at day 8 of the induction course. HAM-associated salvage rate was higher in patients with M-bcr than in those with m-bcr ALL (55% vs 30%; P =.05). In the 103 patients eligible for SCT, the existence of a donor and the negative BCR-ABL status after HAM were independently predictive of remission duration (P <.001 and.01, respectively) and survival (P =.02 and.01, respectively). Relapse was the most common cause of treatment failure in all patient groups. Allogeneic SCT in first CR is the current best treatment option in adults with the disease. New strategies must be tested during early phases of therapy to increase the rate of BCR-ABL(-) remissions.