Retrospective Study from the French AML Intergroup Core-Binding Factor

From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

2014 124: 1312-1319 doi:10.1182/blood-2014-01-549212 originally published online July 8, 2014

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup

Marie-Anne Hospital, Thomas Prebet, Sarah Bertoli, Xavier Thomas, Emmanuelle Tavernier, Thorsten Braun, Cécile Pautas, Aurore Perrot, Bruno Lioure, Philippe Rousselot, Jérôme Tamburini, Thomas Cluzeau, Johanna Konopacki, Edouard Randriamalala, Céline Berthon, Marie-Pierre Gourin, Christian Recher, Jean-Yves Cahn, Norbert Ifrah, Hervé Dombret and Nicolas Boissel

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From www.bloodjournal.org by guest on November 19, 2014. For personal use only. Regular Article

MYELOID NEOPLASIA Core-binding factor acute myeloid leukemia in ﬁrst relapse: a retrospective study from the French AML Intergroup

Marie-Anne Hospital,1 Thomas Prebet,2 Sarah Bertoli,3 Xavier Thomas,4 Emmanuelle Tavernier,5 Thorsten Braun,6 Cécile Pautas,7 Aurore Perrot,8 Bruno Lioure,9 Philippe Rousselot,10 JérômeTamburini,11 Thomas Cluzeau,12 Johanna Konopacki,13 Edouard Randriamalala,14 Céline Berthon,15 Marie-Pierre Gourin,16 Christian Recher,3 Jean-Yves Cahn,17 Norbert Ifrah,18 HervéDombret,1 and Nicolas Boissel1

1Department of Hematology, EA-3518, Paris 7 University, Hôpital Saint-Louis, Paris, France; 2Department of Hematology, Institut Paoli-Calmettes, Marseille, France; 3Department of Hematology, Centre Hospitalier Universitaire Purpan, Toulouse, France; 4Department of Hematology, HôpitalEdouard Herriot, Lyon, France; 5Department of Hematology, Institut de Cancérologiede la Loire, Saint Etienne, France; 6Department of Hematology, HôpitalAvicenne, Bobigny, France; 7Department of Hematology, HôpitalHenri Mondor, Créteil, France; 8Department of Hematology, Hôpitalde Brabois, Nancy, France; 9Department of Hematology, HôpitalHautepierre, Strasbourg, France; 10Department of Hematology, Centre Hospitalier de Versailles, Versailles, France; 11Department of Hematology, HôpitalCochin, Paris, France; 12Department of Hematology, Centre Hospitalier Universitaire Nice, Nice, France; 13Department of Hematology, Hôpital d’Instruction des ArméesPercy, Clamart, France; 14Department of Hematology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; 15Department of Hematology, HôpitalClaude Huriez, Lille, France; 16Department of Hematology, Centre Hospitalier Universitaire Limoges, Limoges, France; 17Department of Hematology, Clinique Universitaire d’Hématologie,Centre Hospitalier Universitaire Michallon, Grenoble, France; and 18Department of Hematology, Centre Hospitalier Universitaire et INSERM U892-Centre National de la Recherche Scientifique UnitéMixte de Recherche 6299, Angers, France

Key Points Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/ t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these • GO before transplant patients relapse after standard intensive chemotherapy. The encouraging results of improves outcome of CBF- gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, AML patients in first relapse. incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P 5 .05) and OS (65% vs 44%; P 5 .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality. (Blood. 2014;124(8):1312-1319) Introduction

Core-binding factor (CBF) acute myeloid leukemia (AML) include 2 study.9 No advantage has been shown for autologous or allogeneic major subtypes, respectively associated with translocation t(8;21) hematopoietic stem cell transplantation (autoSCT/alloSCT) in front- (CBFA) and inversion inv(16)/t(16;16) (CBFB), that are both asso- line treatment.10-14 ciated with the disruption of genes encoding subunits of the CBF, About 60% to 70% of CBF-AML patients are alive at 5 years, a heterodimeric transcriptional factor involved in the regulation with disease recurrence being the major treatment failure.12,15,16 of hematopoiesis.1,2 CBF-AML is considered to be a favorable Advanced age, higher white blood count, additional deletion in cytogenetic subgroup, characterized by a low rate of primary drug the long arm of chromosome 9, associated KIT and FLT3 gene resistance, a reduced relapse risk, and an increased overall survival mutations, and high minimal residual disease (MRD) level after (OS).3,4 Although never formally demonstrated, patients with CBF- induction or rising MRD level on serial monitoring have been AML have shown a markedly improved outcome when treated with reported as adverse prognostic factors.17,18 Two prior studies reported consolidation regimens containing repetitive cycles of high-dose that patients with CBFA had a significantly shorter OS than patients cytarabine.5-8 More recently, the adjunction of gemtuzumab ozoga- with CBFB after first relapse.15,16 Postrelapse strategies have not micin (GO) to standard first line chemotherapy has been reported as been evaluated so far in this specific subtype. As in other AML associated with a marked benefit in CBF-AML patients treated subgroups, alloSCT is recommended in second complete remission in the large British Medical Research Council (MRC) AML-15 (CR2),3 with the role of autoSCT being uncertain.13 GO was not

Submitted January 12, 2014; accepted June 20, 2014. Prepublished online as The publication costs of this article were defrayed in part by page charge Blood First Edition paper, July 8, 2014; DOI 10.1182/blood-2014-01-549212. payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. © 2014 by The American Society of Hematology

1312 BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8 From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8 OUTCOME OF CBF-AML IN FIRST RELAPSE 1313 approved in Europe, as the European Medicines Agency consid- platelets .100 G/L, and all extra-medullary disease had resolved. Relapse ered the risk-benefit balance of GO to be unfavorable. However, was defined as the reappearance of leukemic cells in the bone marrow (. 5%). a patient-named compassionate program was available in France for patients with AML relapse. Definition of clinical end points The aim of our study was to retrospectively evaluate the use of OS was measured on the date of relapse until date of death or date last known GO before transplantation in CBF-AML patients in first relapse, alive, censoring patients at last follow-up if alive. Disease-free survival (DFS) treated in 33 centers from the French AML Intergroup. was measured only in patients who achieved a CR2, from the date of CR2 to date of relapse or death, censoring patients at last follow-up if alive.

Statistical methods Patients and methods Patient characteristics and CR rate comparisons were performed using the Fisher’s exact test for binary variables and the Mann-Whitney U test for Patients continuous variables. DFS and OS were estimated by the Kaplan-Meier method. To evaluate the impact of alloSCT and autoSCT, outcome data were A total of 145 patients were included in this study according to the following estimated by the Mantel-Byar method, considering alloSCT or autoSCT as a criteria: 1) CBF-AML was diagnosed according to the French-American- time-dependent covariate.22,23 The method described by Simon and Makuch British criteria with t(8;21), inv(16)/t(16;16), and/or their molecular was applied for appropriate graphical representation of alloSCT and fi fi equivalents in rstrelapse;2)previous rst line treatment with at least autoSCT impact on OS and DFS.24 Differences in OS and DFS between one course of anthracycline, plus cytarabine-based induction chemother- subgroups were assessed by univariate Cox proportional hazard regression apy; and 3) no prior history of treatment with GO or auto/allo SCT. Salvage models. Proportional-hazards assumption was checked before conducting fi fi therapy was de ned as the rst intensive treatment of AML recurrence. multivariate analyses.25 For multivariate analyses, a Cox regression model The presence of t(8;21)(q22;q22), inv(16)(p13q22), or t(16;16)(p13q22) according to the method of Andersen and Gill was used, including first fi at rst diagnosis was detected either by standard cytogenetics or by reverse complete remission (CR1) duration (as continuous variable), GO adminis- transcriptase-polymerase chain reaction detection of corresponding fusion tration, alloSCT (as time-dependent variable), age at relapse (as continuous transcripts. Karyotypes at relapse and gene mutations were not included in variable), CBF subtype (CBFA vs CBFB), and primary trial (ALFA-9801 this analysis due to lack of consistent data. as baseline) as covariates.26 Year of treatment was used as continuous variable to stratify all multivariate analyses. A P value # .05 was considered First-line therapy to indicate statistical significance. Statistical analysis was performed on the STATA/SE 11.0 (StataCorp, College Station, TX) software package. Patients were mostly treated according to the following protocols: Acute Leukemia French Association (ALFA)-9801, ALFA-9802, LAM-2001, and CBF-2006.17,19-21 All patients underwent induction chemotherapy with an anthracycline plus cytarabine-based regimen. This study was conducted Results in accordance with the Declaration of Helsinki. Pretreatment characteristics Salvage therapy Between 1994 and 2011, 145 patients with first relapsing CBF-AML The type of salvage chemotherapy was the investigator’s choice. Following were analyzed with a median CR1 duration of 12.1 months (range, approval of GO by the US Food and Drug Administration for the treatment 2.1-93.6). Patient characteristics are summarized in Table 1. Median of AML in 2000, the French health agency (French Health Products Safety age at relapse was 43 years (range, 16-76). Male/female ratio was Agency) opened a compassionate, patient-named program (authorization 1.13. Translocation t(8;21) was present in 59 patients (CBFA for temporary utilization program) of GO in relapsed CD331 AML. In this patients), including 37 with other chromosomal abnormalities (loss authorization for temporary utilization program, potential combination of GO with standard chemotherapy was also the investigator’s choice. of sexual chromosome and del(9q) were observed in 27 [46%] The 33 centers involved in this study retrospectively included 1 to 20 and 10 [17%] CBFA patients, respectively). Inversion 16 was patients per center. Seven centers included more than 5 patients (N 5 89 of present in 86 CBFB patients, 26 of who had other chromosomal 145, 61%) and 26 included 5 patients or less (N 5 56 of 145, 39%). Patients abnormalities(trisomy22andtrisomy8,in9[10%]and9[10%] who received GO were well balanced between these subgroups: 27 of CBFB patients, respectively). 89 (30%) were in centers that included more than 5, and 21 of 56 (38%) were in centers that included 5 or less (Fisher’s exact test, P 5 .47). Outcome after relapse Salvage regimens were grouped into the following categories: 1) Forty-eight patients were treated with GO, combined in 35 patients (75%) Overall, 127 of 145 patients (88%) achieved CR2 (Figure 1). In with high-dose cytarabine alone without anthracycline; GO dose was univariate analysis, patients withCBFBshowedatrendtoward 6 mg/sqm (single-dose) in 31 patients and fractionated doses (3 mg/sqm higher CR2 compared with patients with CBFA (92% vs 81%; on days 1, 4, and 7) in 4 patients. The other 13 patients received GO in P 5 .07), whereas age at relapse (P 5 .62) and CR1 duration (P 5 .31) combination with cytarabine with additional anthracycline; GO dose was had no prognostic impact. 9 mg/sqm in 7 patients, fractionated 3 mg/sqm on days 1, 4, and 7 in 1 patient, With a median follow-up from relapse of 3.5 years, the estimated and 6 mg/sqm in 5 patients. 2) Ninety-seven patients were treated with 5-year DFS was 50% (95% CI, 41-60) and 5-year OS was 51% (95% chemotherapy alone, defined by standard dose cytarabine and anthracycline CI, 41-60). In univariate analysis, CBF subgroup had no prognostic 5 5 (n 44) or high-dose cytarabine and anthracycline (n 53), without GO. impact: 1) Five-year DFS was 54% (95% CI, 37-70) in the CBFA subgroup and 49% (95% CI, 37-61) in the CBFB subgroup (P 5 .65); Criteria for response and relapse 2) Five-year OS was 45% (95% CI, 29-60) in the CBFA subgroup P 5 Morphologic response was evaluated after salvage therapy. Response was and 54% (95% CI, 29-60) in the CBFB subgroup ( .27) classified as CR or failure, including resistant disease and early death. (Figure 2A and Tables 2 and 3). First-line trial had no prognostic Patients were considered in CR when the bone marrow examination was impact either (Tables 2 and 3). On the other hand, shorter CR1 duration normal with ,5% blasts and no Auer rods, recovery of ANC .1 G/L and (P 5 .005) and older age (P 5 .03) were significantly associated with From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

1314 HOSPITAL et al BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8

Table 1. Patient characteristics and outcome Total GO1 GO2 P Patients, N 145 48 97 Age (years), median (range) 43 (16-76) 46 (20-76) 42 (16-74) .15 Gender (male/female), N 77/68 26/22 51/46 .99 CBFA/CBFB, N 59/86 25/23 34/63 .07 CR1 duration (months), median (range) 12.1 (2.1-93.6) 11.1 (2.1-93.6) 12.7 (2.6-55.2) .04 Primary trial ,.001 ALFA-9801, N (%) 21 (14) 8 (17) 13 (13) ALFA-9802, N (%) 20 (14) 1 (2) 19 (20) LAM-2001, N (%) 47 (32) 7 (14) 40 (41) CBF-2006, N (%) 57 (39) 32 (67) 25 (26) CR2, N (%) 127 (88) 42 (88) 85 (88) .99 Allograft, N (%) 78 (54) 28 (58) 50 (52) .55 a shorter OS, whereas only shorter CR1 duration was associated with toward higher CR2 compared with patients with CBFA (92% vs a shorter DFS (P 5 .002) (Figure 2B; Tables 2 and 3). In patients with 81%; P 5 .07) CR1 duration , 1 year, 5-year DFS was 42% (95% CI, 29-55) and Despite the absence of impact of GO on CR2 rate, long-term 5-year OS was 41% (95% CI, 27-54) vs 59% (95% CI, 46-72) outcome was significantly better in patients receiving GO and 60% (95% CI, 47-73) in patients with CR1 duration $ 1 year (Figure 2C; Tables 2 and 3). The 5-year DFS in GO1 patients was (Figure 2B). 68% (95% CI, 53-84) compared with 42% in GO2 patients (95% CI, 31-54; P 5 .05). Five-year OS was 65% in GO1 patients (95% Impact of GO therapy CI, 48-82) compared with 44% in GO2 patients (95% CI, 33-55; P 5 .02). When the analysis was restricted to patients with CBFA, Forty-eight of 145 patients (33%) were treated with a combination GO1 was associated with a significantly higher 5-year DFS (84% of GO and standard chemotherapy (GO1 subgroup). There was no [95% CI, 68-100] vs 38% [95% CI, 19-57]; P 5 .01) and OS (70% significant difference between both GO1 and GO2 subgroups in [95% CI, 51-89] vs 33% [95% CI, 16-51]; P 5 .06). In patients with term of age, gender, and CBF subtype (Table 1). The CR1 duration CBFB, GO1 subgroup only showed a trend toward higher 5-year was shorter in GO1 patients (11.1 vs 12.7 months; P 5 .04). As the DFS (58% [95% CI, 36-79] vs 45%; P 5 .24) and OS (65% [95% CI, rate of patients to whom GO was proposed as salvage increased 41-88] vs 50% [95% CI, 37-64]; P 5 .08). with time, patients who received GO were more likely treated in the CBF-2006 trial than in previous ALFA-9801, ALFA-9802, or Feasibility and impact of SCT after relapse LAM-2001 trials (P , .001). There was no impact of GO on the CR2 rate. Overall, 42 of 48 We analyzed the role of alloSCT since this is typically regarded as the patients (88%) treated with GO and 85 of 97 patients (88%) treated only potentially curative therapeutic option after relapse. Allogeneic with standard chemotherapy alone achieved CR2 after 1 salvage SCT was performed in 78 of the relapsing patients. Among them, 77 cycle (P 5 .99). Respectively, 6 (12%) and 11 (11%) patients failed patients received alloSCT as consolidation performed after achiev- to reach CR because of resistant disease (P 5 .99). One early death ing a CR2 following first salvage. One patient underwent alloSCT (due to infection) was reported during salvage in the standard che- while in active disease after first salvage failure. There was no motherapy (GO2) group. Two cases of reversible hepatic sinusoidal difference between patients who proceeded to alloSCT or not in term obstruction syndrome were documented and occurred during salvage of sex ratio (P 5 .25), CBFA/B (P 5 .74), CR1 duration (12.4 vs therapy. One patient died after relapse and the other is alive and in 12 months; P 5 .43), or GO administration (58% vs 42%; P 5 .48). CR. The use of GO had no significant impact on CR2 rate according As expected, patients who proceeded to alloSCT were significantly to CBF subtype, even though patients with CBFB showed a trend younger (41 vs 52 years; P 5 .0002). Median time from first

Figure 1. Patient flowchart. Induction and consolidation therapy according to GO administration in salvage therapy. From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8 OUTCOME OF CBF-AML IN FIRST RELAPSE 1315

Figure 2. Outcome of CBF-AML patients after first relapse (N 5 145). DFS and OS according to (A) CBFA vs CBFB status, (B) CR1 duration (,1vs$1 year), and (C) administration of GO in salvage therapy. relapse to transplant was 2.2 months (range, 0.4-11.3). Condi- (Figure 3A). Therefore, in order to evaluate the impact of alloSCT, tioning regimens before alloSCT included standard myeloablative and due to the low number of patients who received autoSCT in CR2, regimens (MAC) such as TBI or busulfan and cyclophosphamide patients who received autoSCT were analyzed with those who were (n 5 55), or reduced-intensity conditioning (RIC) regimens with treated with chemotherapy alone. For patients who received alloSCT fludarabine (n 5 23). Forty patients underwent alloSCT from a in CR2, the Mantel-Byar 5-year DFS estimate was 57% (95% CI, related donor (sibling donor [SIB]), and 35 patients underwent SCT 43-69) compared with 42% (95% CI, 27-56) in nonallografted from an unrelated donor (URD). patients (HR .58, [95% CI, .34-.99]; P 5 .05; Figure 3B). Mantel- Eighteen patients received autoSCT in CR2. In time-dependent Byar 5-year OS estimates were 59% (95% CI, 44-72) in allografted analysis, there was no benefit of autoSCT when compared with patients and 45% (95% CI, 31-57) in nonallografted patients chemotherapy alone (N 5 49) in terms of DFS (autoSCT vs (HR .55, [95% CI, .32-.94); P 5 .03; Figure 3B). The benefitof chemotherapy, 5-year DFS 41% vs 39%, Hazard ratio [HR] 1.06, alloSCT in terms of DFS was observed in CBFB patients (alloSCT [95% CI, .48-2.35]; P 5 .88) and only a trend for OS (autoSCT vs vs nonalloSCT: HR .43 [95% CI, .22-.86]; P 5 .02), but not chemotherapy, 60% vs 36%, HR .63, [95% CI, .27-1.50]; P 5 .30) in CBFA patients (alloSCT vs nonalloSCT: HR .97 [95% From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

1316 HOSPITAL et al BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8

Table 2. Univariate and multivariate analysis for DFS Univariate Multivariate HR 95% CI P HR 95% CI P CR1 duration* .93 .88-.97 .002 .92 .86-.98 .01 GO .45 .23-.84 .01 .40 .17-.90 .03 AlloSCT .58 .34-.99 .05 .75 .37-1.50 .41 Age*† 1.19 .99-1.44 .07 1.40 1.03-1.90 .03 CBFB vs CBFA 1.15 .66-1.99 .65 .48 .23-1.01 .05 Primary trial ALFA-9801 as baseline ALFA-9802 .69 .28-1.67 .42 .42 .09-1.99 .27 LAM-2001 1.11 .54-2.28 .77 1.90 .65-5.60 .24 CBF-2006 .48 .22-1.08 .08 .73 .17-3.09 .67

*Continuous variable. †HR for a 10-year increment.

CI, .37-2.50]; P 5 .94). Neither the type of donor (ID vs SIB) nor the were independently associated with a longer OS (P , .001, P 5 .02, conditioning regimen (RIC vs MAC) had an impact in terms of DFS and P 5 .002, respectively) (Tables 2 and 3). (URD vs SIB: HR .91 [95% CI, .42-1.98]; P 5 .81; RIC vs MAC: HR .86 [95% CI, .36-2.04]; P 5 .73) or OS (URD vs SIB: HR 1.00 [95% CI, .44-2.30]; P 5 .99); and RIC vs MAC, HR 1.00 (95% CI .42-2.46), P 5 .98). Discussion In patients receiving alloSCT in CR2 (Figure 3B), those who received GO before transplant (N 5 27) had a significantly higher This study of 145 adult patients with CBF-AML in first relapse is the 5-year DFS (83% [95% CI, 60-93]) than those who received second largest cohort presented so far,14 with a median follow up of conventional chemotherapy (44% [95% CI, 28-60]; P 5 .01). 3.5 years. Should there be a large consensus to consider CBF-AML Mantel-Byar 5-year OS was 82% (95% CI, 53-94) in patients who at favorable risk, relapses have been reported to occur in up to 35% received GO before transplant, as compared with 48% (95% CI, of patients.15-17 There is no established salvage treatment at this stage 30-63; P 5 .01) in patients who received chemotherapy alone of the disease. First relapse is generally treated by chemotherapy (Figure 3C). This benefit of GO administration before transplant was based on a combination of anthracycline with standard- or high-dose mostly observed in CBFA patients (GO vs no GO: HR .10 (95% cytarabine, followed or not by alloSCT. New therapeutic approaches CI .01-.77); P 5 .03) when compared with CBFB patients (GO vs no are being developed, and more particularly, antibody-directed che- GO: HR .49 (95% CI .14-1.76); P 5 .25), although the numbers were motherapy that offers the prospect of delivering chemotherapy small. There was no impact of cumulative dose of GO received to the target while sparing collateral toxicity. The British MRC before alloSCT on DFS or OS (data not shown). Less treatment- AML-15 study was the first to demonstrate the superiority of GO related mortality (TRM) was observed in patients who received GO in CBF-AML patients in CR1.9 In the French ALFA-0701 trial, before transplant (5-year TRM at 7% [95% CI, 0-19] vs 26% [95% GO was shown to benefit patients with favorable cytogenetic.27 CI, 10-41]; P 5 .05). Our observation suggests that GO may also benefit patients in first We performed a multivariate analysis including age, CBFA/B relapse, and that GO combined with chemotherapy followed by subtype, first-line trial, CR1 duration, use of GO, and of alloSCT (as alloSCT, is safe and efficient. time-dependent variable) as covariates. Younger age, CBFB subtype, The aim of this retrospective study was to assess the outcome of longer CR1 duration time, and use of GO were independently as- patients eligible for intensive salvage in order to evaluate the place sociated with a longer DFS (P 5 .03, P 5 .05, P 5 .01, and P 5 .03, of GO and allo-SCT in these patients. Thus, patients, none of whom respectively). Longer CR1 duration, CBFB subtype, and use of GO had a prior history of allo-SCT, were all treated intensively and

Table 3. Univariate and multivariate analysis for OS Univariate Multivariate HR 95% CI P HR 95% CI P CR1 duration* .94 .89-.98 .005 .88 .81-.94 ,.001 GO .48 .26-.88 .02 .38 .16-.87 .02 AlloSCT .55 .32-0.94 .03 .64 .32-1.28 .21 Age*† 1.22 1.02-1.46 .03 1.26 .94-1.71 .13 CBFB vs CBFA .76 .46-1.26 .28 .32 .16-.66 .002 Primary trial ALFA-9801 as baseline ALFA-9802 .71 .31-1.65 .43 .39 .10-1.45 .16 LAM-2001 .99 .50-1.97 .98 1.34 .48-3.72 .58 CBF-2006 .45 .21-.99 .05 1.28 .29-5.74 .74

*Continuous variable. †HR for a 10-year increment. From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8 OUTCOME OF CBF-AML IN FIRST RELAPSE 1317

Figure 3. Impact of autoSCT, alloSTC, and GO administration in CBF-AML patients after relapse. Plots by Simon and Makuch for DFS and OS in nonallogeneic transplanted patients (N 5 67) according to autoSCT. (A) For the whole cohort of patients according to allogeneic transplantation and (B) in allogeneic transplanted patients (N 5 77) according to GO administration before transplant (C). salvage treatment was left to the physician’schoice.Dueto Due to the fact that all patients were intensively treated at relapse, increasing arguments supporting the use of GO in CBF-AML relatively favorable long-term survival was noted in our cohort, with patients, the rate of patients treated with GO at relapse increased about half of the patients still alive at 5 years. In our study, prognosis with time, justifying that all multivariate analyses were stratified after relapse seemed to be preferentially driven by treatment received on the year of treatment. A high overall CR2 rate of 88% was as salvage therapy and the duration of the first CR. The CBFB sub- observed and no patient or disease characteristics were associated group was also associated with a better survival in multivariate with salvage failure. This rate was very similar to the 82% analysis. A shorter survival of CBFA patients after first relapse was recently reported by the MRC study.14 No difference in CR2 rate already noted in a previous study. Marcucci et al reported a 5-year between the two CBF subtypes were observed unlike Schlenk et al postrelapse survival of 14% compared with 34%, respectively.16 who reported a lower second CR rate of 33% in CBFA patients Similar results were also shown by Schlenk et al.15 Interestingly, in compared with 78% in CBFB patients. As already reported in the the present study, GO seemed to have a marked benefit in CBFA literature, white blood count at diagnosis was not a prognosis factor patients. This may have contributed to minimize the difference of for CR2 rate.15 outcome between CBFA and CBFB patients in univariate analysis. From www.bloodjournal.org by guest on November 19, 2014. For personal use only.

1318 HOSPITAL et al BLOOD, 21 AUGUST 2014 x VOLUME 124, NUMBER 8

The reasons for this difference of GO benefit between CBF subgroups remain unexplained and require further investigation. The Acknowledgments importance of receptor tyrosine kinase mutations to predict outcome in front-line CBF patients has been highlighted by many retrospec- The authors thank all the clinicians of the Groupe Ouest-Est des 28 tive and more recent prospective studies. Furthermore, more Leucemies´ Aigues¨ et Maladies du Sang and ALFA groups who recently, MRD monitoring has been shown to be the most powerful referred their patients and all clinical research assistants for their 17 prognostic factor in these patients. Due to the lack of available blast help with data management: Marie-Anne Hospital, Nicolas Boissel, samples at diagnosis and relapse, we were unable to evaluate these Herve´ Dombret, Karine Celli-Lebras (Paris), Thomas Prebet parameters in our study. (Marseille), Sarah Bertoli and Christian Recher (Toulouse), Xavier It is usually considered that CBF-AML patients do not benefit Thomas (Lyon), Emmanuelle Tavernier (Saint Etienne), Thorsten from alloSCT in first CR. In a prospective study by the French Braun (Bobigny), Cecile´ Pautas and Ludovic Cabanne (Creteil), Intergroup, despite a relapse incidence .30%, OS from CR Aurore Perrot (Nancy), Bruno Lioure (Strasbourg), Philippe remained as high as 85%, underlying the relatively good salvage Rousselot and Sandra Gautier (Versailles), Thibaut Leguay 17 rate in CBF-AML patients. Indeed, our observation suggests that (Bordeaux), Jer´ omeˆ Tamburini (Hopitalˆ Cochin, Paris), Jacques intensive salvage in relapsed CBF-AML patients, including GO Delaunay and Marie-Aude Rambaud (Nantes), Thomas Cluzeau and alloSCT, may lead to favorable long-term outcomes with an (Nice), Johanna Konopacki (Percy), Edouard Radriamalala estimated 5-year DFS of 83%. In relapsing patients, alloSCT is (Poitiers), Sandrine Vaudaux (Rouen), Celine´ Berthon (Lille), widely regarded as the only therapeutic option with curative Marie-Pierre Gourin, Florence Bosselut, and Celine´ Philippon 29 potential. However, for CBF-AML patients, this remains a point (Limoges), Celine´ Haby (Mulhouse), Magda Alexis (Orleans), Chantal of debate. A retrospective study from the ALFA group showed that Himberlin (Reims), Norbert Ifrah and Thibaud Lecerf (Angers), donor availability was a positive factor for survival after first Eric Deconinck and Monique Peria (Besançon), Jean-Christophe 12 relapse in CBF-AML. This was not confirmed by a recent MRC Ianotto (Brest), Emilie Marin (Caen), Romain Guieze` (Clermont study that did not observe any benefit of allogeneic transplant Ferrand), Sabine Camara (Colmar), Jean-Yves Cahn and Pierre analyzed as time-dependent variable in this subgroup of patients, Pittet (Grenoble), Julien Lazarovici (Villejuif), Eric Jourdan (Nimes), 14 whatever the CBFA/B subgroup. In the present study, the benefit Madalina Uzunov (Pitie-Salp´ etri´ ere),` and Isabelle Plantier (Roubaix). of alloSCT was restricted to the CBFB subgroup of patients. Previous studies suggested that a combination of GO and alloSCT can be applied in heavily pretreated patients with relapsed AML.30,31 In our experience, TRM after alloSCT was not Authorship increased by previous administration of GO. The 2 cases of hepatic sinusoidal syndromes occurred during induction therapy, Contribution: M.-A.H. and N.B. designed the research, collected and and none after allogeneic SCT. analyzed the data, and wrote the manuscript; T.P., S.B., X.T., E.T., In conclusion, this study shows that half of CBF-AML patients T.B., C.P., A.P., B.L., P.R., J.T., T.C., J.K., E.R., C.B., M.-P.G., C.R., can still be cured at time of first relapse. These results suggest that J.-Y.C., N.I., and H.D. assisted in data collection and manuscript prep- alloSCT should probably be reserved to postrelapse strategy or to aration; and all the authors approved the final draft of the manuscript. front-line very high-risk patients. GO, combined with intensive Conflict-of-disclosure: The authors declare no competing financial chemotherapy, followed by allogeneic SCT in patients achieving interests. CR2 seems to give the best chances of curability. Whether CBFA Correspondence: Nicolas Boissel, Department of Hematology, and CBFB differentially benefit from GO or alloSCT as salvage Hopitalˆ Saint-Louis, 1 Ave Claude Vellefaux, Paris 75010, France; therapy should be further investigated. e-mail: [email protected].

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