Consolidation Courses Research Articles

Favourable Outcome in Infants with Acute Myeloid Leukemia Treated with the AIEOP AML 2002/01 Protocol

AbstractAbstract ▪3585▪This icon denotes a clinically relevant abstract Introduction:The prognosis of paediatric patients (pts) with Acute Myeloid Leukemia (AML) has significantly improved over time not only in standard risk (SR) but also in high risk (HR) children. Pts < 1 year of age (infants) affected by AML are generally considered to be at HR. This is due to the prevalence of prognostically unfavourable clinical and cytogenetic/molecular features and to a greater vulnerability to treatment toxicities. We analyzed clinical and biological characteristics, as well as outcome of infants treated with the AIEOP AML 2002/01 protocol, comparing them to those of older children. Patients and Methods:Between 12/2002 and 06/2011, 63 infants with AML other than promyelocytic leukaemia were treated with the AIEOP AML 2002/01 protocol. Children with Down syndrome were excluded. Clinical and biological features compared to the ones of 3 different age groups (1–<2 years; 2–10 years; >10 years) are reported in Table 1. Treatment was administered according to the following risk-based stratification: pts with isolated CBF-b+ leukemia achieving complete remission (CR) after the first induction course were considered to be at Standard Risk (SR), whereas all the others were assigned to the HR group. The treatment schedule administered to infants was: 2 courses of 7-day induction therapy (idarubicin, cytarabine and etoposide: ICE 3+5+7) and 2 consolidation courses based on high-dose cytarabine (HD-Ara-c), combined with either etoposide during the first course (AVE 3+4) or mitoxantrone during the second course (HAM 3+2). After consolidation, infants were eligible to allogeneic (ALLO) HSCT in first CR from a HLA-identical relative, if available, or from alternative donors, namely unrelated donors or HLA-mismatched relatives. CR rate, early death (ED), induction failure (IF), overall survival (OS) and event free survival (EFS) of infants were calculated and compared to those of other age groups. Results:Compared to pts of other age groups, infants had significantly more CNS involvement at diagnosis (P=0.002), were assigned to the FAB M7 subtype (P=0.000) and to the HR risk group (P=0.001) (Table 1). The median white blood cell (WBC) count at diagnosis was higher in infants (P=0.028), being 71,298×103/ml (range 3,100–653,000). Comparing pts with available cytogenetic data in the different age groups, infants showed a significantly higher incidence of 11q23/MLL-rearrangements (P=0.001). The incidence by partners of 11q23/MLL-rearrangements were 10%, 7%, 1%, 4% and 14% for t(9;11), t(10;11), t(11;19), t(1;11) and other translocation partners, respectively. Infants had CR, ED and IF rates of 84%, 8% and 8%, respectively, with no statistically significant differences with other age groups. Forty-five out of 63 infants (71%) received an ALLO HSCT in first CR. With a median follow up time of 57 months (range 3–130) the 8-year probability of OS and EFS of infants were 74% and 58%, respectively, with no significant differences compared with the other age groups. Conclusions:Infants < 1 year of age at diagnosis enrolled in the AIEOP AML 2002/01 protocol presented with a significantly higher incidence of prognostically unfavourable features, like high WBC count, FAB M7 subtype, 11q23/MLL-rearrangements and CNS involvement. Despite this, a treatment strategy including a wide use of ALLO HSCT in first CR for these pts resulted in a final outcome which was not statistically different from that observed in the other age groups. Our results compare favourably with previously published data on infants with AML. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Imatinib (IM) and Chemotherapy in Combination Improve Remission Rate, Stem Cell Transplantation Rate and Long-Term Outcome

AbstractAbstract ▪662▪This icon denotes a clinically relevant abstract Introduction:In the last 10 years IM was added to chemotherapy to improve outcome of adult patients (pts.) with Ph+ ALL, with encouraging results. The Northern Italy Leukemia Group (NILG) designed a clinical trial with chemotherapy plus short IM pulses (Bassan et al, JCO 2010; 28:3644–52) aiming to increase the CR rate, limit incidence of early failures and increase the number of patients proceeding to SCT with subsequent improvement of survival. Aim:To analyze the long-term results in Ph+ ALL pts. treated with chemotherapy plus IM, in comparison to a prior cohort treated without IM. Patients and Methods:IM 600 mg/d was given orally for 7 consecutive dd. with each chemotherapy block, starting from day 15 of induction (IDR/VCR/PDN±ASP) and day –3 of consolidation courses (5x IDR/VCR/CY/DEXA; 2x HD-MTX/ARA-C). All pts. received CNS chemo-radioprophylaxis and were eligible to allogeneic SCT, or alternatively to HD therapy with autologous SCT and long-term maintenance with 6MP/MTX and intermittent IM.Between April ’00 and November ’08, 100 out of 404 pts. enrolled into NILG trial 09/00 had Ph+ ALL (median age 46 years, range 19–66; male 54). The pts. belonged to two subsequent treatment groups: control arm (IM-, n=35) and IM+ arm (n=65), of whom 59 received IM during induction/consolidation and 6 during consolidation only (pts. included in IM- cohort for remission induction analysis and in IM+ cohort afterwards). From March 2005 ASP was omitted during induction due to increased toxicity, so that in the IM+ group 20 pts. received ASP and 39 did not. Results:The complete remission (CR) rate was: 33/41 (80.5%) in IM- vs. 55/59 (93%) in IM+ pts. (p=0.05). With regard to the use of ASP in IM+ group, CR rate was: 16/20 (80%) with ASP vs. 39/39 (100%) without ASP (p=0.004). With a median follow-up of 1,6 years (maximum 11.3), 24/60 (40%) IM+ pts. are alive in 1st CR compared to 5/28 (18%) IM- pts., (p=0.04). Estimated 5-year OS, DFS and early relapse rates were significantly improved and reduced (relapse risk within 6 mos.), respectively, in IM+ vs. IM- group: OS 0.38 vs. 0.23 (p=0.012), DFS 0.40 vs. 0.25 (p=0.015) and relapse risk 0.05 vs. 0.24 (p=0.003). The probability to receive a SCT (autologous or allogeneic) was increased in IM+ pts. (72% vs. 54%), a difference that was statistically significant for allogeneic SCT (63% vs. 39%, p=0.04). In a cumulative analysis, patients receiving a SCT had the best outcome regardless of prior IM use (n=58; 5-years OS 0.49 and DFS 0.50), while in pts. unable to reach SCT outcome was slightly better in those exposed to IM (Figure). Forty CR pts. (28 IM+ and 12 IM-), were evaluable for minimal residual disease (MRD) response at weeks 10–22. PCR-negativity at weeks 10 and 16 was tendentially higher in IM+ group (32% and 37,5%) rather than IM- pts. (25% and 12,5%, p=ns). Conclusion:This long-term update confirms that short IM pulses in combination with chemotherapy increased the rate of CR, reduced incidence of early failures, and allowed to increase the feasibility of SCT, with a marked outcome improvement. An allogeneic SCT appears the best consolidation option for Ph+ ALL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Patterns of Immune Reconstitution in Patients with Acute Promyelocytic Leukemia Treated with Single Agent Arsenic Trioxide and Its Impact On Time to Molecular Remission

AbstractAbstract ▪3552▪This icon denotes a clinically relevant abstractThere is a substantial data to suggest that immune response to acute promyelocytic leukemia (APL) contributes significantly towards achieving durable remission. The impact of arsenic trioxide (ATO) on immune reconstitution, when used to treat APL, has not been studied. Single agent ATO is able to induce complete molecular remission in practically all patients who complete an induction and consolidation course. However, while ATO is well tolerated approximately 20% of newly diagnosed cases will relapse with such a regimen. We undertook a prospective study to evaluate the pattern of immune reconstitution in patients with newly diagnosed APL treated at our center with a single agent ATO regimen.Peripheral blood samples were obtained from patients before treatment, on day 15 after starting ATO, post induction, pre consolidation, maintenance cycle 2 (6 months from diagnosis) and maintenance cycle 6 (10 months from diagnosis) for flow cytometry analysis. Briefly cells were labeled using a panel of monoclonal antibodies to CD3, CD4, CD8, CD56, CD16, CD19, CD45RO, CD45RA directly conjugated with FITC, PE, PerCP or APC followed by red cell lysis and cells were then washed and analyzed using FACS Calibur. Cells were gated using forward versus side scatter dot-plots. Lymphocyte subset percentages were calculated from the lymphocyte gate and absolute lymphocyte subset counts were calculated for the analysis.Analysis of lymphocyte subset reconstitution patterns have shown that all the subsets were below the normal range at diagnosis. Following treatment there was differential pattern of immune reconstitution in different lymphocyte subsets. The earliest recovery to normal range was seen in the CD8 subset (Figure 1) while the mean CD4 subset reached the normal range only at 3 months from diagnosis. A normal CD4 to CD8 ratio had not been reached even at the last follow up in this study (10 months from diagnosis). There was a significant delay in the immune reconstitution of NK cells (CD56+CD3-) and naïve T cells (CD4+CD45RA+). The pattern of immune reconstitution of some of the lymphocyte subsets that were evaluated is summarized in Figure 1.The number of relapses in this cohort was too few to make any association between relapse and the pattern of immune reconstitution. However, we had previously reported that RT-PCR positivity at the end of induction was a significant independent risk factor for subsequent relapses with this regimen. Among the 29 cases available for evaluation at the time of completion of induction and documentation of hematological remission 14 (48.2%) were RT-PCR negative. At this time point there was a significantly higher number of NK-T cells (CD56+CD3+) in those that were RT-PCR negative versus those that were positive (6.1±4.5 × 107/Lt Vs. 2.9±4.1 × 107/Lt; P=0.040). There was also a trend to lower CD3 and a lower CD56br/CD16dim subset in the cases that were RT-PCR positive at the end of induction.This study demonstrates that there is significant heterogeneity in the pattern of immune reconstitution in different lymphocyte subsets post treatment of APL with ATO. Modulation of immune recovery and response could potentially improve leukemia clearance and maintenance of remission. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Efficacy and Feasibility of High-Dose Cytarabine Plus Idarubicin and Amifostine As Induction Schedule: A Prospective Observational Study of 100 AML Elderly Fit Patients

AbstractAbstract 3621Acute myeloid leukemia (AML) has a dismal prognosis in elderly population because of intrinsic chemoresistance and frailty of patients. High-dose Cytarabine (HiDAC) in induction therapy did not improve the CR in younger AML patients and recent guidelines discourage this approach in elderly because of high extrahematological toxicity. Amifostine showed to selectively protect normal Hemopoietic progenitors from chemotherapy and we previously successfully tested the feasibility of an induction schedule including HiDAC (3 g/m2 days 1,2,3,4,5), Idarubicin 40mg/m2 on day 3 preceeded by Amifostine (740 mg/m2). We designed a prospective observational study including the same induction schedule, aimed to evaluate the outcome (CR rate, OS and EFS) of a larger population of fit AML elderly patients. Fit patients, selected according the Multidimensional Geriatric Assessment, received 1–2 courses and underwent PBSC mobilization after consolidation. Patients who collected ≥3×10e6CD34+/kg received ASCT, while poor mobilizers were considered for alternative regimen including Allogeneic transplantation from an HLA-matched sibling, chemotherapy (CHT) or Gemtuzumab-Ozogamicin (GO).We registered 156 consecutive patients, aged >59 yrs; 56 were unfit for intensive induction chemotherapy and received only palliative care; 100 (64%) fulfilled the inclusion criteria of our protocol: 91 received the scheduled induction regimen, while 9 received a Fludarabine regimen because of reduced cardiac function. These patients were not included in the response evaluation, but were considered for the outcome (according to the ITT criteria). Patients’ characteristics are shown in table 1.CR was achieved in 73.6% of patients; multivariate analysis showed secondary disease as predictive of poor response, with a 65% CR rate (RR = 2.54; 95% CI: 1–6.45; p= 0.05) vs 83% in primary disease. Induction death rate was 5% and not influenced by any prognostic factors. The median time to achieve neutrophil>500× 106/L and platelet>20,000×106/L, were 17 and 19 days (ranges of 9–29 and 3–47 respectively). The main extrahematological toxicity were grade 3–4 mucositis (13%) and hepatic toxicity (9%). We also observed 66 grade III-IV febrile neutropenia/infectious episodes.Overall 65 patients received a first consolidation course and mobilization for PBSC harvest; we observed 6 TRD, a 3% of grade 3–4 hepatic and neurological toxicity and 6% of grade 3–4 cardiac toxicity; in 4 patients we observed rapid early leukemia relapse; overall 55 patients were eligible for post-consolidation therapy.Only 24 patients achieved a succesfull PBSC mobilization and ASCT was performed in 21 (2 relapsed and died before ASCT and 1 received Allogeneic Transplant). Thirty-one patients were poor mobilizers: 3 received Allogeneic Transplant, 3 CHT, 5 stopped treatment because of persistent aplasia and 20 received low-dose GO (3 mg/m2 monthly for 3 times and every 3 months after; median: 3, range 3–6 courses).With a median follow-up of 70 months (range 24–124) 21 patients are alive (19 in continuous CR), 6 after ASCT, 13 after GO, 1 after CHT.The 8 yrs Overall Survival (OS), Disease Free Survival (DFS) and Event Free Survival (EFS) are respectively 20.4% (median: 11.4 months), 24,3% (median 8.8 months) and 17,7% (median: 8.8 months).Secondary AML and hyperleukocytosis are factors predictive of OS at the multivariate analysis. Patients with secondary disease have a 1.59 RR to die with a 9.9% 8 yrs OS vs 27.1% of patients with primary AML. Patients with WBC ≥50,000/mcl had a 2.2 RR to die with a 0% OS at 33 months vs 23.2% 8 yrs OS in patients with WBC<50,000/mcl.In conclusion our novel intensive induction regimen for fit AML patients is safe and effective both in term of CR rate and outcome. The ASCT feasibility was confirmed to be poor in this setting (21%) while GO low-dose seems to be feasible and promising. Finally our prospective study in 156 elderly AML patients describes the real-life outcome of this setting, suggesting that two thirds of AML elderly patients are fit for intensive treatment and that long term OS can be achieved in a relevant proportion of patient with de novo AML.Table 1:Patients' characteristicsN (%)Gender:Male58Female42Karyotype:Favorable5 (5.7)Intermediate49 (56.3)Unfavorable33 (38)De novo AML61Secondary AML39Age:<70 yrs55>69 yrs45WBC count:<50,000/mcl89≥50,000/mcl11PS:0–29634FDI060>040Sorror0–262 (74.7)>221 (25.3) Disclosures:No relevant conflicts of interest to declare.

Minimal Residual Disease After the First Cycle of Chemotherapy in Acute Myeloid Leukemia: A Comparative Study of WT1 RQ-PCR and 4-Color Flow Cytometry.

AbstractAbstract 2535▪▪This icon denotes a clinically relevant abstract Background and aims.Detection of minimal residual disease (MRD) has a relevant prognostic value in Acute Myeloid Leukemia (AML). MRD, when used as early treatment response assessment, allows identification of true low-risk and high-risk patients, who may profit alternative chemotherapy approach. In the present retrospective study, we evaluated the impact of MRD assessed by 4-color flow cytometry and WT1 RQ-PCR gene expression in a cohort of AML patients treated at our institution. Methods.Bone marrow samples of 50 adult AML patients (45 de novo and 5 secondary) with available karyotype (K), FLT3-ITD and NPM-A genes mutational status were assessed for MRD after induction. All included patients had a baseline WT1 expression greater than 1000 copies/Ablx104 (range 1060–346060; lab references for normal values 0–500). Fludarabine-based regimen was used as induction; one course of intermediate dose Ara-C 2g/sqm plus idarubicin, followed by 3 courses of intermediate dose Ara-C (2g/sqm) as further consolidation therapy. WT1 log reduction (DWT1) was used to assess the WT1 clearance (DWT1 = logWT1diagnosis – logWT1 post induction). A positive flow MRD was defined by the presence of no less than 25 clustered leukemic cells/105 total events - threshold of 2.5 × 10−4 residual leukemic cells. In patients submitted to bone marrow transplantation (BMT) only the first consolidation course was administered and disease free survival (DFS) was censored at the date of BMT. Results.Two (4%) patients had favorable, 40 (80%) intermediate, and 5 (10%) poor risk K (3 had no metaphases); 14 (28/%) carried FLT3-ITD mutation: among them 8 carried NPM-A mutation too, while 6 were wild type. After the first induction regimen 42 of 50 (84%) patients achieved a complete remission (CR). Patients with a negative flow MRD (32%) had 3 years DFS of 69.5%, whereas those with a positive flow MRD (68%) had a DFS of 27.3% (p = 0.032). Patients with a DWT1 > 1.5 log (65%) had a 3-years DFS of 58.3%, whereas those with a DWT1 ≤ 1.5 log (35%) had a DFS at 1 and 2-years of 13,5% and 0%, respectively (p < 0.001). All patients with a negative flow MRD had also a DWT1 > 1.5 log, whereas 12 (52%) of those who achieved a DWT1 > 1.5 log were still positive by flow MRD. Fourteen (28%) patients with a high risk (HR) profile at diagnosis (poor risk K, intermediate K with FLT3-ITDpos/NPM-Aneg, AML secondary to therapy or previous haematological disorder), 6 were no responder to induction, whereas no one of 8 patients in CR reached a negative MRD status in both test with a very poor outcome (projected DFS 4.8 months). MRD assessment using both flow and DWT1 allow to discriminate no-HR profile patients in three prognostic group: good (flow MRD neg) intermediate (flow MRD pos and DWT1 > 1.5 log) and adverse prognosis (flow MRD pos and DWT1 ≤ 1.5 log) with a projected DFS of 70.5 months, 38.2 months and 4.2 months, respectively (p < 0.001). Conclusions.DWT1 identified patients who would relapse better than flow, whereas a negative flow MRD was the best predictor of long DFS. Using both test in combination with baseline biologic parameters enabled the definition of discrete prognostic categories (Fig 1). Outcome of patients with DWT1 ≤ 1.5 log was very poor and comparable with that of patients with HR profile at diagnosis. In these patients forecast a cure is very difficult with the current treatment option and clinical trials with new drugs should be used already in up-front setting. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Multicenter Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm

AbstractAbstract 3594 Background:Several regimens composed of clofarabine and cytarabine have exhibited efficacy for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) (Faderl et al Blood 2005, 2006, 2008). Clofarabine's ability to increase araCTP formation and inhibit ribonucleotide reductase confer potent anti-leukemic effect. We previously reported the results of an induction regimen consisting of G-CSF priming, clofarabine, and high dose cytarabine for relapsed/refractory AML (GCLAC) (Becker et al Br J Haematol 2011), which resulted in a complete remission (CR) rate of 46% overall, and a CR rate of 50% in patients with poor risk cytogenetics. Furthermore, we demonstrated that GCLAC is superior to fludarabine/cytarabine combinations in the relapsed/refractory setting (retrospective comparison; Becker et al Haematologica Epub ahead of print, 2012). Because of its activity as a salvage regimen, we examined the response rate and toxicity of GCLAC in the upfront setting. Methods:A multicenter clinical trial (NCT01101880) of G-CSF priming, clofarabine, and high dose cytarabine enrolled newly diagnosed patients < 65 years old with acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN) from September 2010 through May 2012. The GCLAC regimen consists of G-CSF 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy until neutrophil recovery, clofarabine 30 mg/m2/day × 5, and cytarabine 2 gm/m2/day × 5. A second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine 25 mg/m2/day days 1–4, cytarabine 2 gm/m2/day days 1–4, and G-CSF days 0–4. Results:Fifty patients with non-APL AML, RAEB2, or myelofibrosis with >10% blasts were treated. The median age was 53, range 22–64. Twenty-one of the patients (42%) had antecedent hematologic disorders or proliferative/dysplastic disorders with ≥10% blasts or secondary leukemia. Twelve patients (24%) had unfavorable, 32 patients (64%) intermediate, and 4 (8%) favorable cytogenetics. Overall, 37 patients (74%) achieved complete remission (CR; 95% CI 62–86%), 40 (80%) CR + CRp (CR with incomplete platelet recovery). Of these remissions, 5CRs and 1 CRp had been attained after a second induction course in 11 patients. Thirty-four patients received one, 20 two, and 11 three cycles of consolidation treatment. The CR rate was 83% for patients without antecedent hematological disorder (AHD), and 57% for those with AHD. The CR rate was 100% for patients with favorable risk, 84% for those with intermediate risk, and 46% for those with unfavorable risk cytogenetics. The median time to neutrophil recovery (>500/μl) was 19 days (13–35 range) and to platelet recovery >100,000/μl 24 days (16–63 range) after induction. The most significant grade 4 toxicity occurring in 3 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids, and was rarely seen when patients were premedicated with steroids. Out of the 125 cycles of chemotherapy administered, the most frequent grade 3 adverse events (AEs) were pulmonary (11), bacteremia (22), and transaminase elevation (10). There were 11 grade 4 AEs including pulmonary (5), hyperglycemia (2), transaminase elevation (1), acute cholecystits (1), and septic shock (2). The 30 day mortality was 0%. Conclusion:GCLAC is a well tolerated induction regimen and a comparison with 7+3 is in progress, using data from Southwest Oncology Group (SWOG) and the Fred Hutchinson Cancer Research Center (FHCRC). Disclosures:Becker:Sanofi: Research Funding. Off Label Use: Clofarabine is indicated for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia.

Favorable Outcome of Children with Acute Megakaryoblastic Leukemia Treated with the AIEOP AML 2002/01 Protocol

AbstractAbstract ▪3586▪This icon denotes a clinically relevant abstract Introduction:Acute megakaryoblastic leukemia (AMKL) is a biologically heterogeneous variant of acute myeloid leukemia (AML), known as AML-M7 according to the FAB classification. The incidence of AML-M7 among pediatric AML in previously published studies ranged between 7 and 15% of the whole number. Differently from children with Down Syndrome (DS)-AMKL who have an excellent outcome with specifically designed, low-intensity chemotherapy, some studies have reported that the outcome of children with non-DS-AMKL is poor (Ribeiro et al, 1993; Athale et al, 2001). We analyzed the clinical/biological characteristics and outcome of children with non-DS-AMKL treated with the AIEOP AML 2002/01 Protocol. Patients and Methods:Between 12/2002 and 06/2011, 44 patients (pts) were included in the analysis. They were assigned to the high-risk (HR) group. Treatment was administered as follows: pts were given 2 courses of 7-day induction therapy (idarubicin, cytarabine and etoposide); if they obtained first complete remission (CR1), they proceeded to receive 2 consolidation courses based on high-dose cytarabine (HD-Ara-c), combined with either etoposide during the first course (AVE 3+4) or mitoxantrone during the second course (HAM 3+2). At the end of consolidation, pts with AMKL in CR1 were eligible to be treated with allogeneic (ALLO) HSCT from a HLA-identical relative, if available, or from alternative donors, namely unrelated donors or HLA-mismatched relatives. We analyzed CR, early death (ED) and induction failure (IF) rate of pts with AMKL; moreover, we calculated the cumulative incidence of relapse and the probability of both overall survival (OS) and event-free survival (EFS). Results:AMKL was diagnosed in 44 of 482 (9.1%) children and adolescents below 18 years of age without DS enrolled in the AIEOP AML 2002/01 protocol. Twenty-one pts were males and 23 females. Median age at diagnosis was 1.6 years (range 0.3–15), with 12/44 (27%) pts aged < 1 year. The median count of white blood cells (WBC) at diagnosis was 18,910×103/ml (range 2,490–59,000). Involvement of central nervous system (CNS) at diagnosis was documented in 5/44 (11%), whereas extramedullary disease in sites other than CNS was found in 3/44 pts (7%). Cytogenetic results were available in 34/44 (77%) pts; they showed t(1;22)(p13;q13) in 3/34 (9%) pts, either as sole abnormality or together with other numerical and structural changes and 11q23 rearrangements in 4/34 (12%). Complex karyotype was present in 5/34 (15%) pts. Three out of 44 pts (7%) showed FLT3-ITD mutation. The induction treatment outcome of pts with AMKL was as follows: the CR rate was 86%, while ED and IF rates were 5% and 9%, respectively. The cumulative incidence of leukemia recurrence was 27% [standard error (SE) 8.7]. Thirty out of 44 pts with AMKL (68%) received an ALLO HSCT in first CR. With a median follow up of 57 months (range 3–130), the 8-year OS and EFS of AMKL were 58.4% (SE 7.9) and 55.6% (SE 7.7), respectively, these values being similar to those of children with other variants of AML. Conclusions:Although AMKL is generally considered an AML variant characterized by a poor prognosis, our data indicate that an intensive treatment strategy including a wide use of HSCT in first CR results in a favorable outcome, more than 50% of pts being alive and disease-free. The main cause of treatment failure remains leukemia recurrence; once relapsed, children with AMKL have a dismal probability of being rescued by second-line treatment. Overall, our results compare favorably with previously published data on AMKL, including those recently reported by Rubnitz et al (Lancet Oncol 2010;11:543–52). Disclosures:No relevant conflicts of interest to declare.

Attempts to Optimize Post-Induction Treatment in Childhood Acute Myeloid Leukemia without Core Binding Factors: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract ▪3545▪This icon denotes a clinically relevant abstract Background:With intensive chemotherapy and optimal risk stratification, 80–90 % of children with acute myeloid leukemia (AML) achieve complete remission (CR) which translates into a long-term disease-free survival in as many as 50–60% of patients. We have previously reported that risk stratified therapy and intensive use of cytarabine improved the outcome of childhood AML in AML99 study with 5-year event free survival (EFS) of 61.6% and 5-year overall survival (OS) of 75.6% (Tsukimoto I. J Clin Oncol 2009;27:4007–13), which gave us an additional impetus to reduce the number of consolidation courses with more restrictive indication for stem cell transplantation (SCT). We here report the outcome of successor nation-wide multi-institutional study AML-05, focusing on the AML patients without core binding factor (CBF). Patients & Methods:47 eligible children (age <18 years) with de novo AML (acute promyelocytic leukemia and Down syndrome patients were excluded). Three patients were excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Low risk (LR) children were defined as those with t(8;21) or inv(16), and good bone marrow response (BMR) to the first induction course. High risk (HR) children were those with abnormalities of monosomy 7, 5q-, t(16;21)(p11;q22), t(9;22), FLT3-ITD, and/or poor BMR to the first induction course. Intermediate risk (IR) children were those who were neither LR or HR group. Only patients assigned to HR were candidate for SCT in first CR in AML-05, whereas patients with IR were also allocated to SCT, if HLA-matched siblings were available in the former AML99. Patients with CR after two courses of induction therapy further received 3 courses of consolidation chemotherapy in AML-05; whereas 4 courses of consolidation therapy were given in AML99. The total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was 375 mg/m2 in the IR/HR chemotherapy both in AML-05 and AML99. Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results:Three-year EFS and 3y-OS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.1 years (range, 0.8 – 5.4 years). Two hundred eighty-nine non-CBF-AML patients [t(9;11), N=39 (13.5%); 11q23, N=27 (9.3%); Normal, N=81 (28.0%); Others, N=137 (47.4%)] in the AML-05 and 151 patients [t(9;11), N=15 (9.9%); 11q23, N=26 (17.2%); Normal, N=53 (35.1%); Others, N=55 (36.4%)] in AML99 were compared. There were no significant differences in basic characteristics such as sex and age/WBC at diagnosis. Incidence of FLT3-ITD in AML-05 cohort were identical to that in AML99 [AML-05 cohort, N= 42/289 (14.5%); AML99, N= 15/82 (18.2%), p=0.41]. CR rate in AML-05 was inferior to that in AML99 (81.0% vs. 90.7%, p = 0.008). There was no significant differences in 3y-EFS of non-CBF AML among 2 cohort [47.5% in AML-05 (95%CI, 41.2– 53.6%) vs. 49.7% in AML99 (41.5 – 57.3%), p= 0.43], however, there was a tendency of lower 3y-OS among them [62.8% in AML-05 (95%CI, 56.2– 68.7%) vs. 70.9% in AML99 (62.9 – 77.4%), p = 0.083]. The early death within 42 days in AML-05 (2.1%) were equivalent to that of AML99 (2.0%), whereas non-relapsed mortality were significantly increased in AML-05 compared with that of AML99 [44/289 (15.2%) in AML-05; 11/151 (7.3%) in AML99, p=0.022], which was due to increased mortality among infants. SCT rate in the 1stCR was lower in the non-CBF AML-05 compared with that in AML99 [47/289 (16.3%) in AML-05; 40/151 (26.4%) in AML99, p=0.011]. Conclusions:Reduction on consolidation chemotherapy courses from four to three, together with incorporation of repetitive cycles of high-dose cytarabine were adequate for non-CBF childhood AML, and did not compromise the treatment results in AML-05 despite of adaptation of more restrictive indication for SCT in 1st CR. Non-CBF-AML is a cytogenetically heterogeneous disease, hence the mechanism underlying these prognostic differences should be studied. Disclosures:No relevant conflicts of interest to declare.

Minimal Residual Disease Assessed by WT1 Expression and NPM1 Mutations Specific RQ-PCR Assays Identifies Patients with Distinct Outcomes in the ALFA 0701 Trial and Is Decreased by Treatment with Gemtuzumab Ozogamicin

AbstractAbstract ▪659▪This icon denotes a clinically relevant abstract Background:NPM1 mutations and WT1 expression are frequently identified in acute myeloid leukemia (AML). Both markers have been reported as suitable molecular target for minimal residual disease (MRD) monitoring. Recently, Gemtuzumab Ozogamicin (GO) has been shown to improve event free survival and overall survival in adult AML. Aims:To follow MRD in AML patients with NPM1 mutations (NPM1mut) and/or WT1 expression (WT1+) and treated in the randomized ALFA 0701 GO trial conducted by the Acute Leukemia French Association (Castaigne et al, Lancet 2012), in order to validate their prognostic significance and to evaluate the effect of GO on MRD response. Methods:The ALFA 0701 trial included 278 patients aged 50–70 years with newly-diagnosed de novo AML, randomized to receive or not five doses of 3 mg/m2 GO, on day 1, 4 and 7 of standard induction chemotherapy and on day 1 of two consolidation chemotherapy courses, respectively. A total of 77 NPM1mut (35 in control arm, 42 in GO arm) and 178 WT1+ (87 in control arm, 91 in GO arm) AML patients were studied. WT1 + at diagnosis was defined as a ratio WT1/ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples. PB and BM samples were collected at diagnosis, after induction and after each consolidation course. MRD levels were assessed using cDNA-based real-time quantitative PCR (RQ-PCR) and reported as the ratio NPM1mut or WT1 transcript/100 ABL transcript. Occurrence of a MRD level below the threshold (NPM1mut <0.1% and WT1 transcript < 0.5% in PB) was defined here as a good MRD response. The prognostic value of MRD was assessed by comparing the outcome of good versus poor MRD responders after induction in terms of cumulative incidence of relapse (CIR) at 18 months. Effect of GO was then evaluated by comparing MRD response in both treatment arms. Results:178 patients (favorable cytogenetics: 4%, intermediate: 69%, unfavorable: 27%) were WT1+. WT1 transcript levels at diagnosis had no prognostic impact on complete remission (CR) rate or CIR. In the 104 patients who achieved CR, post-induction WT1 MRD level was predictive of relapse: 18-month CIR was 70% (95%CI: [49% - 84%]) in poor responders (n=31) versus 38% [26% - 50%] in good responders (n=73) (p=0.0001). When adjusted on cytogenetics, randomization arm and FLT3-ITD status, WT1 MRD remained independently associated with relapse (HR: 2.43, [1.25 – 4.75], p=0.009).Similarly, NPM1mut transcript levels at diagnosis had no prognostic impact on CR rate or CIR. Among the 67 NPM1mut patients who achieved CR, post-induction NPM1mut MRD level was predictive of relapse: 18-month CIR was 64% [45% – 70%] in poor responders (n=50) versus 25% [10% – 42%] in good responders (n=17) (p=0.0007). When adjusted on randomization arm and FLT3-ITD status, NPM1 MRD remained independently associated with relapse (HR: 4.2, [1.2 – 14.3], p=0.02).We were able to evaluate both MRD markers in 53 patients after induction (NPM1+/WT1+ n=16, NPM1+/WT1- n=24, NPM1-/WT1- n= 13). 18-month CIR was significantly different in the 3 groups (respectively 69% [38% - 87%], 40% [19% - 60%] and 25% [5% - 51%], p=0.008). In patients with poor MRD response assessed by NPM1mut, the presence of a positive WT1 MRD level was associated with a higher CIR.NPM1 MRD good response was more frequently observed in GO arm as compared to control arm (OR: 4.38 [2.12 – 9.03], p<0.0001). The rate of good NPM1 MRD response was 41% versus 7% after induction, 76% versus 35% and 93% versus 62% after first and second consolidation in GO and control arms respectively. WT1 MRD good response was more frequently observed in GO arm, although not reaching statistical significance (OR: 1.84 [0.89 – 3.77] p=0.098). The rate of good WT1 MRD response was 76% versus 65% after induction, 87% versus 66% and 87% versus 80% after first and second consolidation, respectively in GO and in control arms (figure 1). Conclusion:Our study confirms the predictive value of MRD based on NPM1 mutations and WT1 expression in patients treated in the ALFA 0701 randomized trial. In multivariate analysis, WT1 and NPM1 MRD levels remained independent prognostic factors for relapse. We showed that treatment with GO significantly improved MRD response in adult AML. [Display omitted] Disclosures:Castaigne:Wyeth: Consultancy.

Intensive Chemotherapy Does Not Prolong Survival Compared to 5-Azacitidine in Patients Aged 70 Years or More with Untreated Acute Myeloid Leukemia

AbstractAbstract 3596Intensive chemotherapy (IC) is associated with significant mortality and morbidity in elderly with acute myeloid leukemia (AML); particularly in patients aged ≥ 70 years, it is currently debated whether or not to deliver IC. Recent findings suggest that hypomethylating agents have encouraging clinical and biological activity in AML, with limited toxicity. Based on this background we wanted to evaluate retrospectively: 1) the efficacy of azacitidine (AZA) in elderly patients with untreated AML, diagnosed according to WHO criteria; 2) the impact of AZA on overall survival (OS) of this category of patients. For comparative purposes a historical group of matched patients who received IC was also analyzed. The AZA group included 57 patients, median age was 76 yrs (range 63–88) with 91% (52) of the patients being 70 yrs old or more, 32 were males and 25 females. Forty-two (78%) had a white blood cell count (WBCc) < 10×109/L, 17 (30%) a secondary AML supervening after an antecedent hematological disorder and 28 (49%) a bone marrow (BM) blast count < 30%. Karyotype was evaluable in 38 (67%) patients and, according to the refined Medical Research Council criteria, 27 (47%) had intermediate-risk abnormalities (25 normal karyotype) and 11 (20%) an unfavorable risk karyotype. A diagnosis of AML according to WHO classification, absence of uncontrolled infections, adequate renal and hepatic function, life expectancy longer than 4 months were the criteria to receive AZA. IC historical control group consisted in 83 patients enrolled sequentially in the AML13 and AML17 EORTC/GIMEMA protocols between 1995 and 2008. In these prospective trials patients aged 61–80 years received an induction course consisting in mitoxantrone, cytarabine (ARA-C), and etoposide (ICE) followed by 2 consolidation cycles including idarubicin, ARA-C, and etoposide (mini-ICE). In AML17 trial, the patients were also randomized to receive or not gemtuzumab ozogamicin, during induction and consolidation courses. Median age was 67 yrs (range 61–78) with 34% (28) of the patients being 70 years old or more, 47 were males and 36 females; 43 (52%) had a WBCc < 10×109/L and 79 (95%) a BM blast count ≥ 30%. Karyotype was evaluable in 65 (78%) patients: 52 (63%) belonged to the intermediate category (43 normal karyotype), 2 (2%) and 11 (13%) carried a favorable and unfavorable risk karyotype, respectively. Thirty-nine patients (68%) received AZA subcutaneously at the conventional dose of 75 mg/m2, the remaining 18 at a flat dose of 100 mg daily; all patients were given a schedule of 7 consecutive days per month. The median number of cycles delivered was 6 (range 1–39) and 77% of the patients received at least 4 cycles of therapy. Median follow up was 244 days (range 30–1281). Overall response rate, estimated according to the revised recommendation of the International Working Group in AML, was 17% and consisted in 11 (8%) complete remission (CR), 4 (3%) CR with incomplete blood count recovery (CRi) and 9 (6%) partial remission (PR). The chance of obtaining a response to AZA was significantly associated with a WBCc < 10×109/L (p=0.002). The median duration of response was 183 days (range 60–1067). Projected 2-years OS for patients on AZA treatment vs IC was 14% and 38%, respectively (p=0.008). Since the median age of the AZA group was 76 years, we broke down the analysis focusing on patients aged 70 years or more. By doing so, we observed that the projected 2-years OS for patients receiving AZA vs those receiving IC was 12% and 28%, respectively (p=0.11). Finally, among the category of patients aged ≥ 70 yrs, we extrapolated those who achieved a response with AZA (22 patients) or IC (22 patients); for these individuals, 2-years OS rate was 25% and 36%, respectively (p=0.46). In conclusion, our retrospective analysis suggests that in AML patients aged ≥ 70 yrs and with a WBCc < 10×109/L, AZA is as effective as IC and could be considered a valid therapeutic option. In this context, the manageable and limited toxicity of AZA will also allow for the quality of life objective to be accomplished. Patients aged < 70 yrs or those who, whatever the age, have a WBCc ≥ 10×109/L are likely to benefit more from IC than AZA. Controlled, randomized, clinical trials are warranted to further explore this matter and confirm our conclusions. Disclosures:No relevant conflicts of interest to declare.

CPX-351 Is Effective in Newly Diagnosed Older Patients with AML and with Multiple Risk Factors

AbstractAbstract 3626 Background:CPX-351 is a liposomal formulation of cytarabine (Ara-C) and daunorubicin (DNR) in a 5:1 molar ratio designed to maximize anti-tumor synergy. CPX-351 accumulates within bone marrow with preferential uptake of liposomes by leukemia cells followed by intracellular release of encapsulated drug. A Phase 2b study randomized untreated older patients with AML 2:1 to CPX-351 or standard 7+3. At entry patients were stratified by age, cytogenetics, and presence or absence of antecedent hematologic disorder (AHD)/prior cytotoxic treatment that evolved into AML (sAML) into a high-risk group (age ≥70 or adverse cytogenetics or sAML) or standard-risk group (age 60–69 and non-adverse cytogenetics and de novo AML). The standard-risk group was relatively homogeneous, while the high-risk group gathered together patients with one, two or all three risk factors. Response after CPX-351 was increased in all patients (66.7% vs. 51.2%). Patients with secondary AML had coherent improvement in survival (HR=0.40, p=0.01), EFS (HR=0.51, p=0.04), and CR + CRi rate (57.6% vs. 31.6%). This report presents the results of uni/multivariate analyses for survival and event free survival. Methods:Untreated de novo or sAML patients, aged 60–75, PS= 0–2, serum creatinine < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 × ULN, and LVEF ≥50% were eligible. Patients with history of treatment for their AHD were eligible. Patients received up to 2 induction and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or 7+3 (Ara-C= 100 mg/m2/d and DNR= 60 mg/m2). Consolidation with hematopoietic stem cell transplantation (HSCT) was permitted. The primary endpoint was CR + CRi rate. Event free survival was calculated from randomization to the date of documentation of persistent leukemia after induction, relapse after achievement of response, or death, whichever occurred first. Allogeneic transplants were permitted for post remission treatment. The association between baseline characteristics and survival was assessed by univariate and multivariate Cox regression analyses. Response was included as a time-dependent variable. The multivariate model used stepwise selection to identify prognostic factors after accounting for potential treatment effects. Results:Significant factors affecting overall survival (OS) in the univariate analysis included: response (p=0.01), ≥2 risk factors (p=0.013), secondary AML (p=0.021), and adverse cytogenetics (p=0.038). After accounting for treatment, response (p=0.003) and ≥2 risk factors (p=0.005) were strongly associated with OS in the multivariate model.Table:Comparison of Response, 60-day Mortality, Median EFS, and Median OS Among Patients with 2 or more of Risk Factors2 or 3 Risk FactorsCPX-3517+3n2615No. w/Risk Factor (%)223 (88.5)12 (80.0)33 (11.5)3 (20.0)CR Rate (%)11 (42.3)4 (26.7)CRi Rate (%)7 (26.9)0CR + CRi Rate (%)18 (69.2)4 (26.7)60-day Mortality Rate (%)1 (3.8)6 (40.0)Median EFS (mos.)9.11.1Median OS (mos.)10.76.1Response and 60-day deaths were similar in both study arms for patients with 0 or 1 risk factor. Patients with 2 or 3 risk factors treated with CPX-351 had rates of response and 60-day death rates that were similar to those with only 0 or 1 risk factor. Control arm patients with multiple risk factors did much worse, with fewer CRs, no CRi's, and a substantially higher rate of early deaths. Conclusions:CPX-351 is highly active in every subgroup of older patients with newly diagnosed AML. This analysis demonstrates that CPX-351 minimizes the loss of response and increase in 60-day mortality that occurs with 7+3 treatment among patients with secondary AML and adverse cytogenetics. The relative benefit of CPX-351 is greatest among patients with ≥ 2 risk factors. Disclosures:Lancet:Celator Pharmaceuticals: Research Funding. Cortes:Celator Pharmaceuticals: Research Funding. Kovacsovics:Celator Pharmaceuticals: Research Funding. Hogge:Celator Pharmaceuticals: Research Funding. Kolitz:Celator Pharmaceuticals: Research Funding. Hoering:Celator Pharmaceuticals: Consultancy. Chiarella:Celator Pharmaceuticals: Employment. Louie:Celator Pharmaceuticals: Employment. Feldman:Celator Pharmaceuticals: Research Funding.

Comparable Toxicity and Outcome of Acute Myeloid Leukemia (AML) Fit Patients Therapy Independently If Daunorubicin or Idarubicin Were Added to Cytarabine/Cladribine Induction Regimens – the Single Centre Study

AbstractAbstract 4337This trial is a continuation of the earlier studies concerning optimalization of induction chemotherapy in acute myeloid (AML) patients using purine analogues (Ho≥owiecki J., Grosicki S., Robak T. et al. Leukemia 2004, Holowiecki J, Grosicki S, Giebel S. et al. J Clin Oncol. 2012).The goal of the study was to evaluate the toxicity and efficacy of combination including idarubicin – IAC (idarubicin 10 mg/m2/d iv, d 1–3; cytarabine 200 mg/m2/d ci, d 1–7, cladribine 5 mg/m2/d d 1–5) in comparison with DAC (daunorubicin 60 mg/m2/d iv d 1–3 in place of idarubicin).The primary endpoints were complete remission rate (CR) and toxicity, the secondary one was overall survival (OS).Patients who achieved CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study.Between 03.2009 and 03.2012, 52 adult untreated patients aged median 57 years (20–72), treated in one center - Department of Hematology of City Hospital in Chorzow/Poland were included to this study; 46% of study participants were male, 54% female and they were evaluated as fit with possibility of intensive chemotherapy including HSCT. PML/RAR alfa positive – FAB M3 cases were excluded.DAC regimen was a standard induction in this group of AML patients. When there was no possibility to apply DAC regimen because of not having access to daunorubicin in our center, the IAC regimen was used.Material and the results are summarized in the table.OutcomeDAC (n = 30)IAC (n = 22)pAge (median)20–72 (55)38–70 (59)NSSex (%)K-53, M-47K-55, M-45NSWBC at dgn. × 103/L median (range)27,7 (2,3–257)11,0 (0,9–210)NSCytogenetic risk (%)Low00NSintermediate5064NSHigh75NSNo data4331NSHSCT (n) auto/allo2/71/5NSCR rate (%)7059NS3-yr OS (%)2623NS2-yr LFS (%)2836NSThe study groups were well balanced with respect to age, sex, WBC and cytogenetics. The entire CR rates in both groups did not differ, and they were similar to previously published results after DAC induction regimen. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. There were no significant differences in the OS and LFS rates.In conclusion, the results of our study authorize the replacement of daunorubicin to idarubicin in DAC induction regimen without risk of additional toxicity, and with similar outcome. Disclosures:No relevant conflicts of interest to declare.

Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial

AbstractThe clinical value of serial minimal residual disease (MRD) monitoring in core binding factor (CBF) acute myeloid leukemia (AML) by quantitative RT-PCR was prospectively assessed in 278 patients [163 with t(8;21) and 115 with inv(16)] entered in the United Kingdom MRC AML 15 trial. CBF transcripts were normalized to 105ABL copies. At remission, after course 1 induction chemotherapy, a > 3 log reduction in RUNX1-RUNX1T1 transcripts in BM in t(8;21) patients and a > 10 CBFB-MYH11 copy number in peripheral blood (PB) in inv(16) patients were the most useful prognostic variables for relapse risk on multivariate analysis. MRD levels after consolidation (course 3) were also informative. During follow-up, cut-off MRD thresholds in BM and PB associated with a 100% relapse rate were identified: for t(8;21) patients BM > 500 copies, PB > 100 copies; for inv(16) patients, BM > 50 copies and PB > 10 copies. Rising MRD levels on serial monitoring accurately predicted hematologic relapse. During follow-up, PB sampling was equally informative as BM for MRD detection. We conclude that MRD monitoring by quantitative RT-PCR at specific time points in CBF AML allows identification of patients at high risk of relapse and could now be incorporated in clinical trials to evaluate the role of risk directed/preemptive therapy.

Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup

Identifying true therapeutic progress in patients with acute myeloid leukemia (AML) requires a comparison of treatment strategies and results on the basis of uniform patient selection. To foster comparability across five clinical studies, we introduced a common standard arm combined with a general upfront randomization and performed prospective analyses with adjustment for differences in prognostic baseline characteristics. Whereas the studies' own regimens differed in chemotherapies, risk adaption, and guidelines for allogeneic stem-cell transplantation, the standard arm contained uniform cytarabine- and anthracycline-based standard-dose remission induction and high-dose consolidation courses. Of 2,995 evaluable patients aged 16 to 60 years, 290 patients were randomly assigned to the common standard arm. Seventy percent of the 290 achieved complete remissions (62% with complete recovery, 8% with incomplete recovery; 95% CI, 65% to 76%). Five-year survival probabilities were 44.3% (95% CI, 37.7% to 50.7%) for overall survival, 44.8% (95% CI, 37.0% to 52.2%) for relapse-free survival, and 31.5% (95% CI, 25.7% to 37.4%) for event-free survival. Neither the unadjusted survival probabilities of the Kaplan-Meier method nor their adjustment for prognostic variables in multiple Cox regression models led to statistically significant different results in the three survival end points when the outcomes of each study were compared with the standard arm. A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared through a common standard treatment arm. The results provide a representative basis for further therapeutic approaches.

Disseminated Langerhans cell histiocytosis associated with acute myeloid leukaemia: complete remission with daunorubicin and cytarabine

Dear Editor, A 68-year-old man presented with cervical lymphadenopathy and bilateral tonsillar enlargement and ulcerations. Computed tomography (CT) showed an infiltrative disease (Fig. 1a, arrow). A blood count showed haemoglobin, 13.1 g/dL; leucocytes, 41.9 × 109/L (89 % blasts); and platelets, 48 × 109/L. Bone marrow examination confirmed acute myeloid leukaemia (AML) without maturation (Fig. 1b). Cytogenetic analysis showed 46,XY,t(7;14)(p13;q32), the significance of which was unknown. NPM1 and FLT3 genes were wild type. Unexpectedly, a biopsy of the tonsillar mass showed infiltration by medium-sized atypical cells with indistinct cytoplasmic borders (Fig. 1c) and irregular and grooved nuclei (insert). These atypical cells were positive for CD1a (Fig. 1d) and S100 (Fig. 1e). Myeloblasts were not evident. Pathological features were consistent with Langerhans cell histiocytosis (LCH). Marrow trephine biopsy showed myeloblasts intermixed with numerous atypical cells (Fig. 1f), which were also S100 positive (Fig. 1g). The overall diagnosis was therefore consistent with concomitant disseminated LCH and AML. As leukaemia treatment was more urgent, a standard AML regimen of daunorubicin (60 mg/m2/day × 3 days) and cytarabine (100 mg/m2/day × 7 days) was administered. Interestingly, the tonsillar masses and cervical lymphadenopathy subsided, and a day-22 marrow examination showed complete remission of AML and LCH. A positron emission tomography/CT (PET/CT) also confirmed complete response of the LCH. Two consolidation courses of high-dose cytarabine have since been given, with the patient remaining in CR 6 months after diagnosis. Fig. 1 Concomitant disseminated Langerhans cell histiocytosis and acute myeloid leukaemia. a Computed tomography showing bilaterally enlarged tonsils, more prominent on the left side (arrow). b Marrow aspirate showing predominance of myeloblasts. c Tonsillar ... LCH in association with leukaemia occurs mainly in two clinical patterns: LCH preceded by acute lymphoblastic leukaemia (pathogenesis undefined) and LCH treated by etoposide/vinblastine followed by therapy-related AML [1]. Concomitant LCH and AML have very rarely been reported [2,3]. Two explanations for this extraordinary phenomenon have been proposed: LCH and AML deriving from the same neoplastic precursors or LCH being reactive to the AML [1–3]. In our patient, the LCH was infiltrative with marrow metastasis, supporting that it was neoplastic. In addition to its diagnostic interest, this case had therapeutic implication. The optimal treatment of disseminated LCH remains undefined. The use of vinblastine, etoposide, 2-chlorodeoxyadenosine, cyclophosphamide and cytarabine has been described [4]. Anthracyclines have apparently not been studied before. Our case showed fortuitously that a standard daunorubicin/cytarabine regimen was highly effective in inducing a remission for disseminated LCH, an observation that requires further validation.

Initial salvage therapy in first relapse AML: A phase IIb study of CPX-351 versus investigator’s choice—A subset analysis by prognostic group.

6525 Background: CPX-351 encapsulates cytarabine and daunorubicin within liposomes at a 5:1 molar ratio, shown in vitro to maximize synergy. Liposomal encapsulation enables preferential uptake of drug within leukemic blasts followed by intracellular release enhancing efficacy in AML. A randomized Phase 2b study in 1st relapse AML completed 1-year follow up with improvement in event free (EFS) and overall survival (OS). This report describes patient outcomes with a focus on the unfavorable subset per the European Prognostic Index (EPI) (Breems DA, et al. J Clin Oncol, 2005 Mar 20;23:1969-1978). Methods: Patients (pts) ≤65yo in 1st relapse AML after an initial CR &gt;1 month, ECOG PS= 0-2, serum creatinine&lt; 2.0 mg/dL, total bilirubin &lt; 2.0 mg/dL, ALT/AST &lt; 3 x ULN, and LVEF &gt;50% were eligible. Pts with APL, daunorubicin exposure &gt;368 mg/m2 (or other anthracycline equivalent), active CNS leukemia, uncontrolled infections were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or investigators choice of intensive salvage treatment. Post remission allo-transplantation was permitted. 126 pts were stratified by EPI into favorable, intermediate, and unfavorable groups (with projected 1-year OS of 70%, 49%, and 16%). The primary efficacy endpoint was % survival at 1-year. Results: CPX-351 increased the rate of morphologic leukemia-free state (77% vs. 60%), the rate of CR + CRi (51% vs. 41%), and the median EFS (4.0 vs. 1.4 mo) and OS (8.5 vs. 6.3 mo) in the overall patient population. Significant survival improvement occurred amongst those with unfavorable EPI scores (HR=0.55, p-value=0.02) with improved 1-year survival (29% vs. 10%). CPX-351 treatment resulted in more prolonged cytopenias with increased febrile neutropenia and grade 3-4 infections, but not in the D 60 mortality (overall: 15% vs. 16%; unfavorable: 16% vs. 24%). Conclusions: CPX-351 is highly active in AML and induces remission even in patients with prior cytarabine and anthracycline exposure. Efficacy was evident in every prognostic group, particularly in the unfavorable EPI group where a statistically significant improvement in 1-year survival was observed.

Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients

Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤ 1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥ 60 years) patients with relapsed AML with low cardiac toxicity. This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives. One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease. The study did not show significant superiority of 7+GO over standard 7+3.

Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups

SummaryThe most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group.

Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study

AbstractThe LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients. This study was registered at clinicaltrials.gov as no. NCT01015196.

Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia

ObjectiveMethotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. MethodsFrom 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. ResultsIn 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). ConclusionsRelapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings.