Abstract 2154
Myeloid Sarcoma (MS) is defined as an extramedullary mass composed of myeloid blasts occurring at an anatomical site other than the bone marrow. Furthermore, the term extramedullary ...manifestation (EM) is applied if it accompanies overt acute myeloid leukemia (AML) and represents non-effacing tissue infiltration. EM is reported to correspond often to the skin but can affect almost every site of the body. The prognosis of MS or EM has been discussed controversially in the past. EM at diagnosis of AML is generally thought to be a rare event. However, data defining the prevalence of EM at diagnosis of AML and its prognostic value are missing. The aim of this analysis was to provide data for estimating the prevalence of EM at diagnosis of AML and to determine its relevance by including clinical and laboratory data from patients being treated in the prospective AML96 trial of the Study Alliance Leukemia (SAL) study group.
A total of 326 patients with AML (age 17 – 83 years) and EM were treated within the AML96 trial with a median follow up of 8.8 years (95% CI, 8.4 to 9.3 years). All patients received double induction chemotherapy. Consolidation therapy contained high-dose cytosine arabinoside and for patients ≤ 60 years of age the option of autologous or allogeneic hematopoietic stem cell transplantation (HSCT). Logistic regression analyses were used to identify prognostic variables for CR rates. The method of Kaplan-Meier was used to estimate OS and EFS. Confidence interval (CI) estimation for the survival curves was based on the cumulative hazard function using the Greenwood's formula for the SE estimation. Survival distributions were compared using the log rank test.
17% of the AML patients entered into the AML96 trial were diagnosed with EM. In 313 of the 326 patients (96%) EM was evident at diagnosis. The majority of patients with EM were diagnosed with de novo AML (84%, n=273), whereas gingival infiltration (51%, n=166) displayed the main EM of AML with CNS involvement being less common (4%, n=14). The majority of patients had a cytogenetic intermediate risk profile (71%, n=221) with a total of 172 patients (56%) harboring a normal karyotype. Patients with EM had a statistically significant lower median CD34-positivity of bone marrow blasts, higher percentage of FAB subtypes M4 and M5, higher WBC counts and LDH at diagnosis and higher percentage of NPM1 mutations compared to those patients without EM (all p<.001). When comparing achievement of CR between patients with EM to patients without EM, no statistical difference between these two groups was observed. Analysis according to the NPM1/FLT3-ITD mutation status revealed highest 5-year-OS (37%, 95% CI: .24 - .508) and 5-year-EFS (36%, 95% CI: .224 - .448) in the NPM1-mut/FLT3-wt group and lowest 5-year-OS (12%, 95% CI: 0 - .261) and 5-year-EFS (4%, 95% CI: 0 - .124) in the NPM1-wt/FLT3-ITD group, p=.007 and p=.001, respectively. Of the 49 relapsed patients with EM who had a NPM1-mutation at diagnosis 48 deceased despite of intensified relapse therapies.
This analysis represents the largest study so far investigating the impact of EM AML. Patients with EM AML have distinct differences from AML patients without EM regarding their clinical and molecular characteristics at diagnosis. However these differences do not translate into differences in response to induction chemotherapy. Compared to patients without EM, survival analysis revealed differences according to the NPM1/FLT3-ITD mutation status which is also described for patients without EM AML. However, the prognosis for patients with EM who harbor a mutated NPM1 the prognosis at relapse seems to be dismal.
No relevant conflicts of interest to declare.
Abstract 2156
Acute myeloid leukemia (AML) at initial diagnosis or relapse may present with extramedullary (EM) AML. Data on the prevalence of EM AML at diagnosis are scarce and rely mostly on ...retrospective, clinical analyses. However, previous studies attributed EM AML as an impacting prognostic factor in AML. Furthermore, studies have not been carried out so far in order to define the prevalence and the prognostic impact of EM AML at diagnosis prior to initiation of therapy. 18Fluorodesoxy-Glucose Positron Emission Tomography (18FDG-PET) is able to detect highly metabolic tissue and has proven efficacy in imaging studies in various types of malignant diseases. The aim of this pilot study was to perform 18FDG-PET-CT scans on patients with newly diagnosed AML as well as relapsed AML in order to study its feasibility on detection of EM AML.
A total of 15 patients with AML (newly diagnosed AML, n = 10 and relapsed AML, n = 5) had total body 18FDG-PET-CT scans at diagnosis after giving informed consent to the study. Patients were included only if a delay of ≤ 5 days of initiation of induction- or re-induction chemotherapy was necessary to perform the study. 18FDG-PET-CT scans were performed using a Siemens Sensation 16 as part of a biograph with i.v. application of 18FDG (range of activity of 225 to 391 MBq).
A total of 15 patients with newly diagnosed or relapsed AML (age 26 to 80) underwent total body 18FDG-PET-CT imaging prior to initiation of induction- or re-induction therapy. Adverse reactions due to the application of i.v. 18FDG were not observed. A positive 18FDG-PET imaging result detecting an EM manifestation of AML was observed in 8 patients (53%). Sites of EM AML were soft tissue (n=7), mammary gland (n=1), liver (n=1), ovary (n=1), and lymph nodes (n=2). In 6 patients with clinically overt EM AML additional EM manifestations were detected. In 5 patients in whom there was no EM manifestation suspected, 2 had 18FDG-PET positive findings. Finally, most patients with positive 18FDG-PET uptake with either isolated EM or in combination with systemic AML relapsed within a short period of time after initiation of therapy or had a progressive disease despite therapy.
18FDG-PET-CT imaging is a useful tool in order to study EM AML either in combination or as a solitary event without fulfilling the criteria of systemic AML. 18FDG-PET is a feasible and safe imaging procedure and can therefore be performed prior to initiation of chemotherapy without a delay of time. 18FDG-PET might be a diagnostic tool in order to delineate the prevalence of EM AML and to define its impact to the prognosis of AML patients. Future studies to identify the prevalence and define the relevance of imaging studies in order to detect extramedullary AML are necessary.
Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract 1326
Assessment of the individual risk of mortality after allogeneic hematopoietic cell transplantation (HCT) is essential for decision-making and patient counseling. For patients with AML ...several risk factors have been identified, including patient age, comorbidity, unfavorable cytogenetics, prior history of myelodysplasia and the remission status at HCT. The hematopoietic cell transplantation – specific comorbidity index (HCT-CI) has been designed and validated to predict mortality by concurrent disease and organ dysfunction prior to HCT at the Fred Hutchinson Cancer Research Center. Local data-dependence may affect the transportability of a prognostic system. Cross center validation of prognostic systems is therefore essential. In order to check the performance of the HCT-CI for our center, we applied the HCT-CI in a well defined cohort of AML patients. Our unit represents a large German transplant center characterised by referral of a large proportion of elderly patients with advanced myeloid leukemias.
We performed a retrospective cohort analysis in patients with AML according to the WHO definition who were transplanted between January 2000 and December 2008. Second allogeneic HCTs and haploidentical HCTs were excluded. Baseline variables were extracted from the local database by a trained data manager. Supplementary data were collected by comprehensive review of medical records by the investigator. For each patient we assessed the HCT-CI prior to transplant. Overall survival (OS) was estimated using the Kaplan-Meier method. Non-relapse mortality (NRM) was calculated with cumulative incidence statistics. The effect of the HCT-CI on the OS and NRM was analyzed in a multivariate Cox regression model, considering age, Karnofsky score, type of AML, cytogenetic risk (according to the ELN classification), treatment and remission status, sex match, CMV match, donor type, and conditioning intensity.
340 patients were eligible for the analysis. The median age of our patients was 53 years (range, 11 to 76 years). Eighty-six patients (26%) were in CR-1 of standard risk AML and 45 patients (14%) were in CR-1 of high risk AML while the remainder had more advanced disease. The median HCT-CI was 4 (range, 0 to 10). Donors were HLA-identical siblings in 116 patients (34%), matched unrelated donors in 130 patients (38%) and partially matched unrelated donors in 94 patients (28%). Overall survival at 2 years was 41±12%, 49±6% and 49±3% in the low, intermediate and high-risk HCT-CI groups (p=0.7), respectively. The corresponding NRM at 2 years was 33±23%, 26±10% and 23±5% (p=0.6). In multivariate analysis the HCT-CI failed to predict OS and NRM. In multivariate regression modeling neither its inclusion as a categorical variable (low, intermediate or high risk) nor as a numerical variable demonstrated adequate discrimination.
Comparing our population with the original validation cohort of the index hepatic impairment (51% vs. 20%, p=0.06), infection (47% vs. 4%, p=<0.001) and heart valve disease (44% vs. 2%, p=<0.001) were significantly more frequent in our population. These differences led to a statistically highly different distribution among the three HCT-CI risk categories of our patients (5% low risk, 21% intermediate risk, and 74% high risk patients) compared to the Seattle cohort of AML patients (51% low risk, 29% intermediate risk, and 21% high risk patients) (chi square test, p<0.0001). Referring to heart valve disease, we strictly applied the definitions from the original publication and considered even trace or mild regurgitation as heart valve disease. The fact that the resulting frequency of valvular dysfunction in our cohort is within the expected range for elderly patients (∼35% according to the Framingham Heart Study) leads to the suggestion that different working definitions had been applied. However, even after correction of this potential misclassification the modified HCT-CI did not discriminate OS and NRM.
We found no predictive value of the HCT-CI for OS and NRM in our patients. Our results suggest that different working definitions for the assignment of comorbidities had been applied. Refined definitions could therefore help to improve the performance of the index. Until its validity has been shown across different patient populations, its use as decision making tool for transplantation eligibility needs to be reconsidered.
Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract 229▪▪This icon denotes a clinically relevant abstract
The optimal timing of hematopoietic cell transplantation (HCT) in AML and its use in risk groups defined by genetic markers or early ...blast clearance is still under debate. We addressed this question in the AML 2003 study, a large multicenter, randomized, open-label study within the German SAL group. All patients received one cycle of induction therapy (IT) with a 3+7 regimen combining daunorubicin and continuous infusion cytarabine. Upfront cytogenetic and molecular characterization, HLA typing, related donor search and a preliminary search for an unrelated donor were performed for all patients. The subsequent transplant strategy was tailored to the biological risk and donor availability.
Patients aged 18–60 years were randomly assigned upfront 1:1 to either of two transplant strategies: In the control arm allogeneic HCT was scheduled in first complete remission for patients with intermediate risk cytogenetics and an HLA-identical sibling and for patients with a complex karyotype (CK) and a related or unrelated HLA-compatible unrelated donor. In the experimental arm the indication for allogeneic HCT was extended to patients with an FLT3-ITD allelic ratio >0.8 (mutant/wild type), >10% marrow blasts on day 15 after IT1 and patients with adverse karyotypes, including: −7, −5, del(5q), inv(3q), t(3;3), t(6;9), t(6;11), t(11;19)(q23;p13.1). Furthermore, allogeneic HCT was scheduled at an early time-point, i.e. in aplasia after the first or the second cycle of IT in the experimental arm. Patients without an HLA-compatible donor assigned to the transplant strategy were scheduled for high-dose busulfan and cyclophosphamide followed by autologous SCT. Here, we present the final analysis of this study according to the intent-to-treat principle.
Between December, 1, 2003 and November, 26, 2009 1179 patients were randomized between the experimental (N=598) and the control intervention (N=581). The median age was 48 years (range, 18 to 60 years). The distribution of age, ECOG performance status, type of AML, cytogenetic risk groups, NPM1- and FLT3-ITD-mutations, LDH, white blood cell and platelet count was not statistically different between the two treatment arms. However, more males and patients with higher marrow blast counts at diagnosis were randomized to the experimental treatment arm. The median observation time for all patients was 52 months.
The hazard ratio of the treatment effect (experimental versus control) was 0.92 (95% CI, 0.75 to 1.14; p=0.45) for primary endpoint overall survival and 0.85 (95% CI, 0.71 to 1.02; p=0.08) for the secondary endpoint event-free survival. Patients in both arms had an excellent long-term overall survival of 50% (95% CI, 46% to 54%) at 5 years after enrollment in the experimental arm and 47% (95% CI, 42% to 51%) in the control arm (see Figure). Across all risk groups the rate of early allogeneic HCT performed per protocol was 22% in the experimental arm and 8% in the control arm. Among patients with high risk cytogenetics this rate was 48% and 17%, respectively. These numbers point at the difficulty to deliver allogeneic HCT within two months after diagnosis of AML in the context of a multicenter trial. However, since HLA-typing and preliminary donor search was done for all patients and allogeneic HCT was standard for relapsed or refractory AML in both arms, the rates of allogeneic HCT as first post remission therapy or after induction failure/relapse were substantially higher than in previous studies and almost equal in the experimental and control arm (63% versus 56%).
Although a survival benefit by early allogeneic HCT could not be demonstrated in this large randomized study in newly diagnosed AML, the study treatment resulted in excellent overall survival rates in both arms. Relatively small differences between the per-protocol transplantation rates and crossover effects may partially explain why a benefit of early allogeneic HCT could not be demonstrated. Early awareness of donor availability and the option of allogeneic HCT in patients with primary induction failure or AML relapse resulted in a high overall rate of allogeneic transplantation. This may have contributed to the excellent overall survival in both arms. Display omitted
No relevant conflicts of interest to declare.
Abstract ▪921▪This icon denotes a clinically relevant abstract
This 3+3 dose escalation phase I trial by the German MDS study group aimed to determine the dose-limiting toxicity (DLT) and maximum ...tolerated dose (MTD) of sequential azacitidine (AZA) 75 mg/m2 for 5 days followed by 14 days of up to 25 mg lenalidomide (LEN) in patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and del(5q) cytogenetic abnormalities. Twenty patients (median age 69 years) were enrolled, including 16 (80%) with complex cytogenetic abnormalities and 65% of patients harboring at least one TP53 mutation. Nine patients (45%) had no prior treatment while relapse or progression to single agent azacitidine or lenalidomide treatment (30%) and allogeneic HSCT (15%) were the most common regimens among previously treated patients.
Three of 6 patients treated with LEN at the 25 mg dose level experienced DLTs, with 20 mg subsequently identified as MTD. All eligible patients experienced treatment-related Grade 3/4 thrombocytopenia and neutropenia. Hematologic responses occurred in 4 of 9 (44%) previously untreated patients with complex karyotypes, including 3 with a TP53 mutation and were preceded by a significant decrease of del(5q) CD34+ progenitor cells in the blood during cycle 1. In fact, compared with baseline, the percentage of peripheral blood CD34+ cells with del(5q) clone was decreased in the hematologic responders after 1 cycle of azacitidine followed by lenalidomide therapy (P = 0.001) (Figure 1A). In contrast, the percentage of peripheral blood CD34+ cells with del(5q) remained unchanged in hematologic non-responders (Figure 1B). By applying TP53 mutation directed deep-sequencing technology we observed a concomitant early reduction and disappearance of minimal residual disease in MDS patients achieving a complete cytogenetic response. In one patient, a reemergence of the TP53 clone was observed later despite continuation of the treatment but by consolidation (lower dose and every 8 weeks compared to 4 weeks with induction) and it preceded the hematologic and cytogenetic relapse by several months.
In conclusion, in a population of higher-risk MDS/AML patients with del(5q) that included a high proportion of patients with complex karyotypes and mutations of TP53, the sequential combination of azacitidine and lenalidomide was shown to be a feasible and potentially effective treatment strategy, even in those patients with TP53 -mutated clones. We additionally observed a correlation between the percentage of peripheral CD34+ cells with del(5q) and hematologic response, suggesting that monitoring of this cell population may be a surrogate marker of response in this setting. Our results encourage an application of sequential azacitidine and lenalidomide as first line therapy for higher-risk MDS patients in future trials.
Display omitted
Platzbecker:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kuendgen:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Germing:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
Abstract 1481▪▪This icon denotes a clinically relevant abstract
Acute erythroleukemia (AEL) represents a rare type of acute myeloid leukemia accounting for less than 5% of all cases. So far, ...according to WHO classification this AML entity is thought to have a poor prognosis in itself.
3267 patients with newly diagnosed AML were treated according to the protocols of the AML96, AML2003 or AML60+ studies of the Study Alliance Leukemia (SAL). 116 of these patients had acute erythroleukemia (AEL). The median age both for patients with AEL and non-AEL was 57 years.
We assessed the influence of relevant clinical and demographic parameters, FLT3-ITD, NPM1 status and cytogenetics on complete remission rates (CR), overall survival (OS) and event free survival (EFS) separately in AEL and non-AEL patients.
Compared to non-AEL AML, significantly more AEL were due to secondary causes than non-AEL AML (31% versus 20.4%; p=0.024). NPM1 mutations were found in 11.1% (out of 99) of the patients with AEL and in 32.8% (out of 2693) of the patients with non-AEL AML (p<0.001). Surprisingly, both the FLT3-ITD mutation and high FLT3-ITD ratios > 0.8 were found less frequently in AEL (FLT3-ITD mutation in 4.9% vs 23.3%; p=0.001; FLT3-ITD ratio >0.8 in 0% vs. 33.4%; p<0.001).
The cytogenetic aberrations +8, −7 and complex aberrant karyotype (>/= 3 independent aberrations) were found more often in the AEL cohort (14.8%, 10.3% and 26.7%) than in the non-AEL AML cohort (8.9%, 5% and 13.2%) (p=0.036, p= 0.01 and p <0.001, respectively).
Despite these differences, no significant differences in CR rates, OS and EFS were found between both groups. This finding was confirmed in a multivariate analysis including cytogenetics, molecular markers and clinical parameters (LDH, WBC, blast count, platelet count and ECOG). According to the analysis, ALE morphology was not an independent prognostic factor for OS and EFS.
With the AEL group, patients with monosomy 7 (n=12) had a higher median blast count (NEC) of 62% and shorter median OS with 5.7 months compared to patients with AEL and no monosomy 7 (n=104) with a median blast count (NEC) of 43% (p=0.013) and an median OS with 15.7 months (p=0.016).
A complex aberrant karyotype was found more often in patients with secondary AEL than in patients with de novo AEL (p=0.037). Significant differences were also seen in patients with AEL and complex aberrant karyotype compared to AEL without complex aberrant karyotype with respect to CR rates (54.8% versus 77.6%; p=0.016), OS (6.2 versus 17.4 months; p<0.000) and EFS (2.9 versus 6.2 months; p=0.007).
In patients with AEL and abn17p/-17 (n=15), lower median platelet counts (31 versus 48 ×106/μl; p=0.017), a worse OS (6.4 vs 15.7 months; p=0.011) and EFS were observed (1.7 vs 5.7 months; p=0.046).
According to our data, the characteristic morphological features of acute erythroleukemia do not confer an unfavorable prognosis in itself. Furthermore, we can confirm the relevant influence of established prognostic factors such as cytogenetics and disease status within the AEL subgroup.
Off Label Use: sorafenib for the treatment of acute myeloid leukemia.
A fludarabine-based "nonmyeloablative" preparative regimen was investigated in 42 patients with hematological malignancies receiving hematopoietic stem cell grafts from unrelated volunteer donors.
...Recipient conditioning consisted of fludarabine 30 mg/m(2) on days -6 to -2 and i.v. busulfan 3.3 mg/kg on days -6 to -5. Antithymocyte globuline was added at 2.5 mg/kg i.v. on days -5 to -2. The patients were grafted with bone marrow (n = 13) or peripheral blood stem cells either unmanipulated (n = 20) or CD34+ selected (n = 9). Graft-versus-host disease prophylaxis was performed with cyclosporine A (CsA, n = 12), CsA/methotrexate (n = 12), or CsA/mycophenolate mofetil (n = 18).
With a median follow-up of 13 months (range, 5-26 months), the actuarial disease-free survival is 64% and 38% for patients with lymphoid malignancies and standard-risk leukemia compared with only 14% for patients with high-risk disease. The main cause of treatment failure was relapse of disease in high-risk patients (n = 14). An increased incidence of primary (n = 1) or secondary graft-failure (n = 8) was observed (21%). Chimerism analysis of CD56+/CD3--sorted natural killer (NK) cells, available in 10 patients, showed an impaired increase of donor NK cell chimerism between day 10 and 30 after transplantation in three of four patients with graft failure, whereas the percentage of donor NK cells surpassed 75% in all of the six patients with stable engraftment.
Unrelated transplants after dose-reduced conditioning are associated with a higher risk of graft-failure. Pretransplant host immunosuppression has to be optimized to overcome resistance to grafts from unrelated donors after nonmyeloablative conditioning therapy.
Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict ...haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.
The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK–NUP214, RUNX1–RUNX1T1, CBFb–MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1–7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018.
Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44–72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5–22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32–59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82–94; hazard ratio 6·6 95% CI 3·7–11·8, p<0·0001). The most common (grade 3–4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment.
Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.
Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
Zusammenfassung
Im Jahr 1997 wurde durch den Zusammenschluss der führenden Leukämie-Studiengruppen in Deutschland das Kompetenznetz Akute und Chronische Leukämien (KNL) gegründet. Wichtige Resultate ...sind neue Kooperationsstudien und Forschungsprojekte, die Fortführung und Erweiterung bestehender und die Gründung neuer nationaler Studiengruppen, die Verbesserung der Studieninfrastruktur sowie die Einrichtung von Patientenregistern und Biomaterialbanken. 2003 führte das Konzept des KNL zur Gründung des European LeukemiaNet (ELN). In der Folge wurden in internationaler Kooperation zahlreiche europäische Managementleitlinien erarbeitet und mehrere länderübergreifende Projekte und Studien durchgeführt. Ziel des Netzes ist die Heilung der Leukämien durch kooperative Forschung.
Abstract 144▪▪This icon denotes a clinically relevant abstract
Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases, which may play a role in the pathogenesis of ...acute myeloid leukemia (AML). In-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. So far, no randomized-controlled data are available for treatment of newly diagnosed AML patients up to the age of 60 years. We present the first results from the randomized placebo-controlled SORAML trial of the Study Alliance Leukemia (SAL).
Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were: newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3–5 plus cytarabine 100 mg/m2 cont. inf. days 1–7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1–3 plus mitoxantrone 10 mg/m2 days 3–5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a family donor and for all high-risk patients with a matched donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10–19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial is event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the planned interim analysis (intent to treat) after the occurrence of 50% of EFS events. The O’Brien/Fleming adjusted significance level was set at p=0.0052.
Out of 276 randomized patients, 264 were evaluable for EFS, 132 in each arm. Demographic and disease characteristics were equally distributed between the two arms; the FLT3-ITD incidence was 16%. The median cumulative dose of administered study medication was equal in both arms. The CR rates were 56% versus 60% in the placebo versus sorafenib arm (p=0.622). By the time of analysis, a total number of 100 events had occurred. After a median observation time of 18 months, the median EFS was 12.2 months in the placebo arm and was not reached in the sorafenib arm, corresponding to a 1-year EFS of 50% versus 64% (p=0.023). The median OS had not been reached in both arms, the 2-year OS was 66% versus 72% in placebo and sorafenib arms, respectively (p=0.367). The most common reported AEs CTC Grade ≥3 were infectious complications including fever and pneumonia, followed by bleeding events, cardiac and hepatic toxicity, hypertension, skin toxicity and headache. The risk for hepatic toxicity (relative risk 6.2, p=0.025) and bleeding events (relative risk 3.6, p=0.016) was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences.
In younger AML patients, the addition of sorafenib to standard chemotherapy is feasible but associated with a higher risk of liver toxicity and bleeding events. Sorafenib treatment resulted in a marked EFS prolongation; this difference is not significant according to the adjusted significance level of this interim analysis. Results from the final analysis including post-hoc exploration of molecularly defined subgroups are necessary for drawing final conclusions on the efficacy of sorafenib. Display omitted
Off Label Use: sorafenib for the treatment of acute myeloid leukemia. Serve:Bayer: Research Funding. Ehninger:Bayer: Research Funding.
