12 research outputs found
A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients
Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules
No Evidence that CD33 rs12459419 Polymorphism Predicts Gemtuzumab Ozogamicin Response in Consolidation Treatment of Acute Myeloid Leukemia Patients: Experience of the PETHEMA Group.
Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the CD33 rs12459419 CC genotype might benefit from the addition of GO to intensive treatment in contrast to patients with CT/TT genotypes. Nevertheless, contradictory results have been reported. We sought to shed light on the prediction of GO response in AML patients with rs12459419 polymorphism who were treated with GO in the consolidation (n = 70) or reinduction (n = 20) phase. The frequency distribution of the rs12459419 polymorphism in the complete cohort of patients was 44.4% (n = 40), 50% (n = 45), and 5.6% (n = 5) for CC, CT, and TT genotypes, respectively. Regarding the patients treated with GO for consolidation, we performed a Kaplan-Meier analysis of overall survival and relapse-free survival according to the rs12459419 polymorphism (CC vs. CT/TT patients) and genetic risk using the European Leukemia Net (ELN) 2010 risk score. We also carried out a Cox regression analysis for the prediction of overall survival, with age and ELN 2010 as covariates. We found no statistical significance in the univariate or multivariate analysis. Additionally, we performed a global Kaplan-Meier analysis for the patients treated with GO for reinduction and did not find significant differences; however, our cohort was too small to draw any conclusion from this analysis. The use of GO in consolidation treatment is included in the approval of the compound; however, evidence regarding its efficacy in this setting is lacking. Rs12459419 polymorphism could help in the selection of patients who might benefit from GO. Regrettably, in our cohort, the rs12459419 polymorphism does not seem to be an adequate tool for the selection of patients who might benefit from the addition of GO in consolidation cycles
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Outcomes of Patients with Newly-Diagnosed Acute Myeloid Leukemia and Hyperleukocytosis Who Did Not Undergo Intensive Chemotherapy: Results from a Large International Database
Abstract
Introduction: Hyperleukocytosis at time of acute myeloid leukemia (AML) diagnosis is associated with increased disease-related complications as well as early mortality. Many AML patients are not candidates for intensive chemotherapy (IC) because of disease-related or patient-specific factors. Limited data is available regarding the characteristics and outcomes of newly-diagnosed AML who present with hyperleukocytosis and do not receive IC.
Methods: We retrospectively analyzed data from patients with newly-diagnosed AML and hyperleukocytosis (defined as white blood cell count [WBC] of 50 × 109/L or greater) who were reported not to have received IC at 12 major institutions in the United States, Spain, Germany and France from 1982 to the end of 2016. Collected variables included age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), WBC, hemoglobin level, platelet count, renal and hepatic chemistry parameters, cytogenetic risk group, molecular abnormalities (if available), presence of tumor lysis syndrome (TLS), disseminated intravascular coagulation (DIC), clinical evidence of leukostasis, admission to an intensive care unit (ICU) at presentation, receipt of hydroxyurea, and administration of leukapheresis. Clinical evidence of leukostasis was defined as new onset hypoxia, chest pain, headache, focal neurological symptoms, priapism, intestinal ischemia and acute renal failure attributed to hyperleukocytosis by the primary provider of the patient. Kaplan-Meier analysis was used to estimate overall survival (OS) from time of presentation until death or end of follow-up. Patients with hyperleukocytosis who received IC are described in a separate abstract.
Results: Of 1050 patients with AML and hyperleukocytosis reported to our dataset, 220 patients were reported not to have received IC and were included in this analysis. For those 220 patients, median age was 75 years, 57.7% were male, and most (62.8%) had an ECOG PS of 2 or greater. Median WBC, hemoglobin, and platelet count at presentation were 131.4 × 109/L (range [R], 50.4-620), 8.96 g/dL (R, 3.6-15.9), and 34 (R, 3-393), respectively; 61.5% presented with a WBC greater than 100 × 109/L. Cytogenetically-defined poor risk AML was diagnosed in 26.1% of patients. TLS, DIC or clinical leukostasis was present in 25.6%, 15.7%, and 32.5% of patients, respectively. Pulmonary, central nervous system, renal, cardiac, gastrointestinal, or retinal clinical evidence of leukostasis was present in 52.9%, 17.1%, 11.4%, 10%, 5.7% and 2.9%, respectively, of those with clinical leukostasis. The majority (72.9%) of patients received initial therapy with hydroxyurea with a median time from presentation to administration of 12 hours (R, 1-144). Only 15% of patients underwent leukapheresis. Commonly-used non-IC therapies included hypomethylating agents, clofarabine, low dose cytarabine, or best supportive care. The median OS of the entire cohort was only 22 (95%CI: 13-37) days. The 30-day mortality was 57.4%. The 60-day, 90-day, 180-day, and one-year OS probabilities were 37%, 31%, 20%, and 12%, respectively. Only 4.3% of patients proceeded to allogeneic stem cell transplant. Patients presenting with WBC >100 × 109/L (N=79) had a worse OS than those presenting with WBC <100 × 109/L (N=126), (median OS 0.4 [95%CI, 0.3-0.7] vs. 2 [95%CI, 1.2-3.5] months, respectively, p=0.02) and those with clinical evidence of leukostasis (N=50) had worse OS than those who did not (N=104), (median OS, 0.2 [95%CI, 0.1-0.8] vs 2.2 [95%CI, 1.3-3.5] months, respectively, p<0.0001) (Figure). Patients who underwent leukapheresis (N=31) did not have a significantly improved OS compared to those who did not undergo leukapheresis (N=175) with a median OS of 1.2 (95%CI, 0.2-12.4) vs. 0.7 (95%CI, 0.4-1.2) months, respectively (p=0.12) (Figure). The small number of patients undergoing leukapheresis limited assessment of impact of leukapheresis in multivariable analysis.
Conclusions: We report the largest studied cohort of patients with newly-diagnosed AML presenting with hyperleukocytosis who did not receive IC. Outcomes were very poor with a median OS of 22 days and only 12% alive at one year. WBC >100K x 109/L and clinical leukostasis were associated with inferior survival, while leukapheresis did not seem to impact survival. Novel and effective therapies are urgently needed for this group of AML patients.
Disclosures
Montesinos: Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Bhatt:Incyte: Research Funding; CSL Behring: Consultancy; Pfizer: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Roboz:AbbVie: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Argenx: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Argenx: Consultancy. Cluzeau:Pfizer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Mukherjee:Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Projects in Knowledge: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LEK Consulting: Consultancy, Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; BioPharm Communications: Consultancy; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Podoltsev:Astex Pharmaceuticals: Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Gore:Celgene: Consultancy, Research Funding. Zeidan:Otsuka: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria
PLZF-RAR(alpha), NPM1-RAR(alpha), and other acute promyelocytic leukemia variants: the PETHEMA registry experience and systematic literature review
It has been suggested that 1-2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RAR alpha) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR(alpha) being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR(alpha) and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR(alpha) and 2 NPM1-RAR(alpha)), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 x 10(9)/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far
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Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study
Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 10
/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value
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Impact of Leukapheresis and Time to Chemotherapy on Outcomes of Newly Diagnosed Patients (pts) with Acute Myeloid Leukemia (AML) Presenting with Hyperleukocytosis: An Analysis from a Large International Patient Cohort
Abstract
Introduction: Hyperleukocytosis, defined as a white blood cell count (WBC) of >50 × 109/L or >100 × 109/L, is seen in newly diagnosed AML and often results in leukostasis, increased risk of complications, and potentially early death. Those pts often require urgent evaluation and therapy. Leukapheresis is also sometimes used despite limited evidence supporting its use. There is limited data regarding the impact of time (day/night) and day (weekday/weekend) of admission and time to initiation of IC on outcomes in pts with hyperleukocytosis.
Methods: Data were collected from 12 centers in USA and Europe (EU). Eligible pts had newly diagnosed AML, presented with a WBC > 50 × 109/L, and received IC. Univariate and multivariable logistic regression models stratified by centers (EU vs. USA) estimated odds ratios for death during induction (30-day mortality) and achievement of composite complete response (CRc) defined as CR+CR with incomplete count recovery (CRi). Univariate and multivariate Cox proportional hazard models stratified by centers (EU vs. USA) estimated hazards ratios (HR) for overall survival (OS). We evaluated the impact of leukapheresis, day of presentation (weekend vs. weekday), time of presentation (nighttime = 6pm-6am vs. daytime=6am-6pm), and time to initiation of IC. Studied covariates included age, Eastern Cooperative Oncology group performance status (ECOG PS), cytogenetics and molecular abnormalities, WBC, hemoglobin, platelet count, bone marrow and blood blast percentage, and presence of clinical leukostasis, tumor lysis syndrome (TLS) or disseminated intravascular coagulation (DIC) at presentation.
Results: Among 1050 pts with AML and hyperleukocytosis whose data were collected, 787 were reported to have received IC and were included in this analysis. Of 787 pts receiving IC, 16.6% (95%CI, 13.9-19.3%) died during the first 30 days of IC. Leukapheresis was used in 117 pts (15%) in 8 of the 12 centers. In univariate analyses, neither weekend nor nighttime presentation nor use of leukapheresis impacted odds of death in the first 30 days. In multivariate analysis, higher odds of death during first 30 days were associated with age ³ 55 years (OR 3.2, p=0.015), ECOG PS ³ 2 (OR 4.4, 0.004), WBC > 100 × 109/L (OR 6.0, p=0.01) and presence of leukostasis (OR 4.5, p=0.005) and TLS (HR, 3.2, p=0.049). However, neither initiation of IC beyond 48 hours of presentation (vs. less than 48 hours) or use of leukapheresis significantly affected the odds of death in first 30 days (Figure 1A). Median OS of the entire cohort was 12.6 months (95%CI, 11.5-14.9) (Figure 2A). In multivariate analyses, age ³ 55 years (HR 2.6, p<0.001), ECOG PS ³ 2 (HR 1.5, p=0.02), poor cytogenetic risk group (vs. intermediate/good, HR 1.6, p=0.02) and clinical presence of leukostasis (HR 1.4, p=0.03) all predicted inferior OS. The use of leukapheresis showed a trend towards improved OS with borderline statistical significance in univariate analysis (HR 0.77, 95%CI 0.6-1.0, p=0.052) (Figure 2B) but this was not statistically significant in multivariate analysis (Figure 1B). Initiation of IC beyond 48 hours of presentation (vs. less than 48 hours) did not significantly impact OS. CR was achieved in 51% (95%CI, 46.9%-54.1%) of pts and 14% (95%CI, 11.4%- 16.4%) had a CRi. In multivariate analysis, age ³ 55 years (OR 0.3, p<0.001), ECOG PS ³ 2 (OR 0.5, p=0.012), adverse cytogenetic risk group (OR 0.4, p=0.007), and presence of leukostasis (OR 0.5, p=0.04) were associated with decreased odds of achieving CRc. However, initiation of IC beyond 48 hours of presentation (vs. less than 48 hours), and use of leukapheresis did not significantly impact odds of achieving CRc (Figure 1C). Day and time of presentation were not significantly associated with OS, 30-day mortality or CR/CRi rare in univariate analysis. Impact of leukapheresis in pts with clinical leukostasis and sensitivity analyses including propensity score matching are ongoing and will be presented at the meeting.
Conclusions: In this very large international cohort of newly diagnosed AML pts who presented with hyperleukocytosis and treated with IC, neither day (weekend vs weekday) nor time (day vs night) nor the use of leukapheresis had significant impact on odds of death during the first 30 days or on OS. Our data further highlight the limited evidence behind use of leukapheresis and support the urgent need to conduct randomized clinical trials to study any of its benefits.
Disclosures
Montesinos: Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Bhatt:Pfizer: Consultancy; CSL Behring: Consultancy; Incyte: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Roboz:Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Eisai: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Orsenix: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Cellectis: Research Funding; Cellectis: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy. Cluzeau:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Sanofi: Speakers Bureau. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Mukherjee:LEK Consulting: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Projects in Knowledge: Honoraria; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib: Honoraria, Speakers Bureau; BioPharm Communications: Consultancy; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Brunner:Novartis: Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Ritchie:NS Pharma: Research Funding; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Podoltsev:Daiichi Snakyo: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Celator: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Gore:Celgene: Consultancy, Research Funding. Zeidan:AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria
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Characteristics, Treatment Patterns and Outcomes Among Newly Diagnosed Patients (pts) with Acute Myeloid Leukemia (AML) Who Present with Hyperleukocytosis: Findings from a Large International Patient Cohort
Abstract
Introduction: Pts with AML often present with hyperleukocytosis, defined with a white blood cell count (WBC) of >50 or >100 × 109/L. Hyperleukocytosis is associated with higher rates of complications and death especially when associated with clinical leukostasis. There are no clear guidelines outlining the best cytoreductive strategy and the use of leukapheresis is based on institutional practice. Limited data is available regarding characteristics of AML pts with hyperleukocytosis, treatment patterns, short and long-term clinical outcomes.
Methods: Data were collected retrospectively from 12 centers in the United States and Europe. Eligible pts had newly diagnosed AML, WBC > 50 × 109/L, and had received intensive chemotherapy (IC). Pts with hyperleukocytosis who did not receive IC are described in a separate abstract. Kaplan-Meier methods estimated overall survival (OS) from time of presentation till death or end of follow-up. Clinical evidence of leukostasis was defined as new onset hypoxia, chest pain, headache, focal neurological symptoms, priapism, intestinal ischemia and acute renal failure attributed to hyperleukocytosis by the primary provider of the pt.
Results: Among 1050 pts with AML and hyperleukocytosis whose data were collected, 787 were reported to have received intensive chemotherapy and were included in this analysis. The median age was 55 years (range [R], 15-86), and 51% were male (Table 1). Median WBC at presentation was 109 × 109/L (R, 47-561) and 57% had WBC > 100 × 109/L. Median hemoglobin was 9.2 g/dL (R, 3.6-126) and median platelet count was 31 x 109/L (R, 3-1268). A good, intermediate and poor risk karyotype were present in 31%, 51% and 18% of pts, respectively. Clinical leukostasis, tumor lysis syndrome (TLS) and disseminated intravascular coagulation (DIC) were present in 27%, 28% and 18% of pts at time of presentation, respectively (Table 1). Organs affected by leukostasis were the lung, CNS, retina, heart, kidney and GI tract in 44%, 36%, 6%, 6%, 5% and 4%, respectively. Leukapheresis was administered in 117 pts (15%) (Figure 1). Four centers did not use leukapheresis. 31% of pts with clinical leukostasis underwent leukapheresis and 10% of pts without clinical leukostasis received leukapheresis (p100 × 109/L (p=0.11) (Figure 1B). Median OS was 15.2 months (95%CI, 13.4-17.5) for pts without clinical leukostasis, significantly longer than the median OS of 7.4 months (95%CI, 3.9-9.8) for pts with symptoms of leukostasis (p<0.0001) (Figure 1C).
Conclusions: To our knowledge, this is largest reported cohort of pts with AML and hyperleukocytosis treated with intensive chemotherapy. Clinical leukostasis was present in about a quarter of pts and was associated with worse OS. Most pts were managed with chemotherapy alone, and leukapheresis was only used in a small subgroup of pts (15%). The impact of leukapheresis and other variables on outcomes are presented in a separate abstract.
Disclosures
Montesinos: Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Bhatt:Pfizer: Consultancy; CSL Behring: Consultancy; Incyte: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Fathi:Boston Biomedical: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Roboz:Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Argenx: Consultancy; Aphivena Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy. Cluzeau:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Pfizer: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Mukherjee:Pfizer: Honoraria; Projects in Knowledge: Honoraria; BioPharm Communications: Consultancy; LEK Consulting: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib: Honoraria, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Ritchie:Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding. Podoltsev:Pfizer: Research Funding; Sunesis Pharmaceuticals: Research Funding; LAM Therapeutics: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Daiichi Snakyo: Research Funding. Gore:Celgene: Consultancy, Research Funding. Zeidan:Otsuka: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria
Characteristics and outcomes of adult patients in the PETHEMA registry with relapsed or refractory FLT3-ITD mutation-positive acute myeloid leukemia
Simple Summary Most adult patients with acute myeloid leukemia (AML) relapse after achieving complete remission with chemotherapy; however, there is no standard second-line (salvage) treatment. We retrospectively investigated 404 patients aged >= 18 years with relapsed/refractory (R/R) AML with an FMS-like tyrosine kinase 3 (FLT3) mutation, treated at a PETHEMA (NCT02607059) site between 1998 and 2018. Patients received salvage treatment with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care (n = 80). Complete remission was achieved by 48% of patients who received intensive therapy vs. 19% with non-intensive therapy. Intensive/non-intensive therapy prolonged overall survival significantly compared with supportive therapy. Of evaluable patients, 22% received an allogeneic stem-cell transplant after complete remission. The majority of patients with FLT3-mutated R/R AML received intensive salvage therapy, with the best outcomes being obtained when intensive salvage treatment was combined with stem-cell transplant. This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant