ABSTRACT
Background: Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate Antibody is currently approved in combination with 7 + 3 in low- and intermediate risk acute myeloid leukaemia (AML). These patients are candidate for consolidation with autologous stem cell transplantation (ASCT) particularly when MRD- is obtained. GO can improve the rate of MRD negativity. There are limited data on the effect of its addition on the mobilization of Hemopoietic Stem Cells (HSC). Aims: To assess the feasibility of mobilization of HSC after re-introduction into market of GO at 3mg/m2 in 2019. Methods: We retrospectively studied AML patients undergoing 3+7 + GO induction and Ara-C + Daunorubicine + GO, consolidation (doses are derived from label instructions and ALFA0701 study) and mobilization on day +20 using GCSF 10μg/kg. CD34+ were monitored, and patients were harvested when a threshold of 20 cells/μL was reached in peripheral blood. Results: In 2020 and 2021, also considering constrains caused by COVID-19 pandemics, we attempted mobilization in our 3 Italian centres of 14 patients with a diagnosis of CD33+ de novo-AML. The median age was 52 years (range 29-65 yrs.), 4 were males and 10 females;11 patients carried a mutation of NPM1 and all had a normal karyotype except one with t(10p12;11q14) (Table 1). All received 3+7+GO induction and achieved a CR. Therefore, we started consolidation (total ARA-C 8g/m2) + GO as inpatient. Ten patients (71%) reached the established threshold of 20 CD34+ /μL and were successfully harvested, while 4 patients (29%) failed mobilization. The median day of apheresis was D+26 from the start to chemotherapy (range 22- 39). The median number of circulating CD34+ cells on the day of collection was 35.9 cells/μL (range 20-2153 cells/μL). The median CD34+ harvested was 4.65 x 106/kg (range 1.8- 44.6 x 106/kg). In our cohort, 4 patients (28% of the entire cohort and 40% of the harvested patients) underwent ASCT, 3 achieved favourable engraftment, while in the last patient ASCT is ongoing. Several reasons prevented ASCT in the remaining 6 patients: 3 patients underwent allogeneic SCT (2 had positive MRD on harvested apheresis;1 was reclassified as high-risk ELN2017 due to RUNX1 mutation resulting from NGS panel), 2 refused ASCT and one suffered early relapse. Summary/Conclusion: In our patients, the addition of GO did not impair HSC mobilization and harvesting that was reached in about 71% of cases, similarly to the AML-10 trial of the EORTC and GIMEMA Leukemia Groups where 70% of patients were successfully harvested. Our data are particularly interesting because in the pivotal ALFA0701 study, only one patient underwent Autologous- SCT, but in the control arm. An important limit of our case-series is that only 4 patients were auto-transplanted, so we have scant data on engraftment. In particular, evaluating day to engraftment of platelets would be interesting, given the known increase of thrombocytopaenia in patients treated with GO. In conclusion, mobilization with GO is feasible and further studies are warranted to evaluate the effects of fractioned doses of GO on HSC mobilization and ASCT outcome;the ongoing trial GIMEMA AML1819 - EudraCT number 2019-003871-20 - will prospectively assess the effect of GO, but with lower doses of ARA-C (total ARA-C 6 g/m2). (Table Presented).
ABSTRACT
Introduction: Acute Myeloid Leukaemia (AML) is one of the mostcommon haematological malignancies in adults. Molecular mutationsin AML are major determinants of the patient's response to therapyand outcomes. Nucleophosmin 1 (NPM1) confers a good prognosiswhile fms-like tyrosine kinase-3 gene (FLT3-ITD) is associated witha poor prognosis.Aims &Objectives: To study the prognostic molecular markers andcytogenetics of all newly diagnosed and de novo AML cases andassess the impact of the same on treatment outcome.Materials &Methods: 23 patients with newly diagnosed (adult andpaediatric) de novo AML from Jan 2021 to Aug 2021 at GauhatiMedical College, Guwahati were included in this study. We analysedthe bone marrow aspirates, clinical significance of NPM1, CEBPA,FLT3 (by real time PCR) with disease progression. Cytogenetics bykaryotyping and immunophenotypic parameters were also documented and corelated with disease progression.Result: There were (12/23)52.2% males and (11/23)47.8% female. 2patients (8.7%) were positive for FLT3 and 4(17.4%) were positivefor NPM1. (7/23)30.4% patients had t(8,21) of which 3 had normalkaryotype while 2 patients (8.7%) had turner's genotype(45,X). 4patients (17.4%) expired while receiving Induction chemotherapy, ofwhich one had 45,X,t(8,21)genotype, one had NPM1 mutation andone expired during 3 rd cycle of consolidation due to covid 19pneumonia. 6(26.1%) patients had treatment failure following intensive induction therapy of which 2 had t(8,21) with normalkaryotype(40%) and one had NPM1 mutation with wildtype FLT3.All patients with NPM1 mutation were negative for CD34 andHLADR. All patients with NPM1 and FLT3 uniformly expressed CD33.Conclusions: 3/6 patients had failure of induction in spite of havingstandard risk cytogenetics. So, next generation sequencing (NGS) iswarranted upfront for all diagnosed AML cases. It should now beincorporated as a standard of care in the management of AML. Onepatient with turner's genotype and t(8,21) expired during inductiontherapy, hence, prognostic significance of 45,X needs to be furthervalidated in AML.
ABSTRACT
Introduction: Patients with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) are a known high-risk AML subgroup with historically poor outcomes. In December 2018, CPX-351 (Vyxeos ® Liposomal) received a positive reimbursement decision in England for the treatment of adults with newly diagnosed t-AML or AML-MRC. The objective of this retrospective study was to utilize the Cancer Analysis System (CAS) database available through the National Cancer Registration and Analysis Service (NCRAS) to describe the demographics, clinical characteristics, and treatment pathways for patients with t-AML or AML-MRC in England from 2013 to 2020, including the use of CPX-351. Methods: The NCRAS systematically collects and curates population-level data about cancer diagnoses, treatments, and outcomes across England. Adults (aged ≥18 years) diagnosed with t-AML or AML-MRC between January 2013 and March 2020 were identified either directly using International Classification of Diseases for Oncology, Third Edition(ICD-O-3) codes or indirectly using non-specific ICD-O-2, ICD-O-3, or ICD-10 AML codes in combination with a record of prior systemic anticancer therapy or radiotherapy (t-AML) or a prior diagnosis of MDS or CMML (AML-MRC;other AML-MRC subtypes could not be distinguished from de novo AML). First-line and second-line treatments identified included clinical trials, intensive chemotherapy (IC) treatments (CPX-351;daunorubicin plus cytarabine [DA];fludarabine, cytarabine, idarubicin and granulocyte-colony stimulating factor [FLAG-Ida];or “other IC” consisting of mitoxantrone-based therapy or high-dose cytarabine alone), or less-intensive therapies (azacitidine, low-dose cytarabine [LDAC], or hydroxycarbamide alone). Patients who did not receive active systemic therapy (ie, those who received best supportive care alone) were not included. Results: A total of 2,891 patients with t-AML or AML-MRC were identified. Most patients were male (62%), white (91%), and aged ≥60 years (80%). Overall, 590 (20%) patients received first-line treatment in a clinical trial, 1,474 (51%) received less-intensive therapy, and 827 (29%) received an IC regimen. Patients aged ≥60 years at diagnosis were less likely than those aged <60 years to either enter a clinical trial (18% vs 32%, respectively) or receive IC (22% vs 54%). In patients treated with IC, those who received CPX-351 were slightly older (mean [standard deviation] age: 63.9 years [8.3]) than those who received DA (60.5 years [11.4]) or FLAG-Ida (55.6 years [12.6]);28% of patients treated with CPX-351 were aged <60 years compared to 37% for DA and 55% for FLAG-Ida. When treatment patterns were analyzed per annum, utilization of less-intensive therapies remained stable over time (Figure 1A). Azacitidine was the most common less-intensive therapy both overall (64%) and across all yearly time points, followed overall by LDAC (22%) then hydroxycarbamide alone (14%). In contrast, the IC treatment patterns were more dynamic over time (Figure 1B). DA chemotherapy was the most common IC overall (48%), followed by FLAG-Ida (23%) and other ICs (18%). However, CPX-351 uptake started in 2018 (5% of all IC) and by the end of 2019 had displaced DA chemotherapy as standard-of-care IC (40% vs 22%, respectively). Excluding patients who were alive but had not received subsequent therapy (ie, censored), most patients who received front-line azacitidine or LDAC died without receiving salvage therapy (89% and 92%, respectively). In comparison, non-censored patients who received front-line DA chemotherapy or FLAG-Ida were more likely to receive salvage treatment (52% and 34%, respectively). Key salvage treatments following DA included azacitidine alone and FLAG-based therapy. Key salvage treatments following front-line CPX-351 included FLAG-Ida or DA ± hematopoietic cell transplant and azacitidine. Conclusions: This large population-level, retrospective analysis of CAS data provides a detailed overview of the management of patients with t-AML and AML-MRC. Historically a high proportion of these high-risk patients have received less-intensive treatment. Since 2018, CPX-351 has been rapidly adopted into the IC treatment pathway, displacing DA chemotherapy. These analyses will be repeated after the CAS database has been updated to determine the impact of COVID-19. [Formula presented] Disclosures: Legg: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Muzwidzwa: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Adamson: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Wilkes: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Medalla: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.
ABSTRACT
Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013);BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a “pick a winner” design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male;70% de novo AML, 23% secondary AML, and 6% high risk MDS;2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393;and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months;overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity;although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients [Formula presented] Disclosures: Knapper: Jazz: Consultancy, Speakers Bureau;Pfizer: Consultancy, Speakers Bureau;Astellas: Ended employment in the past 24 months, Speakers Bureau;Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abb ie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria, Speakers Bureau;Cyclacel Ltd: Research Funding;Astellas: Honoraria, Speakers Bureau;Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees;Jazz: Research Funding, Speakers Bureau.
ABSTRACT
Introduction: CPX-351 (US: Vyxeos ®;Europe: Vyxeos ® Liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Since November 2018, the National Institute for Health and Care Excellence (NICE) has recommended its use for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) due to either prior myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) or de novo AML with myelodysplasia-related cytogenetic changes. The key aims of this study were to utilize the Cancer Analysis System (CAS) database available through the National Cancer Registration and Analysis Service (NCRAS) to describe the demographics and clinical characteristics of adults with AML in England who have received CPX-351, as well as to estimate overall survival (OS) and survival within stratifications of interest. Methods: The NCRAS systematically collects and curates population-level data about cancer diagnoses, treatments, and outcomes across England. Adults (aged ≥18 years) diagnosed with AML and treated with CPX-351 were included in this study. A diagnosis of t-AML or AML-MRC between January 2013 and March 2020 was determined either directly using International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes or indirectly using non-specific ICD-O-2, ICD-O-3, or ICD-10 AML codes in combination with either prior systemic anticancer therapy or radiotherapy (t-AML) or a prior diagnosis of MDS or CMML (AML-MRC;other AML-MRC subtypes could not be specifically identified and are included within the de novo AML subgroup). OS was measured from the date of diagnosis;a separate analysis of OS landmarked from the date of hematopoietic cell transplant (HCT) was also performed. Within this preliminary analysis, no OS adjustments have been made to account for any COVID-19-related deaths. Results: A total of 172 patients with AML who were treated with CPX-351 were identified: 37 (22%) had t-AML, 57 (33%) had AML-MRC, and 78 (45%) had de novo AML. At diagnosis, the mean (standard deviation) age was 62.8 years (10.1), with 49/172 (28%) patients aged <60 years;66% of patients were male;87% were white;and most had an Eastern Cooperative Oncology Group performance status of 0 or 1 (68%). Six (3%) patients had received azacitidine treatment for a prior malignancy. To date, 43/172 (25%) patients had undergone HCT overall, including 43/97 (44%) patients with ≥3 months of follow-up. The cut-off date for OS was December 31, 2020, giving a median (interquartile range) follow-up of 11.2 months (3.6, 16.9). Overall, 91 patients had died, with an estimated median OS (95% confidence interval [CI]) of 16.6 months (11.0, not estimable) and probability of survival (95% CI) at 1 and 2 years of 0.54 (0.47, 0.62) and 0.39 (0.30, 0.50), respectively (Figure 1). Early mortality rates were 7% at 30 days and 15% at 60 days. When OS was landmarked from the date of HCT, median OS was not reached, with a probability of survival (95% CI) at 1 year of 0.74 (0.62, 0.89;Figure 2). When stratified by age, estimated median OS (95% CI) was not reached for patients aged <60 years and 12.8 months (8.9, 17.6) for patients aged ≥60 years. In a treatment patterns analysis that evaluated second-line treatments after CPX-351, 68 patients died without salvage therapy and 64 were alive without receiving subsequent therapy by the end of the study period. The most common salvage treatments were fludarabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor (FLAG-Ida;n = 15), daunorubicin plus cytarabine (DA)-based therapy (n = 6), and azacitidine alone (n = 7). Of the 43 patients who received an HCT, 6 (14%) underwent HCT following salvage therapy. Conclusions: This is the largest study to date examining the real-world outcomes for patients with AML who were treated with CPX-351. The estimated median OS of 16.6 months is consistent with reported real-world outcomes for CPX-351 in French and Italian studies. Median OS has not been reached in patients aged <60 years or when landmarked from the date of HCT. Once the CAS database has been updated, these analyses will be repeated to increase follow-up and patient numbers and to determine the impact of COVID-19 on OS following CPX-351 treatment. [Formula presented] Disclosures: Legg: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Doubleday: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Reich: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Lambova: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Medalla: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.
ABSTRACT
Background Based on early evidence of a high rate of coronavirus mortality in patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy (IC), the national health service (NHS) in the United Kingdom temporarily made venetoclax available as an alternative therapy, with the aim of reducing both mortality and healthcare resource use. From late April 2020, venetoclax was available to patients aged >16y with NPM1 mutation without FLT3 internal tandem duplication (ITD), patients aged >50y with NPM1, IDH1 or IDH2 mutations (regardless of FLT3 status) and patients aged >60y without favourable-risk cytogenetics. Venetoclax could be given with either azacitidine or low-dose cytarabine (LDAC), with the latter recommended mainly for patients with NPM1 mutation. We report a health-system-wide real world data collection for toxicity and patient outcomes across 65 NHS Hospitals. Methods Each patient was registered on a central NHS database. Clinicians certified that their patient met the above criteria, had not received previous AML treatment, and was fit for induction chemotherapy. Anonymised data were retrospectively collected by treating physicians. Venetoclax dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 870 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results There were 301 patients, median age 72y (range 34 - 90) with 62% male. The majority (81%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 33%, therapy-related in 10% and de novo in the remaining 57%. MRC cytogenetic risk was intermediate in 70% and adverse in 27%. NPM1 mutations were detected in 28% and FLT3-ITD in 12%. Next-generation sequencing results were available in 86% of patients, which detected mutations in IDH1 or IDH2 in 28%, ASXL1 in 20%, RUNX1 in 17% and TP53 in 12%. The ELN risk was favourable for 23%, intermediate for 30% and adverse for 44%. A majority received venetoclax in combination with azacitidine (85%), with the remaining 15% receiving LDAC. The LDAC cohort was enriched for de novo AML (76% vs 54%) and NPM1-mutated disease (56% vs 23%). Most patients (81%) followed the recommended initial schedule of venetoclax 100mg daily for 28 days in combination with posaconazole or voriconazole. Patients spent a median 14 days in hospital in cycle 1, then a median of 0 days for cycles 2-4. In cycles 1, 2, 3 and 4, the median number of days for recovery of neutrophils to >0.5x10 9/L was 33, 25, 24 and 14 respectively, and the median number of days to recovery of platelets to >50x10 9/L was 22, 3, 0 (no drop below 50) and 0. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 70%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 2%, partial remission in 7% and refractory disease in 11%. CR/CRi was higher in de novo (78%) compared to secondary AML (57%, p=0.02);NPM1 mutated (78% vs 67%, p=0.02) and IDH1/IDH2 mutated disease (85% vs 62%, p=0.02). ELN favourable risk patients had the highest CR/CRi rate (85%, intermediate 71%, adverse 60%, p=0.01). Median follow-up was 8.2 months (95%CI 7.8 - 9.0) with median overall survival (OS) 12.8 months (95%CI 10.9 - not reached). Mortality at day 30 was 5.7% and day 60 was 8.4%. 12-month overall survival was 51%, increasing to 71% in those who achieved CR/CRi. Survival was poorer in secondary (HR 1.9, p <0.01) and therapy-related AML (HR 2.1, p=0.02), better in NPM1 mutated (HR 0.6, p=0.02) and IDH mutated (HR 0.5, p=0.02) disease and poorer with TP53 mutation (HR 2.0, p=0.01). Overall survival did not differ for patients treated with LDAC compared to azacitidine (HR 1.1, p=0.7). Conclusion This large real-world study demonstrates CR/CRi and survival rates comparable to those reported in prospective clinical trials. Importantly, during t e COVID-19 pandemic, the adoption of venetoclax regimens permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. The data support prospective comparisons of venetoclax-based regimens to IC in fit adults with AML particularly in older patients with de novo AML, NPM1-mutated and IDH-mutated disease. [Formula presented] Disclosures: Belsham: Celgene: Other: meeting attendance;Abbvie: Other: meeting attendance. Khan: Abbvie: Honoraria;Astellas: Honoraria;Takeda: Honoraria;Jazz: Honoraria;Gilead: Honoraria;Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau;Jazz: Consultancy, Honoraria;Daiichi Sankyo: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Astellas: Consultancy, Honoraria, Speakers Bureau;Takeda UK: Speakers Bureau. Loke: Pfizer: Honoraria;Amgen: Honoraria;Janssen: Honoraria;Novartis: Other: Travel;Daichi Sankyo: Other: Travel. Murthy: Abbvie: Other: support to attend educational conferences. Smith: ARIAD: Honoraria;Pfizer: Speakers Bureau;Daiichi Sankyo: Speakers Bureau. Whitmill: Daiichi-sankyo: Other: travel fees;EHA in stockholm: Other: conference support. Craddock: Novartis Pharmaceuticals: Other: Advisory Board;Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Jazz: Other: Education events;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events;Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau;Menarini: Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Other: Educational Events, Speakers Bureau;Amgen: Other: Research support (paid to institution);Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.
ABSTRACT
Introduction The COVID-19 pandemic disrupted non-urgent and preventive medical care. During the early peak of the pandemic, an estimated 41% of US adults delayed or avoided medical care (Czeisler et al, CDC, 2020). While there were documented declines in the number of emergency department visits for myocardial infarction, stroke and hyperglycemia, similar data is not available related to acute myeloid leukemia (AML) (Lange et al, CDC, 2020). A delay in the diagnosis of AML could lead to presentation when patients are less able to withstand chemotherapy or have a higher disease burden which could compromise overall survival (OS). In this retrospective analysis, we aim to elucidate if there was a difference in clinical, cytogenetic, or molecular presentations and if there was an effect on early mortality as determined by overall survival at 1 and 6 months. Methods We compared the clinical, cytogenetic, and baseline molecular genetics of consecutive adult patients diagnosed with de novo AML at Dana-Farber Cancer Institute/Brigham and Women's (DFCI/BWH) Hospital from March 23, 2020, the date of the Massachusetts COVID State of Emergency, to August 23, 2020 to a historical cohort of similar patients between presenting between March 23, 2017 and August 23, 2020. Data was obtained from the Hematological Malignancy Data Repository and via review of the medical record. Patients were excluded from this cohort if they were diagnosed with acute promyelocytic leukemia, had known antecedent myeloid malignancy, or if they did not have DFCI/BWH 96-gene next-generation sequencing panel (RHP) performed at the time of diagnosis. Baseline clinical, laboratory, cytogenetic, and molecular characteristics and outcomes were compared between the pre-pandemic and pandemic cohorts using chi-squared, Fisher's exact, and Wilcoxon rank sum analyses (where appropriate) at a significance of p<0.05. Results Thirty-eight AML patients presented during the COVID-19 pandemic (PAN) and 308 in the pre-pandemic (PREPAN) period. There was no statistically significant difference in the monthly rate of new patients presenting in PREPAN and PAN cohorts (8 vs. 6 new patients/month, p=0.73). The median age at presentation (64 PREPAN vs. 65 PAN, p=0.77), sex, and therapeutic approach (intensive, non-intensive, supportive care, other) were not statistically different between cohorts. Presenting white blood cell count, platelet count, and fibrinogen were not different between cohorts, while hematocrit was significantly lower in the PAN cohort (23.8% vs. 26.0%, p=0.001). There was a trend for a higher median blast percentage (28.5% vs. 13%, p=0.09) in the PAN cohort. There were no differences between the cohorts in the median number of cytogenetic abnormalities, nor in the incidence of complex karyotype, (25.3% vs. 23.7%) across PREPAN and PAN respectively. There were also no significant differences in the European LeukemiaNet (ELN) risk classification scores across the PREPAN and PAN time periods, with 57.8% vs. 52.6% of total patients presenting with adverse risk disease respectively. When specific mutations of TP53, NPM1, and FLT3 were evaluated, only FLT3 demonstrated a statistical difference with a higher proportion in the pandemic group (p=0.04). OS at 1-month (97.4% and 93.2%, p=0.15) and 6-months (71.1% and 75.0%, p-0.87) were not statistically different in the PREPAN and PAN cohorts, respectively. Conclusion These data represent a novel analysis of the presenting clinical, cytogenetic and molecular characteristics of de novo AML during the COVID-19 pandemic. In contrast to other diseases, we did not see fewer de novo AML presentations during the peak of the COVID pandemic. While the reasons are unknown and require validation in large cohorts, the symptoms of leukemia including symptomatic anemia (low hematocrit) and higher WBC and blast count possibly driven by FLT3 mutations may drive patients to seek emergent clinical evaluation despite COVID pandemic barriers. The lack of difference in cytogenetic or other prognostic entities may demonstrate a lack of ymptom correlation causing patients to present for care. The higher incidence of FLT3 mutations and lower hematocrit could reflect more symptomatic presentation of AML during the COVID pandemic. Since these differences may be a surrogate for a higher disease burden, it will be important to compare outcomes at longer time points. [Formula presented] Disclosures: DeAngelo: Pfizer: Consultancy;Novartis: Consultancy, Research Funding;Jazz: Consultancy;Incyte: Consultancy;Forty-Seven: Consultancy;Autolus: Consultancy;Amgen: Consultancy;Agios: Consultancy;Takeda: Consultancy;Glycomimetrics: Research Funding;Blueprint: Research Funding;Abbvie: Research Funding;Servier: Consultancy. Stone: Bristol Meyers Squibb: Consultancy;Astellas: Membership on an entity's Board of Directors or advisory committees;BerGen Bio: Membership on an entity's Board of Directors or advisory committees;Boston Pharmaceuticals: Consultancy;Innate: Consultancy;Foghorn Therapeutics: Consultancy;Gemoab: Membership on an entity's Board of Directors or advisory committees;Glaxo Smith Kline: Consultancy;Celgene: Consultancy;Elevate Bio: Membership on an entity's Board of Directors or advisory committees;OncoNova: Consultancy;Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees;Syndax: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;Agios: Consultancy, Research Funding;Amgen: Membership on an entity's Board of Directors or advisory committees;Aprea: Consultancy;Arog: Consultancy, Research Funding;Jazz: Consultancy;Macrogenics: Consultancy;Novartis: Consultancy, Research Funding;Actinium: Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy;Syros: Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy. Garcia: AstraZeneca: Research Funding;Prelude: Research Funding;Pfizer: Research Funding;Genentech: Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Winer: Abbvie: Consultancy;Takeda: Consultancy;Novartis: Consultancy.