FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Our experience confirms the safety of maintenance therapy in AML FLT3 patients after IC. We also observed a benefit for maintenance versus W&W in the low- and intermediate-risk population.

Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.

Background:Differentiating agents (ATRA/ATO) with or without anthracycline‐based chemotherapy have led to significant improvements in APL. We acknowledge that early death remain as the unsolved issue in this disease, especially when we analyse real‐life population cohorts (this cause of failure is underreported in clinical trials/protocols).Aims:To review the incidence or early death in APL in a large real life setting, as well as in patients who were eligible for protocols. To identify patterns of early death and risk factorsMethods:Between 1996 and 2017, consecutive adult and pediatric patients were reported to the PETHEMA registry data‐base (120 Institutions from Spain (PETHEMA), Poland (PALG), The Netherlands (HOVON), Uruguay, Argentina (GATLA), and Colombia). All patients with suspicion of APL had to be reported. Exclusion criteria for LPA96/99/2005 and 2012 PETHEMA trials were: unfit for chemotherapy/ECOG 4; death before starting ATRA; lack of genetic diagnosis, protocol violation; and secondary APL (sAPL). Induction therapy consisted of AIDA schedule (3 days IDA for older patients). Supportive measures defined per protocol. Early death (ED) defined as induction death plus death before starting ATRA.Results:Overall 2421 patients were registered, of whom 1962 (81%) were considered eligible for PETHEMA trial (exclusion because of sAPL (n = 189), unfit or ECOG4 (n = 154), no genetic diagnosis (n = 32) and protocol violation (n = 77)). ED occurred in 352 patients (14.6%) (hemorrhage n = 170, 7%, infection n = 77, 3%, DS n = 46, 2%, Thromboischemic events n = 31, 1.4%, and other/unknown n = 28, 1.3%). The rate of ED was similar among the 4 consecutive protocols (p = .98), with a non‐significant decrease of hemorrhagic death form the LPA96 trial (9%) to the later LPA2012 trial (5%). ED rate was significantly lower among patients included in trial (8.6%) vs non eligible (22.2% among sAPL, 77.9% in unfit/ECOG4, 40.6% among non‐genetic diagnosis), p < .001. In all subsets hemorrhage was the main cause of ED, except sAPL (8% hemorrhagic ED and 8% infectious ED rate). Univariet analysis showed the following risk factors for ED: age>60 yo, male, ECOG>1, sAPL, high‐risk, fever, platelet count <40 x 109/L, circulating blasts >30 x 109/L, M3variant, BCR3, FLT3‐ITD, prolonged PT, prolonged APTT, any bleeding at presentation, thrombosis at presentation, BMI>25, elevated creatinine, uric acid, bilirubin, LDH, GOT>50 UI/L, glucose >150 mg/dL, albumin <3.5 gr/dL, CD34neg, CD56+, and CD2+ (all p < .05). The multivariate analysis, performed in 1854 patients showed that age (RR 1.03 per year), WBC >10x109/L (RR 2.1), ECOG (RR 1.9 per unit), elevated LDH (RR 1.7), elevated creatinine (RR 4.2), circulating blasts (RR 1.009 per 1x109/L), and sAPL (RR 1.7), were independent risk factors for ED. The Figure 1 shows the cause of death by timing since diagnosis date. CNS was the more frequent site of lethal bleeding (72%, vs 24% pulmonary). In addition, we identified specific risk factors according to the main cause of ED. The time from diagnosis to starting ATRA (median 0 day) had no impact on ED rate.Summary/Conclusion:ED rate in this real‐life cohort was 14.6%, higher compared with 8.6% in selected patients for PETHEMA trials. Hemorrhage, but also infection, DS and thrombosis remain challenging issues to solve.image

Background:The combination cytarabine + anthracycline (IC) remains the standard of care for 60 year and above AML patients (Lowenberg et al. N Engl J Med 2009). Decitabine (Dec) has been EMA approved for first line AML patients not fit for intensive chemotherapy (Kantarjian et al JCO 2012). IC vs Dec have been not previously compared.Aims:The aim of this study is to analyze effectiveness and tolerability of IC vs Dec as first lines in 60 and above AML patients and to identify risk factors.Methods:We carried out the analysis on previously untreated AML ≥60yrs old patients included in PETHEMA AML epidemiological registry (NCT02607059) and in the MDA‐AML‐2017–05 (AEMPS code). Selection criteria for the study were as follows: Age >60, diagnosis of AML under WHO criteria, treated with IC or Dec during the period 01/01/2012 to 31/12/2016. Response was assessed using the ELN‐2010 criteria, toxicity by the CTCAE v4.0 scale, OS by Kaplan‐Meier, as well as mortality within the first 8 weeks (M8wks).Results:A total of 756 of previously untreated AML patients were analyzed (625 treated with IC and 131 with Dec), baseline characteristics are summarized in table 1. A higher incidence of risk factors was observed in the Dec cohort. Safety: A total of 1051 IC and 716 Dec cycles were analyzed, mean 2.4 and 6.1, febrile neutropenia 74% and 47%, M8wks was 22.5% and 25.5% (p = 0.15) and composite complete response (CCR) 64% and 18% (p < .001). for IC and Dec respectively. In this study serum creatinine>1.3 mg/dL (p = 0.02, p < 0.01), ECOG≥2 (p < 0.01) and adverse cytogenetic (p < 0.01) were adverse prognostic factors for OS in both cohorts, and WBC pre‐Dec >10.000/μL (p < 0.01) in Dec and Secondary AML (p = 0.02) in IC cohort. IC resulted superior for OS (11 vs 8 months p = 0.04) but this was not significant in 70 and above (7 vs 8 months p = 0.94) or after matching by mentioned risk factors.Summary/Conclusion:IC and Dec are not used for the same patients due to physicians judgement. Even the outcome seams superior with IC we observe similar OS after matching by risk factors age, creatinine, ECOG, or cytogenetic. The ongoing EORTC phase III randomized trial (INDACTION) will compare a Dec‐based vs IC front‐line approach for older patients with AML.image

Background:Elderly patients with ALL are frequently excluded from clinical studies, especially if they have criteria of frailty. Treatment of these patients is considered palliative, but here are scarce studies analysing the tolerability and outcome of elderly frail patients included in specific trials.Aims:Here we present the clinicobiologic characteristics and outcome of elderly frail patients with Philadelphia chromosome‐negative (Ph‐neg) ALL included in the ALL‐07FRAIL (NCT01358201) study from the Spanish PETHEMA Group.Methods:Older (55–65 yrs.) and elderly (>65 yrs.) patients with Ph‐neg ALL with Charlson comorbidity index >3 were included in this study. Treatment schedule: pre‐phase (dexamethasone [DXM] for 1 week + triple intrathecal therapy [TIT]). Induction: vincristine (VCR) 1 mg/week x 4 wks and DXM (10 mg/m2/d x 28d) and TIT (d1 and d35). No consolidation. Maintenance: mercaptopurine (MP) (50 mg/m2/d) and methotrexate (MTX) (20 mg/m2/wk) for 2 years from CR, with monthly reinductions with VCR (1 mg), DXM (40 mg/m2, d1,2) and TIT during the 1st year.Results:From 2008 to 2018, 58 patients (pts) were included in the ALL FRAIL07 study. Mean (SD) age 73 (7) yrs., 42 pts (72%) over 70 yrs., 38 males (66%), median WBC count 8.2 x109/L (0.3–475), CNS involvement 5 pts (9%), B‐cell precursor ALL 48/56 (86%)(pro‐B [n = 12], common [n = 23], pre‐B [n = 12], non‐specified [n = 1]), T‐ALL 8/56 (14%)(pro‐T [n = 1], pre‐T [n = 4], mature T [n = 1], non‐specified [n = 2]). Results of induction treatment (n = 57, 1 on treatment): early death 9 (16%), failure 17 (30%), complete remission 31 (54%). The most frequent Grade 3–4 toxicities in induction were: neutropenia 39/51 pts (77%), thrombocytopenia 30/51 (59%), infection 11/51 (22%), neurologic 4/49 (8%) and gastrointestinal 2/49 (4%). Outcome of CR patients: treatment‐related mortality 6 (19%), withdrawn from study 2 (6%), relapse 20 (65%), persistent CR1 3 (10%). The cumulative incidence of relapse at 3‐yrs was 80% (median: 11.1 months [95%CI: 5.2–25.9]). With a median follow‐up of 23.7 months (0.1–53.7), 4 patients are alive, with a median OS of 7.7 months (95% CI, 5.6–9.9)(Figure 1).Summary/Conclusion:Older and elderly frail patients with Ph‐neg ALL can benefit from a structured study using non‐genotoxic drugs, with good tolerability and acceptable CR rate and survival. These results could serve as control for strategies including new drugs in this difficult‐to‐treat population.image

Abstract Although additional cytogenetic abnormalities (ACA) do not affect the prognosis of patients with t(15;17) acute promyelocytic leukemia (APL), the role of a complex karyotype (CK) is yet to be clarified. We aimed to investigate the relationship of CK with relapse incidence in 1559 consecutive APL patients enrolled in three consecutive trials. Treatment consisted of AIDA induction followed by risk-adapted consolidation. A CK (CK) was defined as the presence of ≥2 ACA, and a very CK (CK+) as ≥3 ACA. Eighty-nine patients (8%) had a CK, of whom 41 (4%) had CK+. The 5-year cumulative incidence of relapse (CIR) in patients with CK was 18%, and 12% in those with <2 ACA (p=.09). Among patients with CK+, the 5-year CIR was 27% vs 12% (p=.003), retaining the statistical significance in multivariate analysis. This study shows an increased risk of relapse among APL patients with CK + treated with ATRA plus chemotherapy front-line regimens.

Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.