Comorbidities Are Frequent in Older Patients with De Novo Acute Lymphoblastic Leukemia (ALL) and Correlate with Induction Mortality: Analysis of More Than 1200 Patients from GMALL Data Bases

Abstract

Outcome of adult ALL has improved considerably during the past decades by intensive chemotherapy, which still remains a challenge in older pts. This may be partly due to comorbidities. So far there are no standards to differentiate pts who will be able to tolerate even age-adapted chemotherapy (fit vs unfit). In addition, little is known about the prevalence of comorbidities. Clinical trials with new compounds often represent a selection of pts w/o comorbidities. There is also no generally accepted tool for comorbidity scoring. The goal of this analysis is to provide reference data for pre-existing comorbidities in a large set of adult ALL pts, to compare two different tools and to evaluate the impact on early death (ED) in older pts. The German Multicenter Study Group for Adult ALL (GMALL) has collected data from trials for younger (18-55 y) and older (>55 y) pts and from a prospective registry. Trials had very limited exclusion criteria and in the registry there are no exclusion criteria. The Charlson Comorbidity Index (CCI) was assessed in the GMALL Elderly trial, whereas the Sorror Score (HCT-CI) was used in trials for younger pts and in the registry. 879 pts had a documented HCT-CI score from GMALL 08/2013 trial (N=282;group 1) and 3 groups from the registry: >55 y but eligible for intensive therapy (N=56, group 2), > 55 y in GMALL Elderly protocol (N=505, group 3) and >55 y in GMALL Frail protocol (N=36; group 4) (Table 1). In addition the CCI was documented in 333 pts treated in the GMALL Elderly Trial. HCT-CI-Score: The most frequent comorbidities were infections (17%), prior malignancies (16%), diabetes (16%), cardiac (14%) and moderate pulmonary disease (12%), obesity (11%) and mild liver disease (10%). Arrhythmias (<1%, 5%, 12% and 22% resp. in groups 1, 2, 3, 4), cardiac disease (2%, 7%, 19% and 42% resp.), prior malignancies (2%, 11%, 25% and 22% resp.) and diabetes (4%, 16%, 22% and 22% resp.) increased with age. Infections (15%, 18%, 22% and 22% resp.) or obesity (9%, 7%, 11% and 14% resp.) were not strongly correlated to age. Comorbidity rates were lower in pts >55 y (group 2) considered eligible for intensive therapy (57%) compared to those considered for the Elderly protocol (76%) (group 3). The proportion of low risk (LR) scores decreased with age (54%, 43%, 25% and 8% resp.;p=.01), whereas high risk (HR) increased (18%, 25%, 50% and 59% resp; p=.01). CCI: The most frequent comorbidities were prior malignancy (14%), diabetes (25%) with (3%) or w/o (22%) end organ damage, cardiac (11%) and vascular disease (8%). The incidence of prior malignancy within the last 5 y was 7%. Risk classification was: LR (0) 51%, intermediate risk (IMR) (1-2) 42% and HR (≥3) 7%. HCT-CI vs CCI in pts >55 y: With HCT-CI the incidence of heart diseases (21% arrhythmias, cardiac disease or valve damage) was higher compared to CCI (9%), which differentiated better into cardiac failure (7%) and myocardial infarction (4%). Peripheral vascular disease (8% with CCI) is not assessed by HCT-CI. Liver disease was less frequent with CCI (1.5%) vs HCT-CI (14%) due to different definitions, whereas moderate pulmonary disease (12%) or infections (18%) are not assessed by CCI. The incidences of prior malignancies and diabetes were comparable. Of note, the overall incidence of distinct comorbidities e.g. cardiac was lower than the sum of subentities because some pts had several comorbidities. ED in pts >55 y: ED rates in pts >55 y in group 3 and in GMALL Elderly trial were comparable (13% vs 12% resp). In group 3 ED rates in risk groups (HCT-CI) were 7% vs 13% vs 15% (p>.05). In the GMALL Elderly trial ED in risk groups (CCI) were 9%, 12% and 35% (p=.05; p=.003 LR/IMR vs HR). Overall the analysis reveals a high incidence of comorbidities in older (57-92%) and even in younger pts (46%), which partly would represent contraindications in clinical trials with novel compounds; thus real world data in pts with comorbidities are required after marketing authorisation. HCT-CI and CCI have a different focus and shortcomings. For ALL pts a more specific score with different organ modules would be helpful. Comorbidity is significantly correlated to ED risk. CCI allows to identify a small HR group (7%) with a mortality of 35%. HCT-CI (24% of pts) and even more CCI (51% of pts) allow to identify LR groups with <10% early mortality. It will be of interest to analyse the impact of individual comorbidities on ED rate. Overall structured comorbidity assessment should be part of all clinical trials in ALL. Disclosures Viardot: Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Fiedler:Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Stelljes:JAZZ: Honoraria; MSD: Consultancy; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Serve:Bayer: Research Funding. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

Real-world outcomes in elderly ALL patients with and without allogeneic hematopoietic stem cell transplantation: a single-center evaluation over 10 years

“…The 3-year OS for all elderly patients was 38%, with allo HCT increasing the 3-year OS to 87% with a leukemia-free survival of 75%, which was in the range of the outcome for younger transplanted and not transplanted adults. The intensive pediatric-inspired therapeutic regimen could be applied in EP in a high proportion of patients (65%) and was well tolerated with a low early death rate (6.7%) compared to historical rates of up to 35% depending on treatment selection and supportive therapy [17]. The low NRM and favorable outcome after allo HCT in general are most likely due to a combination of different factors such as a consequent supportive therapy including antimicrobial prophylaxis, individual selection of candidates, and consequent use of RIC in EP [18].…”

“…Little is known about the exact prevalence and relative contribution of comorbidities in ALL patients and no guidelines exist for the distinction between unfit and fit EP who can tolerate age-adjusted chemotherapy at all. The German Multicenter Study Group for Adult ALL (GMALL) reported a comorbidity rate of 57-92% in patients above 55 years [17] with diabetes, vascular disease, and heart failure accounting for most comorbidities; prior malignancy was present in up to 22%. In our EP cohort, we found a similar comorbidity RIC reduced-intensity conditioning Table 3 (continued) distribution and rate (84%) but with a higher proportion of prior malignancy (42%).…”

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…[20][21][22] Survival rates are especially poor in older adult patients at approximately 20%. 21,23,24 Although the exact OS percentage can vary based on how the age range is defined for pediatric, AYA, and adult patients, the trend is nonetheless clear that OS decreases substantially with increased age. 21 The exception is infants younger than age 1, which is an age group that has not seen any improvement in survival over the last 30 years.…”

Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2019

“…Relative to treatment outcomes in pediatric and young adult patients with ALL, prolonged survival rates for older adults, especially those aged .60 years, remain low at approximately 20%. [1][2][3] In Philadelphia chromosome (Ph)2positive ALL, however, the difference in overall survival (OS) and outcomes between older and younger patients is less than with Ph-negative ALL, due in part to the availability of well-tolerated, effective oral BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy. [4][5][6][7][8][9][10] Current approaches to evaluating older adult patients with newly diagnosed ALL for treatment include assessment of leukemia genetics, fitness for therapy, and performance status.…”

“…11 However, these findings should not be interpreted as an indication to withhold intensive therapy, but rather stress the importance of tailoring therapy, as highlighted by the German Multicenter Study Group for Adult ALL (GMALL). 3 Unfortunately, older patients with newly diagnosed ALL often do not receive chemotherapy or bone marrow transplant, highlighting the need for guidance in this population. [14][15][16][17] Minimal/Measurable residual disease (MRD) after therapy in ALL refers to the presence of leukemic cells below the threshold of detection using conventional morphologic methods, and is a strong predictive factor of outcomes in ALL across all age groups.…”