Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, adult, Non-Biological therapies, Clinical Research, Chemotherapy, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human, Minimal Residual Disease
Improvements in outcome for older patients with Acute Lymphoblastic Leukaemia (ALL) have not kept pace with those for younger persons. Whether there is a survival benefit to more ‘intensive’ chemotherapy for older patients and what is the ‘pay-off’ in terms of adverse events and duration of inpatient hospitalisation is unclear. Few ALL trials recruit older individuals, with 55 or 60 years being common upper age limits. UKALL60+ (NCT 01616238) a UK National Cancer Research Institute Adult ALL subgroup study, was designed to investigate the safety, tolerability and outcomes of varied intensity chemotherapy protocols for patients ≥ 60 years (y) (55y with comorbidities, no upper age limit) with de novo ALL.
Physicians/patients with BCR::ABL1 negative ALL chose freely between three trial chemotherapy pathways; B: based on the UKALL14 adult ALL regimen, but modified to reduce common toxicities eg asparaginase was excluded and dose intensity of certain drugs eg anthracyclines, intravenous (IV) methotrexate were reduced C: the intensive in-patient regimen as used in HOVON100 and D: a regimen designed to be delivered as an ‘outpatient’, wherein vincristine was the only IV-administered agent. A, tyrosine kinase inhibitor combined with modest intensity chemotherapy was offered for patients with BCR::ABL+ ALL. Regimens A-D all included two full years of maintenance therapy. E was a registration-only pathway with free choice of therapy. Baseline characteristics collected included Charlson index, ECOG, Karnofsky, IADL and CRASH scores. The primary end point was complete remission (CR) rate. Secondary end points included EFS and OS at 1 year, treatment related mortality (TRM), minimal residual disease (MRD) response (patient-specific Ig/TCR quantification by PCR, performed in a central laboratory), adverse event (AE) rates, duration of inpatient hospitalisation and assessment of the relationship between baseline characteristics and treatment option chosen. Quality of life was assessed throughout; data are not yet analysed.
Between 01/2013 and 11/2018, 126 patients aged 55-83y were recruited, of whom 5 were ineligible (misdiagnosis) leaving 121 analysable. Fifteen pursued registration only, whereas 106/121 elected treatment pathways A-D. Patient characteristics as well as main outcome measures are shown in panel (i). Those receiving regimen D were significantly older than those allocated to B (73 vs 67y p=0.0001). They were moderately more dependent (IADL score 27 vs 28, p =0.04) with slightly higher Charlson index (8 vs 7, p=0.038), suggesting a mix of drivers for therapy selection. Induction CR rate was 92% for pathway A recipients (BCR::ABL1+), 70.6% for B (intermediate intensity), 55.6% for C (most intensive) and 47.6% for D (least intensive), with the latter low rates being due to TRM and lack of disease response, respectively. Strikingly few (N=22, 18.2%, overall) patients achieved an MRD negative remission, with zero complete MRD responses in the low intensity pathway D. Median EFS (mo) was A 23.0 (11.8 – 54.3), B 18.1 (11.3 – 24.2), C not reached, and D 10.9 (5.0 – 13.2). AE forms were available for 102/106 patients. Grade 3/4 AEs rates were equivalent across the pathways; A 22/25 (88%), B 45/49 (91.8%), C 7/8 (87.5%) and D 19/20 (95%), although febrile neutropenia was uncommon in A 3/23(12%) and D 3/20 (15%) but common in B 23/49 (46.9%) and C 6/8(75%). Duration of hospitalisation as a percentage of total time on therapy was A 6%, B 14%, C 24%, and D 8% (p=0.026). Most inpatient days were during induction: 23%, 62%, 76% and 32% respectively (p<0.001).
We compared the survival of all UKALL60+ participants to the N=65 patients >60 y treated on the UKALL14 study for patients aged 25-65 y between 05/2012 and 07/2017. Although remission rates were higher for those >60y treated on UKALL14 (87.3%), neither EFS (panel ii) nor OS differed between the trials, suggesting that outcome after chemotherapy treatment is poor across the board for older patients with ALL.
Our prospective trial data suggest that maximising chemotherapy intensity in older patients with ALL does not confer long-term clinical benefit for the majority of patients. Older patients should be counselled carefully as to the likely outcome of treatment with chemotherapy alone and offered novel therapies or trials of those agents as de novo therapy, wherever possible.
Disclosures: Patel Wrench: Pfizer: Membership on an entity's Board of Directors or advisory committees. Kirkwood: Kite: Consultancy, Honoraria. Clifton-Hadley: Astra Zeneca, GSK, Pfizer, MSD, BMS, Amgen, Millennium Takeda: Other: CRUK and UCL CTC have received research funding in the past 24 months, Research Funding. Marks: Novartis: Consultancy; Pfizer: Consultancy; Kite: Consultancy. Moorman: Amgen: Honoraria. Morley: Pfizer: Consultancy; Amgen: Consultancy. Rowntree: Pfizer: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; KITE pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Snowden: Gilead: Honoraria; Mallinckrodt: Honoraria; Medac: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Janssen: Honoraria. Fielding: Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.
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