Moderate Intensive Chemotherapy Including CNS-Prophylaxis with Liposomal Cytarabine Is Feasible and effective in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia (ALL): Results of a Prospective Trial From the German Multicenter Study Group for Adult ALL (GMALL)

Abstract

1493 Few older ALL pts are entered into prospective trials and data on characteristics and outcome are scarce. The GMALL started a prospective trial in older ALL (>55 yrs) in 2003. In Ph-neg ALL a prephase (Dexa, Cyclo, MTX i.th.) was followed by induction I (Dexa, VCR, Idarubicin), induction II (Cyclo, AraC), alternating consolidation with IDMTX (d 1,15) ×3, VM26/AraC ×2, reinduction (VCR, Ida, Cyclo, AraC) and maintenance (MP, MTX) up to 2 yrs. In CD20+ ALL Rituximab ×8 was added. CNS-prophylaxis consisted of i.th. triple combination (MTX, AraC, Dexa) ×4 during induction, ×8 during consolidation/maintenance. The original protocol (group 1) was amended to optimize CNS prophylaxis and consolidation (group 2). I.th. therapy was then performed with liposomal cytarabine, 3x during induction, 3x during consolidation. IDMTX dose was increased from 500 to 1000 mg/m2 and native E.coli ASP (10.000 U/m2) was added on d2 and d16 of IDMTX. VM26/AraC was replaced by IDAraC (1000 mg/m2 d1,3,5). In a further amendment the original i.th. prophylaxis was reinserted until final analysis of liposomal AraC became available. Furthermore, after induction, one cycle with pegylated ASP (500 U/m2) (PEG-ASP) was scheduled to evaluate feasibility in older pts (group 3). Results of induction were compared for groups 1–3; outcome analysis was restricted to 1–2 due to still short follow-up for group 3. 268 pts with a median age of 67 (55–85) yrs treated in 94 hospitals were evaluable (180, 43 and 45 pts in groups 1, 2 and 3 resp.). 39% were aged 55–65 yrs, 51% 66–75 yrs and 10% above 75 yrs. 67% had c/pre-B-ALL, 18% pro-B-ALL and 15% T-ALL. WBC was >30/nL in 27%. Poor ECOG status (≥2) before (ECOGb) or after (ECOGa) onset of ALL was described in 7% or 38% resp. 78% had any comorbidity and 9% had a Charlson score (ChS) ≥3. No significant differences were detected between groups 1–3. Overall 76% (N=203) achieved CR after induction, 14% experienced early death (ED) and 10% did not achieve CR. In groups 1–3 CR rates were 72%, 86% and 82% resp. and ED rates 18%, 0% and 11% resp. (p=.03). CR rates were 84%, 74% and 52% in three age groups (p=.002) with ED rates of 7%, 14% and 37% resp. (p=.0004). Immunophenotype and WBC (<> 30.000) correlated with CR but not ED rate. ECOGb 0–1 vs ≥2 correlated with CR (82% vs 33%;p<.0001) and ED (7% vs 53%;p<.0001). Also ECOGa correlated with CR (85% vs 67%;p=.003) and ED (6% vs 19%;p=.003). CR and ED rates were not influenced by comorbidity itself but by ChS < vs ≥3: CR (78% vs 59%;p=.003) and ED (11% vs 33%;p=.0007). Multivariate analysis confirmed ECOGb, WBC and age for CR rate, and ECOGb, age and ChS for ED. Overall survival (OS) at 5 yrs was 23%; 33% at 2 yrs for group 1 and 52% for group 2 resp. (p=.01). Mortality in CR was 6% and 15% of the pts were withdrawn in CR. Probability of continuous complete remission (CCR) was 32% at 5 yrs, 42% and 43% at 2 yrs for group 1 and group 2 resp. (p=>.05). Age (42% vs 37% vs 8%;p=.0007), WBC (43% vs 15%;p<.0006), ECOGb (40% vs 14%;p=.0008) and ECOGa (42% vs 30%;p=.0023) were correlated with OS in contrast to comorbidity and ChS. Age, treatment group, WBC, ECOGb and ECOGa were confirmed in multivariate analysis. Pts younger than 75 yrs with ECOGb below 2 had an 86% CR rate with 10% ED and 36% OS at 3 yrs. WBC and MRD were significant prognostic factors for CCR. MRD results after consolidation I were available in 33 pts. CCR was 11% in molecular failure vs 68% in molecular CR. Preliminary results confirmed feasibility of PEG-ASP. With this age adapted regimen a favorable CR rate was achieved in a large patient group with a median age of 67 yrs. CR was increased (86%) and mortality was decreased (0%) significantly with liposomal cytarabine compared to triple i.th. prophylaxis during induction, since the latter probably induced more bone marrow toxicity. Reduced ED contributed considerably to improved OS. Moderate intensive consolidation was feasible and ASP, including PEG-ASP, was well tolerated. Age was correlated with outcome and 75 yrs appears to be the upper limit for this regimen. General condition was an additional highly relevant prognostic factor whereas comorbidity, measured by Charlson score was associated with ED but not with OS. These results encourage further treatment optimisation in older ALL pts, including those with comorbidities, based on comprehensive diagnostics, geriatric assessment, MRD evaluation, intensified consolidation, use of ASP, dose-reduced stem cell transplantation and integration of new, targeted drugs. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Research Funding; Genzyme: Research Funding; Mundipharma: Research Funding, Speakers Bureau; Glaxo: Research Funding, Speakers Bureau; Micromet/AMGEN: Consultancy; Sigma Tau: Consultancy. Off Label Use: Liposomal cytarabine in prophylaxsis of CNS relapse in ALL.

Inotuzumab ozogamicin in combination with low‐intensity chemotherapy (mini‐HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with Philadelphia chromosome‐negative acute lymphoblastic leukemia: A propensity score analysis

“…[1][2][3][4][5][6][7][8][9][10][11][12] This success rate is not paralleled in older patients, for whom the 5-year survival rate remains dismal (approximately 20%). [13][14][15][16][17] Li and colleagues recently reported a median survival of 10 months among 727 older patients (aged >65 years) who were diagnosed Cancer August 1, 2019 between 2007 and 2012 and treated under Medicare. 16 By using the National Cancer Institute's Surveillance, Epidemiology, and End Results database to assess survival among 1675 older US adults (age ≥60 years) with ALL between 1980 and 2011, Geyer and colleagues reported a median survival of 4 months and a 3-year survival rate of 12.8%.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] Similar intensive chemotherapy strategies have not yielded comparable results in older patients with ALL, who have estimated cure rates of only 10% to 20%. 1,2,[13][14][15][16][17] In older patients with ALL, intensive chemotherapy results in lower response rates than the rates observed in younger patients with ALL and in high rates of toxicities. [13][14][15] One-third of patients who achieve a complete response (CR) may die of myelosuppression-associated complications.…”

“…1,2,[13][14][15][16][17] In older patients with ALL, intensive chemotherapy results in lower response rates than the rates observed in younger patients with ALL and in high rates of toxicities. [13][14][15] One-third of patients who achieve a complete response (CR) may die of myelosuppression-associated complications. 14 Cancer August 1, 2019 under Medicare, the median survival was 10 months.…”

Adult Acute Lymphoblastic Leukemia

“…In the prospective GMALL (German Multicenter Study Group for Adult ALL) study, 268 elderly patients were treated with BFM. 72 The CR and 5-year OS rates were 76% and 23%, respectively; however, the early death rate was 14% and the mortality rate for patients with CR was 6%. Patients younger than 75 years who had a good performance status fared better, with a higher CR rate (86%), lower early death rate (10%), and 3-year survival rate of 36%.…”

Phase 2 study of intensified chemotherapy and allogeneic hematopoietic stem cell transplantation for older patients with acute lymphoblastic leukemia

“…7,8 Cancer and Leukemia Group B reported a 17% 3-year OS for patients older than 60 years who received multi-agent cytotoxic chemotherapy, 9 with others reporting similarly poor results. [10][11][12][13][14][15][16] These suboptimal outcomes are likely related to a greater prevalence of poor risk features, such as the Philadelphia chromosome, in this population. 17 Older patients are also more likely to have organ dysfunction during treatment and thus are less likely to tolerate prolonged and intensive therapies.…”