Pediatric-Type Therapy Including Lineage-Targeted Methotrexate to Improve Early Minimal Residual Disease Response and Survival In Adult Acute Lymphoblastic Leukemia (ALL): Interim Analysis of Northern Italy Leukemia Group Study 10/07

Some studies have shown how the use of pediatric-type therapy (PDT) and minimal residual disease (MRD)-oriented programs could improve outcome of adult ALL.

We included PDT elements in a pilot trial started January, 2008. Protocol 10/07 consisted of standard induction and late reinduction courses plus 3 PDT blocks (modified after BFM therapy) alternating with 3 lineage-targeted Methotrexate (LTM) blocks (B-precursor: 2.5 g/m²; T-precursor: 5 g/m²; Ph+ or age >55 years: 1.5 g/m²). LTM targeted a Methotrexate plasma concentration of ∼35 and ∼65 micromol/L in B- and T-ALL, respectively, in line with a therapeutic concept developed at St. Jude's Hospital (Memphis, TN, USA) in childhood ALL. The program was integrated by (a) a randomised, radiation-free central nervous system (CNS) prophylaxis study comparing intrathecal Methotrexate, Ara-C, and Prednisone (×12) vs. liposomal Ara-C (DepoCyte 50 mg, ×6 [B-ALL]-8 [T-ALL]); (b) the molecular evaluation of MRD at pre-fixed treatment weeks (w), to optimise risk stratification and indications for allogeneic stem cell transplantation (allo-SCT); and (c) by concurrent imatinib in patients with Ph+ ALL. The whole chemotherapy plus MRD study sequence was as follows: prephase (Prednisone, Cyclophosphamide) → induction (Idarubicin, Vincristine, Asparaginase, Dexamethasone) + w4 MRD → PDT₁ (Cyclophosphamide, Vincristine, Idarubicin, Dexamethasone, Ara-C, 6-mercaptopurine) → LTM₁ (plus high-dose Ara-C) + w10 MRD → PDT₂ → LTM₂ (plus Asparaginase) + w16 MRD → PDT₃ → LTM₃ (plus HD Ara-C) + w22 MRD → reinduction (Idarubicin, Vincristine, Cyclophosphamide, Dexamethasone). CNS prophylaxis was administered only during PDT blocks, with a minimum interval >15 days from/to LTM cycles. Risk classes were standard (SR: pre-B and WBC<30; cortical T and WBC<100; CR at cycle 1) and high (HR: other subsets). Allo-SCT was prescribed as soon as possible to all patients with Ph/t(4;11)+ ALL or other highly adverse cytogenetics; with WBC >100, or CD1a-negative early or mature T phenotype; and to SR/HR patients with MRD >10^-4 after LTM₁ (w10) or detectable at any level after LTM₃ (w22). Autologous SCT followed by maintenance was a suitable alternative when allo-SCT was not feasible. All patients not eligible to frontline allo-SCT and with low positive (<10^-4) or negative MRD results were submitted to standard maintenance.

Seventy-five of 81 evaluable patients (median age 40 years [range 18–65], 54% male, 23% T-ALL, 60% HR, 20% Ph+) achieved CR (92.5%); 55 of them (73.5%) were alive in CR1 at time of interim analysis (April, 2010). Sixteen patients relapsed (21.5%) and four died in CR of therapy-related complications (one after allo-SCT and 3 aged >55 years after a PDT cycle). With a maximum follow-up slightly >2 years (27.5 mos.), projected overall survival (OS) at 1.5 years is 73% (95% CI 57%-83%), and disease-free survival (DFS) 66% (95% CI 52%-77%). The best results were observed in patients aged 55 years and less (n=65, OS 79%) and those with T-ALL (n=20, OS 86%). These findings correlated well with a favourable early MRD response in Ph-negative subsets: 49% of evaluable cases achieved a major MRD response (<10^-4) at end of induction cycle (w4: MRD negative 6/13 T [46%] vs. 7/24 B [29%]; <10^-4 2 T and 3 B; overall 61.5% T and 42% B), as did 64% of the patients after LTM₁ (w10: MRD negative 11/15 T [73%] and 16/27 B [59%]; <10^-4 2 T and 1 B; overall 87% T and 63% B). MRD results were predictive of CR durability. Pooled MRD data from all time-points (w4-22) indicated a probability of CR of 92% in 18 patients with all results <10^-4 vs. 60% in 19 patients with at least one MRD value >10^-4 (P=0.039). The flexible risk- and MRD-adapted SCT policy resulted in high early transplantability rate in patients with this indication (70% in T-ALL). Finally, the randomised CNS prophylaxis trial preliminarily confirmed the feasibility of intrathecal DepoCyte as planned (total randomised patients = 57).

This regimen was highly active, yielding a >90% CR rate in unselected adults aged up to 65 years, with a major early MRD response of 63% in Ph-negative B-ALL and 87% in T-ALL. The toxicity observed after PDT blocks in a first group of patients aged >55 years required a reduction of PDT dose intensity in this age group. LTM therapy proved feasible, up to 5 g/m² in T-ALL, and remarkable early OS/DFS rates were obtained in T-ALL and in unselected patients aged <55 years.

Bassan: Mundipharma: Consultancy, Research Funding. Off Label Use: Study is devoted to assess feasibility/toxicity/value of intrathecal liposome-encapsulated cytarabine (DepoCyte) vs standard intrathecal therapy as prophylaxis of CNS recurrence in adult ALL.