Prognostic Value of Minimal Residual Disease (MRD) Detection in Adult Acute Lymphoblastic Leukemia (ALL) – HYPER-CVAD Protocol

Objective: HYPER-CVAD is an intensive treatment protocol of short duration, for ALL and other lymphoid neoplasms. It is consisted of 8 alternating cycles (parts A and B): in part A (cycles 1, 3, 5, 7) fractionated doses of cyclophosphamide, vincristine, doxorubicin and dexamethazone are administrated, while in part B (cycles 2, 4, 6, 8) high doses of methotrexate and aracytin. The two first cycles compose the induction therapy, while the next 6 cycles constitute the consolidation therapy, followed by two years of maintenance therapy. Protection of CNS is achieved with intradorsal injections, whereas in Ph+ ALL patients, imatinib is also administered. The aim of this study was the clinical evaluation of MRD detection in adult patients with ALL, during chemotherapy with HYPER-CVAD.

Patients/Methods: During the period 1999–2008, 30 patients were hospitalized in our hospital for ALL and were treated with HYPER-CVAD therapeutic protocol. Among them, 14/30 (46,7%) were males and 16/30 (53,3%) females (median age 43,5 years, range 16–70). Median follow-up time was 12,8 months (range 0,5–100). ALL of T-origin had 8/30 patients and of B-origin, 22/30 (1 B1-EGIL/pro-B, 17 B2-EGIL/B-common, 4 B3-EGIL/pre-B). Caryotypic analysis and FISH was done in all patients (7/30 bcr/abl+). According to classical prognostic markers of ALL: 21/30 were classified as high, 4/30 as medium and 5/30 low risk, respectively. MRD presence was detected in bone marrow samples, with flow cytometric panels, at three particular treatment time-points: completion of induction therapy (T1), completion of consolidation therapy (T2) and at the end of maintenance therapy (T3). Overall survival (OS) and disease free survival (DFS) were investigated, especially in relation to the influence of MRD presence in (OS) and (DFS), respectively. For statistical analysis, Kaplan-Meier was used.

Results: At treatment time-point (T1), MRD was detected in 10/28 (35,7%) patients, at time-point (T2) in 7/23 (30,4%) and at treatment-point (T3) in 9/17 (52,94%). The influence of MRD detection in (OS) was statistically significant (p<0,05) at (T2) and (T3), while in (DFS) the detection of MRD presence in any of the standardized treatment time-points resulted in decreased DFS (T1/p<0,05, T2 and T3/p<0,001).

Conclusions: Our results suggest that MRD detection during therapy of adult ALL is a negative prognostic indicator for (OS) and (DFS), the independency of which has to be confirmed after prolonged follow-up time and increased number of cases.