Post-induction Measurable Residual Disease Using Multicolor Flow Cytometry Is Strongly Predictive of Inferior Clinical Outcome in the Real-Life Management of Childhood T-Cell Acute Lymphoblastic Leukemia: A Study of 256 Patients

Abstract

Background: Measurable/minimal residual disease (MRD) status is suggested as a powerful indicator of clinical-outcome in T-cell lymphoblastic leukemia/lymphoma (T-ALL). Contrary to B-cell ALL, reports on TALL MRD are limited and mostly based on molecular methods, mainly from developed countries. Multicolor flow cytometry (MFC)-based TALL studies are very few. Clinically relevant cutoff levels and ideal time-point for MRD assessment are still inconclusive. In view of lack of TALL MRD data from the developing world, we evaluated the prognostic value of MFC-based post-induction (PI)-MRD assessment in TALL in the context of standard practice. Methods: We included 256 childhood-TALL patients (age < 15 years) treated with a modified-MCP841 protocol, which uses high-dose cytarabine during consolidation, as a part of standard hospital practice. MRD was studied using 10-color 11-antibody MFC with any level of detectable disease being considered positive. Post-induction (PI)-MRD was available in all patients, and post-consolidation (PC) MRD was available mostly in PI-MRD-positive patients (n = 88). Results: Three years cumulative-incidence-of-relapse (3years-CIR) in PI-MRD-positive patients was inferior to negative patients (46.3% vs. 18.4%). The median relapse-free-survival (RFS), event-free-survival (EFS) and overall-survival (OS) with hazard ratio (HR) of PI-MRD-positive patients were 21.4 months vs not reached (p < 0.0001, HR-4.7), 21.6 months vs. not-reached (p = 0.0003, HR-2.01) and 37.3 months vs. not reached (p = 0.026, HR-1.64) respectively. RFS, EFS and OS of patients with PI-MRD<0.01% (n = 17) were as inferior as PI-MRD ≥ 0.01% in comparison Tembhare et al. Post-induction MRD & WBC Count in TALL with MRD-negative patients with HR of 4.7 (p < 0.0001), 2.45 (p = 0.0003), and 2.5 (p = 0.029), respectively. Three-years-CIR of patients with hyperleukocytosis (≥100 × 109/L) was also higher (50.5 vs. 27.6%) with inferior RFS, EFS, and OS. Among PI-MRDpositive patients, 3years-CIR, RFS, EFS, and OS of PC-MRD-positive were also inferior to that of negative patients. On multivariate analysis any-level detectable PI-MRD and hyperleukocytosis remained independently associated with inferior RFS, EFS, and OS. A combination of PI-MRD-positive status and hyperleukocytosis identified the patients with the worst clinical outcomes. Conclusion: Detectable PI-MRD using MFC was found to be the strong predictive factor of inferior clinical outcome in TALL patients. The combination of PI-MRD status and hyperleukocytosis provides the most influential tool for the management of TALL in resource constrained settings from developing world.

Minimal residual disease level determined by flow cytometry provides reliable risk stratification in adults with T‐cell acute lymphoblastic leukaemia

“…EOI‐MRD was the most powerful predictor of relapse independent of other known risk factors (Table IV). 5,12,17,22,27,28 In our present study, patients who were EOI‐MRD positive had a higher 2‐year CIR than MRD‐negative patients (87·6% vs. 38·8%, P = 0·0020). Although the relapse rate in our present cohort seems high, it was consistent with that previously reported by Krampera et al ., 14 demonstrating that the 2‐year CIR of EOI‐MRD‐positive versus ‐negative patients was 81·5% versus 38·9% in adult patients with T‐ALL.…”

“…EOI‐MRD positivity is the most important independent high‐risk factor for event‐free survival (EFS) and OS in B‐ALL and paediatric T‐ALL (Table IV). 12,22,31 However, in adult T‐ALL, data on the impact of MRD on long‐term outcomes are limited due to its relative rarity 25 . In our present study, adult patients with T‐ALL with EOI‐MRD positivity had inferior RFS and OS compared with MRD‐negative patients (2‐year RFS, 5·4% vs. 61·0%; 2‐year OS, 32·7% vs. 69·7%).…”

“…In our present study, we used 0·01% as a cut‐off value to stratify patients and showed that patients with an EOI‐MRD ≥0·01% had poor clinical outcomes, consistent with published reports that MRD ≥0·01% is clinically significant in predicting the outcome of T‐ALL (Table IV). 12,14,15,17,21,22,25,26,29 These data indicate that FCM is a useful method for MRD assessment and could be adaptable in routine clinical practice for T‐ALL management 7,17,22 …”

“…Minimal residual disease (MRD) has been established as a powerful predictor of relapse and survival in paediatric and adult B‐ALL 3–8 . However, for T‐ALL, most MRD studies have focussed on children 9–12 and few studies have been reported to date about the prognostic impact of MRD in adult T‐ALL due to its relative rarity 13–15 . In addition, many MRD detections in T‐ALL have been based on the polymerase chain reaction (PCR) method 9,10,13 .…”

“…In addition, many MRD detections in T‐ALL have been based on the polymerase chain reaction (PCR) method 9,10,13 . However, 5–15% of patients have no suitable PCR marker, which hampers treatment stratification of these patients 12,16 . Recently, Modvig et al 17 .…”