Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL

Abstract

The potential impact on patient outcome of different Minimal residual disease (MRD) levels at time of transplant in patients with lymphoblastic leukemia undergoing allogeneic hematopoietic SCT (HSCT) remains uncertain. In this study, we quantified MRD levels at time of transplant using multiparameter flow cytometry (MFC). Mononuclear cells from marrow aspirates were obtained from 102 adult and child patients before their conditioning regimen. Quantification of MRD levels was carried out by detecting patient-specific leukemia-associated immunophenotypes using four-color MFC. Thirty patients exhibited measurable levels of MRD at the time of transplant, with low levels (0.01 to p0.1%) in 12 cases, intermediate levels (40.1 to p1%) in 8 cases and high levels (41%) in 10 cases. The leukemia-free survival (LFS) rates were 65.9±7.0%, 42.9±15.7% and 0% for negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Overall survival (OS) was 52.3 ± 7.6%, 28.6 ± 13.8% and 0% for MRD-negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Multivariate Cox analysis confirmed that detection of leukemia cells by flow cytometry at transplant was the most significantly adverse factor for OS, LFS and EFS after transplant.

Clinical value of pre‐transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease‐guided protocol

“…ª 2014 John Wiley & Sons Ltd report a sensitivity of 10 À4 and recent papers describe the prognostic significance of MRD assessed by flow cytometry (Borowitz et al, 2008;Garand et al, 2013;Sanchez-Garcia et al, 2013). Nevertheless, in the present study, the 5-year OS rate for children with pre-transplant MRD score above 10 À3 reached 40Á4%, and therefore high levels of MRD prior to HSCT do not preclude survival.…”

“…We report that IgH/TCR MRD prior to HSCT remains a major prognostic factor for both survival and relapse. We used molecular techniques to assess MRD, but detection of submicroscopic leukaemia cells by flow cytometry may yield comparable results: standardization studies report a sensitivity of 10 −4 and recent papers describe the prognostic significance of MRD assessed by flow cytometry (Borowitz et al , ; Garand et al , ; Sanchez‐Garcia et al , ). Nevertheless, in the present study, the 5‐year OS rate for children with pre‐transplant MRD score above 10 −3 reached 40·4%, and therefore high levels of MRD prior to HSCT do not preclude survival.…”

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

“…Currently, the detection of minimal residual disease (MRD) has been successfully used for hematological relapse prediction and MRD‐guided treatment of acute lymphoblastic leukemia (ALL) . Numerous studies have demonstrated that MRD evaluation during remission induction and consolidation therapy provides unique and valuable information and is the most important prognostic variable in many studies of adult and pediatric ALL . Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its important role in identifying patients who are unlikely to be cured by standard chemotherapy and benefit from receiving allogeneic stem cell transplantation (allo‐SCT) …”

“…In allo‐SCT settings, the importance of pretransplantation MRD (pre‐MRD) status is gaining appreciation based on several publications showing significantly inferior outcomes for ALL patients with positive pre‐MRD, and possibly, the clinical benefit accrued by an allo‐SCT in ALL patients with a suboptimal MRD response to initial induction chemotherapy . However, these studies, with heterogeneous conditioning regimen, stem cell source, and graft‐vs‐host disease (GVHD) prophylaxis, mainly focused on human leukocyte antigen (HLA)‐matched related (MSDT) and unrelated donor transplantation (MUDT) as well as cord blood transplantation (CBT) .…”

Advances in measurable residual disease monitoring for adult acute lymphoblastic leukemia

“…In comparing patients who underwent HSCT, those who had achieved MRD negativity prior to HSCT had superior outcomes compared with those who continued to have detectable MRD . Several other reports also suggest a worse outcome for patients with pretransplant detectable MRD …”