Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia

Abstract

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

“…For those at a higher risk, MAC HCT might be considered to improve the leukemic control. 2,51,52 In patients who do not meet strict CR criteria and so are unfit to undergo a MAC allo-HCT, experimental targeted therapies and/or cellular therapies (for example, tyrosine kinase inhibitors in FLT-3-positive patients, hypomethylating agents 53 or haploidentical natural killer cell therapy 54 ) might be preferred over further conventional drug consolidation as a bridging therapy to allo-HCT. Consolidation chemotherapies did not improve allo-HCT outcome before either MAC or RIC transplantation.…”

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

“…Employing this assumption, as opposed to using the data reported in Leung et al 111 for this population, provided a more consistent prediction of survival data from Lee et al, 164 in which it was reported that all 10 HSCT recipients with a MRD-negative status were leukaemia free and alive at the end of study follow-up.…”

“…110,111,189 These studies have shown, to varying degrees, that MRD status prior to HSCT appears to be an important prognostic determinant of long-term RFS and OS, with MRD-negative (< 0.01% marrow blasts) patients experiencing superior survival compared with MRD-positive (> 0.01% to 5% marrow blasts) patients, including within studies of children with relapsed ALL. These data support the assumption of a continuous relationship between MRD level prior to HSCT and 5-year survival probability.…”

“…This was necessary because the existing survival data for CAR T-cell therapy were not reported in terms of being conditional on remission, MRD or HSCT status. Hence, the parameter estimates for the partitioned survival analyses were sourced from two external studies: Leung et al 111 for the post-HSCT survival probabilities and von Stackelberg et al 160 for the non-HSCT survival probabilities. A summary of the survival rates is provided in Table 16.…”

Acute myeloid leukemia: 2013 update on risk‐stratification and management

“…Walter et al have reported that MPFC detectable MRD prior to HCT is independently associated with relapse after HCT [17]. Since MRD prior to HCT reflects ineffectiveness of chemotherapy prior to HCT these results suggest that ineffective chemotherapy begets ineffective HCT, although the effect pre HCT of a given increment in MPFC detectable MRD seems greater, at least in children, in ALL than in AML [18].…”