A Systematic Literature Review (SLR) of Clinical Outcomes after Stem Cell Transplantation (SCT) in Adult Acute Lymphoblastic Leukemia (ALL) Patients with or without Minimal Residual Disease (MRD)
Authors: Turner Monica , Shah Shweta , Martin Amber , Cong Ze , Stein Anthony S. 
Published: October 2019

Abstract

Background: Most adult patients with ALL will achieve a complete hematologic remission following frontline therapy, but approximately 40% of patients will subsequently have evidence of MRD. This status describes the presence of leukemia cells in the bone marrow, which cannot be detected by conventional methods and is recognized as an independent negative prognostic factor for disease relapse and survival. An SLR was conducted to evaluate evidence comparing clinical outcomes following SCT among patients who are MRD+ vs. MRD- prior to transplant.
Methods: Medline, Embase, and Central databases were systematically searched with keywords for ALL and MRD to identify relevant literature on adults undergoing transplants according to MRD status published through 5/8/2018. Oncology conferences were also searched for relevant data presented between 2014─2018.
Results: 30 primary studies were identified that reported outcomes following SCT in ALL patients with MRD results available prior to transplant. Clinical outcome comparisons between MRD+ and MRD- patients were most commonly reported (27/30 studies). Comparisons between MRD+ and MRD- patients universally suggested that those with MRD+ status prior to SCT had lower survival rates at all time points reported relative to patients who were MRD- with an exception of one study, evaluating patients treated with salvage therapy, which favored MRD+ in survival gains with a non-significant difference between MRD+ and MRD- groups (Table 1).
The available hazard ratio (HR) on overall survival consistently indicated that patients with MRD+ status before transplant were more likely to die after SCT as patients who are MRD- (HRs for OS: 1.51-2.646) (Figure 1). MRD+ status was also associated with higher likelihood of disease progression, (HRs for PFS: 2.15 to 2.8).
Six studies reported data on mean or median survival; median OS after SCT ranged from 1.98 months to 17 months among MRD+ patients compared with 17 months to 67 months among those with MRD- status. This translated to median OS difference ranging from -8 to -50 months for the MRD+ vs. MRD- patients. Data indicated that patients who are MRD- at time of transplant also experienced longer median event-free survival (EFS) (median EFS difference was -8 months for MRD+ vs. MRD- in two studies) and longer median relapse-free survival (RFS) (median RFS MRD+ vs. MRD- of -40.5 months in one study).
While 12 studies reported data on the proportion of patients who relapsed after SCT, timepoints were not consistently reported and population sizes varied widely. Among all studies reporting this data, 16% to 100% of MRD+ patients relapsed after SCT, while 0% to 50% of MRD- patients experienced a relapse after SCT. Only four studies reported complete remission (CR); 35.6% to 86%of MRD+ patients achieved CR after SCT, while 100% of MRD- patients maintained CR after SCT based on one study.
Conclusion: This systematic literature review found consistent evidence of markedly worse transplant outcomes among patients with MRD+ vs. MRD-, including shorter median survival (OS, RFS and EFS), higher risks of death and relapse events and lower likelihood to achieve hematologic remission. Therapies that can eradicate MRD among adult ALL patients can potentially improve the outcomes of SCT in these critically ill patients.

Disclosures
Turner: Evidera: Employment. Shah:Amgen, Inc.: Employment, Equity Ownership. Martin:Evidera: Employment. Cong:Amgen, Inc.: Employment, Equity Ownership. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau.