Factors Influencing Relapse after Allogeneic Hematopoietic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.
Authors: Al-Ali Haifa K. , Nehring Claudia , Krahl Rainer , Becker Cornelia , Leiblein Sabine , Edelmann Jeanett , Poenisch Wolfram , Lange Thoralf , Niederwieser Dietger 
Published: April 2020

Relapse (RI) after HCT especially after RIC remains the major risk factor affecting outcome. Factors influencing relapse in patients (pts) with AML/MDS undergoing HCT after RIC were analysed.

Patients and methods: From July, 1998- December, 2006, 156 consecutive pts [86 m/70 f; median age 61 (range 21–75) years (y)] with AML, n=138 (88%) and high-risk MDS, n=18 (12%) treated within the OSHO studies received HCT after RIC [2Gy TBI ± fludarabine 30 mg/m2/day on 3 days] followed by immunosuppression with mycophenolate mofetil and cyclosporine. Donors were MRD in 40 (26%) and MUD in 116 (74%) pts. Stage of disease was CR1, n= 99 (63%), CR2, n=18 (12%), and &gt;CR2, n=39 (25%). Cytog. was intermediate-, and high-risk in 100 (64%), and 49 (31%) respectively. DCC in unsorted and flow-sorted T (CD3+)-, and CD34+-bone marrow cells at days (d) 28, 56, 84, and at 3 months interval thereafter was monitored by FISH for the XY chromosome in gender mismatched or PCR for polymorphic micro satellite regions in gender matched HCT.

Results: 141 (90%) pts engrafted. OS, DFS, RI, and NRM at 5 y were 38%, 36%, 47%, and 30% respectively. In multivariate analysis, RI for pts in CR1 was significantly lower compared to pts transplanted beyond CR1 (p=0.005). For the entire cohort, type of donor had no influence on RI but for pts in CR1, RI with MUD and MRD was 29% and 60% respectively (p=0.008). NRM did not correlate with the type of donor. Interestingly, high-risk cytog. had no negative impact on outcome. OS, DFS, and RI for pts with high-risk cytog. transplanted in CR1 were 43%, 48%, and 38% respectively compared to 38%, 43%, and 45% for pts with intermediate-risk cytog. (p=0.65). Incidence of acute (grade I-IV) and chronic (limited and extensive) GvHD was 55%, and 58% respectively. GvHD correlated with an improved OS (p=0.0003) and DFS (p=0.003) but was not associated with a higher NRM (p=0.1) compared to pts with no GvHD. Also, RI was markedly influenced by GvHD (p=0.002). RI in pts with no GvHD (n=42), acute GvHD only (n=34), limited chronic GvHD (n=33), and extensive chronic GvHD (n=30) was 63%, 41%, 29%, and 18% respectively. In pts with chronic GvHD, RI was significantly lower compared to pts with no GvHD (p&lt;0.0001). Further, CD34+ DCC ≥90% at d 28 strongly correlated with outcome at 5 y. OS and DFS in pts with CD34+ DCC ≥90% at d 28 (group I) were 50%, and 47% respectively compared to pts with CD34+ DCC &lt;90% at d 28 (group II) (OS 20%, DFS 15%) (p&lt;0.0001). CD34+ DCC ≥90% at d 28 was highly predictive of early (≤100 d) and late (&gt;100 d) haematological relapse. Probability of RI in group I was 29% compared to 76% in group II (p&lt;0.0001). On the other hand, DCC in unsorted- and CD3+-cells at d 28 did not correlate with OS, DFS nor predict relapse.

Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS pts. RI was lowest in pts transplanted from MUD in CR1. High-risk cytog. had no negative impact on RI. GvHD correlated with an improved outcome. CD34+ DCC ≥90% at d 28 was highly predictive of relapse after HCT. Careful monitoring of CD34+ DCC could identify pts at risk of relapse and might allow therapeutic interventions as tapering of immunosuppression.