Abstract

Introduction: MRD positivity after induction/consolidation therapy in pts with de novo ALL has been shown to carry a very negative impact on outcome. However, the significance of MRD status in the salvage setting has not been extensively studied.

Methods: We evaluated 130 pts with R/R B-cell ALL pts who received first (n=68), or second (n=62), salvage therapy between 2010 and 2015. Salvage therapies included single agent inotuzumab ozogamicin (INO; n=75), blinatumomab (n=20), or INO in combination with mini-hyper-CVD (n=35) [Jabbour E et al; EHA 2015]. Of the 130 pts treated, 78 (60%) responded and were assessed for MRD by six-color flow cytometry on marrow samples with a sensitivity of 0.01%. Morphologic responses were defined as follows, complete response (CR); disappearance of all disease with neutrophils ≥ 1.0 X 109/L, platelet > 100 X 109/L and blasts ≤ 5%, CRp; CR without platelet recovery, CRi; CR without platelet and/or neutrophil recovery.

Results: The clinical characteristics of the 78 responding pts with R/R ALL are summarized in Table 1. Overall, MRD negativity was achieved at response in 41 pts (53%). Among the 41 pts who responded to single agent INO (12 CR, 26 CRp, 3CRi), 17 (41%) achieved a negative MRD status. Among the 11 pts who responded to blinatumomab (9 CR, 2Cri), 8 (73%) achieved a negative MRD status. Among the 26 pts who responded to INO in combination with mini-HCVD (21 CR, 4 CRp, 1CRi), 16 (62%) achieved a negative MRD status. Forty-four pts received allogeneic stem cell transplantation (ASCT): of those, 21 pts were MRD negative and 23 pts were MRD positive at the time of response. Median follow-up was 19 months (2-55). Overall, there was a trend for more durable morphologic responses in MRD negative pts compared with MRD positive pts: the median complete remission durations (CRD) were 17 months and 8 months, with a 2-year CRD rate of 47% and 28% respectively (Table 2). The median event-free survival (EFS) was 12 and 6 months, respectively; the 2-year EFS rates were 32% and 8%, respectively. Similarly, there was a trend for better overall survival (OS) with a median of 17 months and 9 months for pts with negative and positive MRD, respectively; the 2-year OS rates were 36% and 27%, respectively. No difference in outcome was reported whether pts were censored or not at the time of ASCT.

Conclusion: In pts with R/R ALL, the achievement of negative MRD in addition to the morphologic response confers an improvement, although not statistically significant, in response duration and survival. Larger number of pts with longer follow-up is needed to validate these findings.

Table 1.

Clinical Characteristics of Pts (n=78)

 N (%)/Median [range] 
Age (years) 38 [18-87] 
Sex (Male) 50 (64) 
Performance Status 1 [1-3] 
WBC (x 109/L) 3 [0.3-38] 
% PB Blasts 0 [0-83] 
% BM Blasts 60 [8-97] 
Cytogenetics  
Diploid 20 (26) 
t(9;22) 4 (5) 
t(4;11) 7 (9) 
Miscellaneous 39 (50) 
Not done/ Insufficient metaphases 8 (10) 
Salvage  
Inotuzumab Ozogamicin 41 (53) 
Blinatumomab 11 (14) 
Inotuzumab Ozogamicin + mini-HCVD 26 (33) 
Number of prior therapies  
1 prior therapy 46 (59) 
2 prior therapies 32 (41) 
 N (%)/Median [range] 
Age (years) 38 [18-87] 
Sex (Male) 50 (64) 
Performance Status 1 [1-3] 
WBC (x 109/L) 3 [0.3-38] 
% PB Blasts 0 [0-83] 
% BM Blasts 60 [8-97] 
Cytogenetics  
Diploid 20 (26) 
t(9;22) 4 (5) 
t(4;11) 7 (9) 
Miscellaneous 39 (50) 
Not done/ Insufficient metaphases 8 (10) 
Salvage  
Inotuzumab Ozogamicin 41 (53) 
Blinatumomab 11 (14) 
Inotuzumab Ozogamicin + mini-HCVD 26 (33) 
Number of prior therapies  
1 prior therapy 46 (59) 
2 prior therapies 32 (41) 

Table 2.

Response Rates and Survival by MRD Status

 MRD Negative (n=41) MRD Positive (n=37) 
CR 24 18 n/a 
CRp 16 14 n/a 
CRi n/a 
CRD, median (m) 17 0.63 
2-year CRD rate (%) 47 28 
EFS, median (m) 12 0.06 
2-year EFS rate (%) 32 
OS, median (m) 17 0.18 
2-year OS rate (%) 36 27 
 MRD Negative (n=41) MRD Positive (n=37) 
CR 24 18 n/a 
CRp 16 14 n/a 
CRi n/a 
CRD, median (m) 17 0.63 
2-year CRD rate (%) 47 28 
EFS, median (m) 12 0.06 
2-year EFS rate (%) 32 
OS, median (m) 17 0.18 
2-year OS rate (%) 36 27 

Disclosures

Cortes:Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. DiNardo:Novartis: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.