The Prognostic Value of Minimal Residual Disease (MRD) after Salvage Therapy in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL)

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)

 

Table 2. Response Rates and Survival by MRD Status
	MRD Negative (n=41)	MRD Positive (n=37)	p
CR	24	18	n/a
CRp	16	14	n/a
CRi	1	5	n/a
CRD, median (m)	17	8	0.63
2-year CRD rate (%)	47	28
EFS, median (m)	12	6	0.06
2-year EFS rate (%)	32	8
OS, median (m)	17	9	0.18
2-year OS rate (%)	36	27