Prognostic Impact of CD47 Overexpression in Patients with Acute Myeloid Leukemia

Background. CD47 is a membrane protein of the so-called “don't eat me signal” of innate immunity, capable of inhibiting phagocytosis by binding to the signal regulatory protein alpha (SIRPα) receptor on the surface of macrophages. Hematological malignancies express high levels of CD47 and interactions between the CD47 expressed on tumor cells and SIRPα of macrophages inhibit phagocytosis and determine immune evasion of neoplastic cells. High expression of CD47 in patients with acute myeloid leukemia (AML) has been associated with poor prognosis and disease relapse. Therapeutic approaches through drugs designed to target the interaction between CD47 and SIRPα are currently being studied in clinical trials. There is no standard technique for assessing CD47 expression in AML blasts in clinical practice and the real prognostic value of CD47 overexpression varies among studies in the current literature.

Methods. In this prospective study, CD47 expression on leukemic blasts was evaluated by flow cytometry in bone marrow aspirate samples of patients (pts) with newly diagnosed AML. CD47 expression was quantified in terms of median fluorescence intensity (MFI) and was compared with control healthy lymphocyte population. CD47 expression in AML blasts was correlated with clinical features and outcome, survival analysis was performed using the Kaplan-Meier method.

Results. To date, CD47 expression was evaluated by flow cytometry in 24 AML pts. Median age was 71 years (range 20-88 years) and 15/24 (62.5%) pts were considered fit for intensive chemotherapy. 15/24 (62.5%) pts showed de novo AML and 5/24 (20.8%), 11/24 (45.8%), and 8 /24 (33.3%) pts were classified as low, intermediate, and high-risk AML, respectively, according to the 2022 ELN criteria. Flow cytometry analysis demonstrated the expression of CD47 in all AML pts with a median MFI on leukemic blasts of 19.6 (range 4.5 - 168.88). In 7/24 (29.1%) pts the expression of CD47 in leukemic blasts was higher than in the control healthy lymphocyte population and were identified as pts with highly expressed CD47. CD47 expression did not correlate with risk stratification according to 2022 ELN criteria and no significant differences were observed in responses to first line therapy. In particular, in the group with high CD47 expression, 3/7 (42.8%) pts achieved CR and 4/7 (57.2%) were primary refractory. CD47 expression was correlated with a higher rate of relapse, although statistically not significant, indeed 5/10 (50%) and 2/3 (66.6%) pts relapsed in the low and high expression CD47 group, respectively. Allogeneic stem cell transplant (ASCT) was performed in 6/24 (25%) pts: 3/6 (50%) pts had relapsed or refractory AML with high CD47 expression at diagnosis, and among these, 2/3 (66.6%) underwent ASCT after responding to salvage therapy and are still in CR. After a median follow up of 12 months, 13/24 (54.1%) pts are still alive with a median overall survival (OS) of 11 mos and a median progression free survival (PFS) of 4.5 months. Kaplan-Meier survival analysis did not demonstrate significant differences in terms of OS related to CD47 expression, however pts with overexpression of CD47 showed a statistically significant reduced median PFS (2 months, p = 0.0036).

Conclusion. Albeit the small sample size of this ongoing prospective study, preliminary results suggest that CD47 overexpression in AML pts is related to a worse PFS compared to pts with low CD47 expression at diagnosis and flow cytometry proved to be a rapid and effective method to define pts with high CD47 expression. ASCT has been shown to be effective in pts with relapsed/refractory AML and CD47 overexpression when performed in complete remission after salvage therapy. The achievement of a larger sample size and a longer follow-up are necessary to confirm the prognostic value of CD47 overexpression in pts with AML and, possibly, to identify a subgroup of pts who could derive maximum benefit from emerging CD47/SIRPα blocking therapies.

Abruzzese:MorphoSys: Consultancy; Ascentage: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy.