Targeting of Various Inflammatory Circuits Does Not Ameliorate Ineffective Hematopoiesis: Results of the Lucas and Canfire Studies Investigating IRAK4 or IL-1β Blockade to Target Anemia in Lower-Risk MDS

Background

Myelodysplastic neoplasms (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematologic malignancies characterized by dysfunctional hematopoiesis. These disorders frequently exhibit upregulation of inflammatory pathways, particularly those involving interleukin-1β (IL-1β) and interleukin-1 receptor-associated kinase 4 (IRAK4) within the bone marrow niche. This upregulation presents a potential therapeutic target for ameliorating ineffective hematopoiesis.

Patients and Methods

The LUCAS and CANFIRE trials are investigator initiated single-arm, phase 2 trials designed to assess the therapeutic efficacy of targeting these inflammatory pathways in adult patients with symptomatic anemia associated with very low, low, or intermediate-risk MDS or MDS/MPN. The LUCAS trial enrolled patients into two distinct cohorts: those refractory or intolerant to erythropoiesis-stimulating agents (ESA) and ESA-naive patients with serum erythropoietin levels greater than 200 U/L. Patients received emavusertib (CA-4948), an IRAK4 inhibitor, at a dosage of 200-300 mg orally twice daily for 21 days within a 28-day cycle, continuing for four cycles. The CANFIRE trial included refractory, intolerant to, or ineligible for ESA treatment. Participants received canakinumab, an IL-1β inhibitor, at a dosage of 200 mg subcutaneously every 21 days for a duration of 6 months. The primary endpoint for both trials was hematologic improvement in erythroid cells (HI-E) as per the International Working Group (IWG) 2018 criteria at the end of the planned treatment period. Bone marrow (BM) and peripheral blood (PB) samples were collected for the quantification of inflammatory cytokine concentrations in plasma utilizing Luminex xMAP technology (Merck).

Results

The LUCAS trial enrolled a total of 36 patients, 27 ESA-refractory/intolerant and 9 ESA-naive. 70% of these patients exhibited a high transfusion burden (HTB) (19/27 and 6/9, respectively); only a minority, 2 and 1 patients respectively, were non-transfusion dependent (NTD). Among all 36 patients treated with emavusertib, 22 (61%) completed the four-cycle treatment regimen. Serious adverse events (SAEs) were reported in 15 patients, with 9 of the 28 SAEs being potentially related to the study medication. One patient developed rhabdomyolysis grade 2 in the first cycle and stopped therapy. Two deaths occurred: one due to neutropenia (possibly related) complicated by pneumonia, and another due to gastrointestinal ischemia (not related). Emavusertib treatment was associated with a reduction in neutrophil counts. None of the 36 participants achieved HI-E. The study was discontinued following a preplanned interim futility analysis. Despite the lack of objective clinical efficacy, three patients continued treatment beyond four cycles due to perceived clinical benefits. Anti-inflammatory modulation was evidenced by an overall reduction in cytokine and growth factor levels in BM plasma over 1-5 months, achieving statistical significance for IL-7, IL-12p40, and PDGF-AA. Conversely, inflammatory markers in peripheral blood, such as TNF, IP10, GCSF, MCSF, IL-15, IL-10, MCP1, MIG, and IL1RA, were significantly elevated during emavusertib treatment. The CANFIRE trial included 11 patients (5 NTD, 2 low transfusion burden, and 4 HTB). Six patients (55%) completed the planned six months of treatment. CANFIRE was early terminated due to inadequate patient accrual. Canakinumab treatment was well-tolerated with no reported SAEs. None of 10 fully evaluable participants achieved an HI-E within eight cycles. Notably, one patient with ASXL1, SETBP1, and U2AF1 mutations achieved HI-E after 28 cycles (19.6 months) and has maintained a response for over 5 months. There was a trend towards lower cytokine levels in both BM and PB plasma in a subset of six patients.

Conclusion

Both LUCAS and CANFIRE demonstrated a lack of short-term clinical efficacy for single-agent anti-inflammatory treatment in patients with lower-risk MDS and MDS/MPN. Despite the observed anti-inflammatory effects in the bone marrow, in LUCAS there was a paradoxical increase in inflammatory markers in peripheral blood, potentially due to compensatory mechanisms. These findings suggest that targeting multiple inflammatory pathways simultaneously may offer a more promising therapeutic strategy, such as the combination of IL-1β and IRAK4 inhibitors.