BTK inhibitor plus CXCR-4 antagonist for CXCR4 mutated Waldenström macroglobulinemia

November 2021 Clinical trials Nalinee Pathak

Waldenström macroglobulinemia (WM) is a cancer of a specific type of white blood cells known as plasma cells. Around 1,500 incidences of WM per year are reported in the United States (US) alone. It is also referred to as lymphoplasmacytic lymphoma (LPL) and is one of the many subtypes of non-Hodgkin lymphoma (NHL).

The MYD88 gene is a commonly mutated gene in WM, and as MYD88 interacts with Bruton’s Tyrosine Kinase (BTK), inhibitors of BTK such as ibrutinib have been explored for efficacy and safety for treatment of WM patients. Unfortunately, patients with a mutation in CXCR4 (CXCR4Mut) tend to show a less robust response to ibrutinib as compared to patients with a mutation in the MYD88 gene alone.

Phase I clinical trial

A phase I clinical trial was conducted by Treon et al with a CXCR4-antagonist ulocuplumab with ibrutinib, evaluating the efficacy and safety of this combination in patients with CXCR4Mut. The study enrolled 13 patients of which 9 were treatment naïve. Drugs were administered to patients in cycles where each cycle was of 4 weeks duration. During the first cycle, ibrutinib was given at 420 mg/d and continued until intolerance or progression. ulocupumab was administered to WM patients in cycles 1 to 6, with a 3+3 dose escalation design.

Main findings

All the enrolled patients were evaluable for response except one. The median serum immunoglobulin M and bone marrow disease showed a significant decrease from 5574 to 1114 mg/dL and from 65% to 10% respectively (p < .001). The treatment with the combination also lead to a significant increase in hemoglobin levels (from 10.1 to 14.2 g/dL, p<.001). Median time to minor and major response to treatment was at 9 and 12 months respectively. Also, the major and VGPR response rates were 100% and 33%, respectively. Also, VGPR response was seen in patients treated with lower dosage of ulocuplumab. Importantly, the estimated two-year progression free survival was 90%, with a median follow-up of 22.4 months. Safety results were consistent with the known tolerability profile of these drugs, and no new safety concerns were reported during the study. The most common grade ≥2 adverse events were thrombocytopenia, rash, and skin infections. However, higher dosage of ulocuplumab had no impact on the adverse events.

Conclusion

These findings demonstrate the efficacy and safety of using ibrutinib with ulocuplumab for CXCR4Mut WM. Moreover, the results provide evidence and motivation towards development of new CXCR4-antagonists.

Reference

Treon SP, Meid K, Hunter ZR, Flynn CA, Sarosiek SR, Leventoff CR, et al. Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated  Waldenström macroglobulinemia. Blood. 2021 Oct;138(17):1535–9.

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