Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasia resulting from clonal expansions of CD207 + CD1a + cells, which causes tissue destruction and a wide range of organ involvement (Allen et al. 2018; Goyal et al. 2022). This disease predominantly affects children, and its clinical presentation can range from mild lesions to life-threatening conditions (Krooks et al. 2018). Patients with single lesions may respond positively to local treatment, while those with multisystem disease may be recurrent and refractory to systemic therapy (Cui et al. 2023). Despite the development in LCH treatment, approximately 30% of high-risk LCH patients experienced treatment failure, and 27% reactivate (Rodriguez-Galindo 2021; Tang et al. 2021; Sakamoto et al. 2023), increasing the risk of long-term complications and death. However, there is no ideal second-line therapy currently available. The treatment options include cladribine with cytarabine, MAPK pathway inhibitors (BRAF or MEK inhibitors), and hematopoietic stem cell transplantation. 2-CdA/Ara-C (cladribine and cytarabine) is an impressive salvage treatment but is associated with high toxicity (Donadieu et al. 2015). Furthermore, TNF-ɑ antagonist and hematopoietic stem cell transplantation are performed in patients refractory to standard chemotherapy (vinblastine, prednisone, and mercaptopurine); however, their dubious curative effects and adverse effects limit their widespread use (Rodríguez et al. 2009; Chohan et al. 2012; Akkari et al. 2003). The high toxicity and potential long-term adverse effects associated with salvage treatment highlight the need for innovative therapies in this patient group.

One promising targeted therapy for LCH is BRAF^V600E inhibitors since the genetic defect driving clonally expanded myeloid precursors to differentiate into LCH cells and cause lesions has been demonstrated to result from this mutation (Rollins 2015; Yang et al. 2021; Bigenwald et al. 2021). Vemurafenib is an oral low-molecular-weight molecule that selectively binds to the ATP-binding site of the kinase and inhibits BRAF^V600E (Garbe and Eigentler 2018). Previous studies have shown that vemurafenib generated nearly universal responses (Mohapatra et al. 2022); however, most patients experience rapid reactivations following therapy discontinuation. The persistence of BRAF^V600E-positive cells in both blood and bone marrow suggests that vemurafenib can interrupt pathogenic mechanisms but is ineffective in eliminating LCH precursor cells (Eckstein et al. 2019). Therefore, alternative approaches are needed for a cure. Conventional chemotherapies can effectively destroy LCH cells and compensate for vemurafenib’s shortcomings. However, the available data regarding the efficacy of vemurafenib plus conventional chemotherapies in curing LCH are limited. We conducted a retrospective analysis to evaluate the safety and effectiveness of this treatment regimen in patients with severe or refractory LCH.

LCH patients with BRAF^V600E mutations often have more severe disease presentations and are less likely to respond to first-line treatment (Heritier et al. 2016). In this study, we found that the combination of vemurafenib with hypotoxic conventional chemotherapies could rapidly induce a sustained and durable response in the majority of patients with severe or refractory LCH, and the associated side effects were tolerable. Our study showed that vemurafenib in combination with chemotherapy can achieve remission at the molecular level, which is difficult to achieve with vemurafenib monotherapy (Eckstein et al. 2019).

During the last decades, several treatment regimens have been demonstrated to be useful for severe LCH patients (Rigaud et al. 2016). However, all of them have their limitations. The combination of cladribine/Ara-C, as a salvage treatment, significantly improved the ORR and the survival rate of severe LCH patients, but the toxicity was high and the response was slow (Donadieu et al. 2015). As a single agent, the BRAF^V600E inhibitor can provide a rapid and robust clinical response, but the relapse rate after discontinuation is about 80% (Mohapatra et al. 2022; Wang et al. 2021). The clinical presentation of Langerhans cell histiocytosis (LCH) is influenced by the location of misdirected myeloid differentiation (Berres et al. 2014). Somatic BRAF^V600E mutations in hematopoietic precursors increase the risk of developing multiple organ involvement in LCH (Rodriguez-Galindo and Allen 2020; Poch et al. 2021). Moreover, the burden of these mutant clones correlates with the probability of relapse (Wang et al. 2021; Milne et al. 2023), emphasizing the importance of eliminating precursor cells for a cure. However, the persistence of BRAF^V600E-positive mononuclear cells in both the blood and bone marrow, along with a high recurrence rate following drug withdrawal, suggests that vemurafenib monotherapy may be ineffective in completely eradicating LCH precursor cells (Eder et al. 2022; Donadieu et al. 2019). The cytotoxicity of chemotherapeutic agents can compensate for this deficiency. In our study, vemurafenib combined with cytotoxic chemotherapies was administrated in severe LCH patients. We observed a significantly high relapse-free rate of 73.3% (11/15) after discontinuation at a median follow-up of 34 months. About 83% (5/6) of patients achieved molecular remission in the bone marrow after treatment. Our results indicated that the combination of vemurafenib and chemotherapies was helpful in the complete elimination of BRAF^V600E mutant clones, thus leading to a more sustainable response.

LCH patients with BRAF^V600E mutations or those presenting with risk organ involvement or multiple organ involvement often exhibit a poor response to first-line treatments (Heritier et al. 2016). To enhance the efficacy of treatment in this patient group, we administered vemurafenib in combination with conventional chemotherapy to high-risk LCH patients following diagnosis. All patients demonstrated a positive response within 3 months and 66.6% of patients remained free of relapse at a median follow-up of 32 months. Vemurafenib as part of the initial chemotherapy regimen for patients with high-risk LCH may improve remission rates and reduce hospitalization costs for salvage therapy after relapse, but more data are needed to support this in the future.

The optimal combination strategy for vemurafenib therapy in Langerhans cell histiocytosis (LCH) patients remains uncertain, and there is limited data available on this therapeutic regimen. Dmitry-Evseev et al. administered a 6-month course of vemurafenib in combination with chemotherapy to young children or infants with aggressive multisystem LCH who were refractory to previous chemotherapy. Among the participants, four patients received vemurafenib combined with vinblastine and prednisolone, while five others received cytarabine and cladribine. However, only one patient who received vemurafenib plus cytarabine and cladribine successfully discontinued vemurafenib. It seems that a too brief course of vemurafenib may be insufficient for eradicating myeloid progenitors of LCH, even when combined with chemotherapy (Evseev et al. 2021). Evseev, D found that combined cytarabine (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with vemurafenib achieved stable remission in LCH patients, but all patients experienced grade 3–4 hematological adverse reactions. One patient developed secondary myelodysplastic syndrome (sMDS) 14 months after vemurafenib therapy cessation (Evseev et al. 2023). In our study, we administered vemurafenib in combination with low-toxicity chemotherapy for over 12 months to the majority of patients, and most of them achieved clinical and molecular remission. These regimens were well-tolerated and suitable for administration in an outpatient setting, with a low incidence of adverse events (Tardieu et al. 2021). We also observed that three patients experienced relapse after drug withdrawal, one experienced molecular reactivation and one patient’s bmBRAF remained consistently positive, despite clinical symptoms having been alleviated. Whether an extended course of vemurafenib or more intensive chemotherapy regimens are needed to achieve a cure in these patients remains unknown. Although our study showed satisfactory efficacy of these regimens in most patients, further randomized trials are needed to confirm their efficacy in the treatment of LCH.

In conclusion, combination therapy of vemurafenib and chemotherapies can clear the bone marrow BRAFV600E gene load and maintain the response after drug withdrawal. As a first-line treatment for patients with high-risk Langerhans cell histiocytosis (LCH), vemurafenib combined with vinblastine and prednisone can potentially improve remission rates. Nevertheless, the optimal combination strategy remains unclear, and large-scale prospective studies are needed in the future to evaluate the effectiveness of the combination and to clarify the optimal regimen.