Progress over perfection: evolving treatments in LCH

In this issue of Blood Advances, Donadieu et al¹ report on long-term outcomes of 288 children with chemotherapy-refractory Langerhans cell histiocytosis (LCH) who were treated with targeted therapies aimed at inhibiting BRAF (v-Raf murine sarcoma viral oncogene homolog B) or MEK, with objective responses observed in most patients.

Conventional treatment for LCH consists of chemotherapy, most often with prednisone and vinblastine, or cytarabine, with clofarabine and cladribine being used in refractory cases. Since the landmark identification of activating mutations in the MAP-kinase pathway in LCH and related disorders, a biologic basis for a novel therapeutic approach has emerged.² Several small studies have demonstrated the therapeutic benefit of BRAF- and MEK-inhibitors in children with refractory LCH.^3,4 However, given the rarity of these disorders, there is a paucity of data on the durability of response, efficacy in reversing vital organ dysfunction, and the long-term tolerance and toxicities of the inhibitors. Donadieu et al sought to address these key questions in their retrospective analysis of a large cohort of pediatric patients with chemotherapy-refractory LCH. Their diverse study population comprised all the disparate clinical forms of the disease, treated with a variety of targeted agents such as vemurafenib, dabrafenib, encorafenib, cobimetinib, trametinib, and binimetinib. As reported previously, MAPK-inhibitor (MAPKi) therapy was extremely effective and expeditious in achieving disease control. With a median duration of therapy of 2 years and a median follow-up of almost 4 years, the responses were durable with no instances of acquired resistance or on-therapy progression/relapses. Treatment was generally quite safe, with rare serious adverse events. In contrast to adults with histiocytic disorders, children appear to tolerate these therapies better, with very few discontinuing treatment due to side effects. Importantly, in contrast to melanoma, these therapies were not associated with skin cancers or other secondary malignancies. However, despite adequate disease control, reversal of organ dysfunction was not uniformly observed. Specifically, sclerosing cholangitis, a rare complication of liver LCH, persisted despite effective control of the LCH, and most of those patients required liver transplantation. Similarly, arginine-vasopressin deficiency (central diabetes insipidus) was also irreversible. The mechanisms of these limitations of MAPKi remain speculative and might include irreversible fibrosis and/or differing drug bioavailability in certain tissues.

Despite response rates nearing 95% or more, capturing nearly 30% more children than chemotherapy, MAPKi therapy in pediatric patients with LCH is not without controversy. One of the primary conundrums clinicians face is the unknown optimal duration of therapy needed to attain cure—a disease-free and treatment-free state, or whether such a state is even possible with targeted therapies. In the current retrospective report, almost half of the patients who achieved complete remission, were taken off therapy after a median of 1 year of treatment. Most (∼70%) of these patients experienced a recurrence, most often within the first few months of stopping treatment. Fortunately, resumption of therapy resulted in disease control. Another therapeutic dilemma is the concern that inhibitors cannot stand alone, that they fall short in their ability to eliminate the LCH-clone. This report trialed the addition of various cytotoxic chemotherapy treatments to the inhibitors, but it did not appear to add any therapeutic benefit to single-agent MAPKi. Notably, the risk of disease reactivation was higher in patients whose LCH involved the liver, spleen, or bone marrow (referred to as risk-organs), and in those with higher levels of circulating tumor cells, as measured by allele-frequency of the BRAF-V600E variant, the most common somatic mutation in LCH. Perhaps the combination of chemotherapy and targeted therapies may not be the right move.

An unpredictable and devastating aspect of LCH is neurodegenerative disease (ND), which can lead to severe, life-altering physical and cognitive disabilities. The pathophysiology of ND-LCH is just beginning to be understood, and the evidence so far suggests that direct infiltration of the brain by LCH cells (BRAF-V600+ microglia-like myeloid precursors) might be the culprit.⁵ In keeping with this notion, there are reports of objective responses of ND to MAPK-inhibitors.⁶ Unexpectedly, however, in this larger study by Donadieu et al, a significant proportion of children developed radiologic and/or clinical ND despite having no active systemic LCH while on MAPKi therapy. There did not appear to be a correlation between the specific agent and development of ND, nor did the combination of MAPKi and chemotherapy prevent ND. Notably, ND only developed in LCH associated with the BRAF-V600E mutation, not with any of the other mutations. Disconcertingly, the median time to MRI changes of ND was 3 years, whereas symptomatic ND took even longer to develop. Because this cohort was already selected for refractory LCH, the rate of ND might not be a true representation of the overall risk. Importantly, these results suggest that current MAPK-targeted therapies are inadequate for controlling the proliferation of BRAF-V600E+ cells in the central nervous system (CNS), despite their efficacy elsewhere. Could this difference be attributed to the blood-brain barrier, and could MAPK-inhibitors with better bioavailability in the CNS overcome this challenge? Or are there other mechanisms at play such as early neuronal loss caused by BRAF-mutant microglia-like cells, with subsequent protracted gliosis, causing delayed appearance of radiologic and clinical ND? Would early initiation of MAPK-inhibitors be beneficial, or does this require different therapies aimed at curtailing the growth of microglia-like cells (eg, CSF1R inhibitors)? The large retrospective study by Donadieu et al highlights the recent advances in therapy with improved outcomes for children with LCH, while also laying out the remaining gaps which are not trivial. Their results offer valuable insights into our efforts thus far, our progress and imperfections, and perhaps most importantly a roadmap for prospective studies as we look to the future.

Conflict-of-interest disclosure: A.K. is a consultant for SOBI and Eton Pharma. A.L.B. declares no competing financial interests.