Recent advances in the understanding and therapeutic management of mastocytosis

New insights into mast cell ontogeny

Recently, Gentek et al. reported that, like macrophages, MCs have two hematopoietic origins in the mouse¹⁷. Unlike MCs in other organs, MCs in the embryonic skin are derived from the yolk sac. These MCs persist after birth before being gradually replaced by the definitive adult MCs. Yolk-sac-derived MCs differ phenotypically from their BM-derived counterparts and have a distinct gene expression pattern. These newly discovered differences might explain the complete, spontaneous remission observed in more than 70% of cases of childhood-onset mastocytosis.

KIT mutations do not account for all mastocytosis phenotypes

More than 85% of patients with adult-onset mastocytosis present a somatic gain-of-function mutation in the KIT gene coding for the KIT transmembrane tyrosine kinase receptor¹⁸. The most frequently detected mutation leads to the substitution of an aspartic acid by a valine (D816V) in the second catalytic domain, resulting in constitutive kinase activity. In turn, this promotes MC activation, survival, and proliferation independently of KIT’s ligand (stem cell factor [SCF]). Under physiological conditions, SCF is critical for MC proliferation, differentiation, survival, and migration. Stimulation (by IgE or otherwise) enhances MC activation through the Ras-MAP kinase, SRC, STAT, and PI3K/AKT pathways. A somatic KIT mutation is present in around 80% of cases of childhood-onset mastocytosis. However, in contrast to adult cases, only 42% of the children present a mutation in codon 816 (exon 17); 44% of cases have a mutation outside exon 17 (mostly in the fifth Ig loop of the KIT extracellular domain, encoded by exons 8 and 9)¹⁹. Although all of these KIT mutations cause the constitutive activation of kinase activity, they cannot fully explain the clonal expansion of MCs and the heterogeneous symptoms observed in different types of mastocytosis. Patients harboring the same mutation can present with very different clinical pictures. In childhood-onset mastocytosis, complete spontaneous remission is typically observed at puberty, despite the presence of KIT-activating mutations, including the D816V mutation. Transgenic mice overexpressing KIT D816V exhibit slow expansion and indolent accumulation of MCs in the tissues, with incomplete penetrance, and they rarely develop aggressive mastocytosis²⁰. Although most patients with mastocytosis did not have a family history of MC disease, around 100 familial cases worldwide have been reported in the literature. However, only 13 of these presented with germline KIT mutations (A533D, M541L, Del419D, S451C, K509I, V559A, R634W, or N822I)^21–31. In the mastocytosis cohort at the CEREMAST, familial forms appear to be more prevalent than in the literature. Indeed, about 7% of our patients have a first- or second-degree relative with mastocytosis. The majority of these relatives do not have a mutation in the KIT gene (unpublished data). Thus, KIT mutations do not account for all familial forms of the disease. Lastly, BaF3 cells overexpressing KIT D816V do not display a transformed phenotype and are even driven towards maturation by the mutation³².

Taken as a whole, these observations strongly suggest the additional involvement of one or more germline or somatic mutations or polymorphisms in genes other than KIT; these would act synergistically with KIT mutations in the development of mastocytosis.

Associated somatic mutations

Somatic mutations in other genes (notably epigenetic regulator genes, such as SRSF2, ASXL1, RUNX1, and TET2) have been described in ASM and are often found in patients with a myeloid neoplasm. These mutations account for, at least to some extent, the different clinical entities in mastocytosis.

Several studies have investigated the prognostic impact of these additional mutations. Most of the mutations have been found in patients with AdvSM, and the presence and number of SRSF2, ASXL1, and RUNX1 (S/A/R) mutations are associated with a poor prognosis, even in patients treated with midostaurin (Figure 2)^33–35. In vitro studies suggest that these mutations act in synergy with abnormal KIT signal transduction to induce MC survival and proliferation. However, the underlying molecular mechanisms have yet to be characterized.

Figure 2. Advanced systemic mastocytosis: clonal architecture and prognosis.

A. A representation of the clonal architecture of the hematopoietic compartment in advanced mastocytosis. The associated mutations occur before the KIT mutation. B. An early D816V KIT mutation inside the hematopoietic progenitor compartment and the presence of SRSF2, ASXL1, RUNX1 (S/A/R) mutations are associated with a poor outcome. A, ASXL1 mutation; R, RUNX1 mutation; S, SRSF2 mutation.

Two studies have investigated the clonal architecture in SM-AHN. First, Schwaab and colleagues reported a correlation among the KIT allele burden, the number of colony-forming unit granulocytes monocytes (CFU-GM) bearing the D816V KIT mutation, and the severity of mastocytosis. This finding strongly suggests that an early D816V KIT mutation inside the hematopoietic progenitor compartment is associated with a poor outcome (Figure 2)⁶. The second study of mutations in both AHN and mastocytosis showed that the D816V KIT mutation could be found in CD15⁺ circulating cells and that MCs carried associated mutations. The results of a colony forming unit assay suggested that the associated mutations arise before the KIT mutation during hematopoiesis³³.

Cutaneous and indolent systemic mastocytosis: the main treatment objective is to decrease handicap and improve quality of life (Table 3 and Figure 3)

Patients with an indolent form of mastocytosis (like CM and ISM) can present two types of clinical symptoms: those related to MC activation syndrome (MCAS) and those related to MC infiltration (particularly skin infiltration). The treatment choice is therefore based on the signs that cause the most severe disability (Figure 3 and Figure 4).

Figure 3. Treatment flow chart for indolent and smoldering systemic mastocytosis.

2CDA, cladribine; DXA, dual-energy X-ray absorptiometry; IFN, interferon; ISM, indolent systemic mastocytosis; SSM, smoldering mastocytosis; TKI, tyrosine kinase inhibitor.

Figure 4. Treatment flow chart for advanced systemic mastocytosis.

ASCT, allogeneic stem cell transplantation; AdvSM, advanced systemic mastocytosis; AHN, associated hematologic neoplasm; ASM, aggressive systemic mastocytosis; BM, bone marrow; ISM, indolent systemic mastocytosis; MCL, mast cell leukemia; SM-AHN, systemic mastocytosis with an associated hematologic neoplasm; SSM, smoldering systemic mastocytosis.

The treatment of signs of MC activation is initially based on antihistamines (anti-H1 and anti-H2), leukotriene receptor inhibitors, and cromolyn. Although aspirin and NSAIDs may induce allergic and/or anaphylactic reactions, there is no absolute contra-indication to these drugs and they may even improve some symptoms like pains and flushing. For children with isolated mastocytoma and severe symptoms, the treatment of choice is topical corticosteroids with occlusive dressings. If this fails, excision in toto can be considered. Ultraviolet A (either alone or combined with oral psoralen) can be used in adolescents and adults to treat skin manifestations (especially pruritus) that are resistant to standard medications. It is essential to eliminate triggering factors (e.g. foods, medications, or environmental factors such as Hymenoptera stings) by testing for IgE-mediated allergy. These measures must be accompanied by patient education on epinephrine self-administration (especially in patients with a history of anaphylactic reactions)⁸. Honeybee- and wasp-allergic patients with a history of severe reactions must be submitted to allergen-specific immunotherapy³⁷. Patients must be warned of the risk associated with anesthesia; for example, the French Society of Anesthesia & Intensive Care Medicine has published specific guidelines on this topic. Most patients are improved by these initial therapeutic measures³⁸.

In our experience, we prescribe anti-H1 medications almost systematically for MCAS, especially for pruritus, urticaria, flushing, recurrent hypotension/anaphylaxis, or neuropsychic manifestations. We use anti-H2 medication and cromolyn with or without a proton pump inhibitor for gastrointestinal symptoms. Leukotriene antagonists seem particularly effective for flushing and pollakiuria. We are currently testing the effect of NMDA receptor inhibitors (such as ketamine) in patients (about 20%) with fentanyl-refractory chronic pain³⁹. Our preliminary results suggest that these treatments can be efficient. Lastly, as there is no prospective study published so far on the role of bone-forming therapies for mastocytosis-associated osteoporosis, we are investigating the efficacy of denosumab in a phase III study (NCT03401060). In addition to signs of MC activation, patients may experience disability due to the psychological and social impact of the skin involvement in MPCM. It is difficult to accurately assess the disability related to acute and chronic symptoms. Several consultations are necessary to confirm the patient's willingness to accept the potential risks associated with certain treatments, particularly for esthetic reasons, because the treatment of cutaneous lesions requires the use of cytoreductive drugs.

At present, there are no guidelines on MC activation that is refractory to antihistamine medications or on when cytoreductive drugs should be used. With the exception of masitinib, prospective clinical trials have not been performed. Hence, treatment choice is based solely on the specialist center’s own experience (Table 3)^15,40–45.

Tyrosine kinase inhibitors. Given the involvement of constitutive KIT tyrosine kinase activity in the pathophysiology of mastocytosis, several drugs used to block both BCR-ABL and KIT in cases of chronic myeloid leukemia have also been evaluated in SM.

The results of several prospective studies of first-generation (imatinib) and second-generation (dasatinib and nilotinib) inhibitors have been disappointing, with low response rates^44,45. On the molecular level, the presence of the D816V KIT mutation in the vast majority of cases of mastocytosis confers resistance to the above-mentioned inhibitors. We therefore reserve these treatments for the small proportion of patients who do not have a KIT exon 17 mutation; the results for MC activation and cutaneous involvement are encouraging.

Masitinib was evaluated in the first phase III study of patients with CM or ISM and significant disability¹⁵. Although masitinib lacks direct activity on the D816V KIT mutation, its action (particular on Lyn) appears to block MC degranulation in vitro. In Lortholary et al.’s study, masitinib had an acceptable safety profile and showed significant efficacy on symptoms; a reduction of more than 75% in symptoms was observed in 18.7% of the patients treated with the inhibitor and 7.4% of those treated with placebo (P = 0.0076). This drug is currently being evaluated in a confirmatory phase III trial.

Cladribine. Cladribine has never been prospectively evaluated in SM, although long-term follow-up data from patients with SM have been reported retrospectively. This drug has a positive effect on both skin involvement and the symptoms of MC activation. Barete et al. studied cladribine treatment in 36 patients with ISM/SSM; the overall response rate was 92%, and the median response duration was 44.5 months⁴⁰. Although the treatment induced significant neutropenia and prolonged CD4⁺ T-cell lymphopenia, the toxicity was mild and acceptable for an indolent disease. However, given the risk of secondary cancer observed in other indications, it is recommended to exclude patients with a history of cancer and to limit the number of courses of cladribine (0.14 mg/kg/day, for 5 days) to 6. We are currently looking at whether lower-dose maintenance treatment with cladribine might be as efficacious.

Omalizumab. Omalizumab is an anti-IgE monoclonal antibody indicated in the treatment of asthma and chronic urticaria. Given the drug’s mode of action and lack of cytoreductive activity, it has been suggested that omalizumab can decrease the signs of MC activation associated with mastocytosis⁴². The initial results in a small cohort were encouraging. In an analysis of the CEREMAST database, we reported on the largest-yet cohort of omalizumab-treated patients (n = 56) with indolent, cutaneous forms and MCAS⁴³. The results were particularly encouraging, with an overall response rate of 76.8% and reductions in all symptoms assessed, even the difficult-to-treat neuropsychiatric symptoms. Omalizumab is therefore an option that we often consider in patients who are very disabled by their signs of MC activation. Further work is needed to define the population that will benefit most from omalizumab treatment. At present, the optimal dosing frequency (150 to 300 mg every week to every four weeks) remains to be determined. Furthermore, omalizumab may be of value for Hymenoptera venom desensitization in patients with mastocytosis.

Other options. Pegylated interferon (pegIFN) has been used for decades in the treatment of mastocytosis. It effectively reduces both the signs of MC activation and the extent of cutaneous lesions⁴¹. The main limitation relates to the associated neuropsychiatric side effects in a patient population that frequently suffers from psychiatric signs in general and major depressive episodes in particular. However, pegIFN remains a valuable option, especially when other treatments are contraindicated or for cladribine sparing. PegIFN can be used also to treat the myeloproliferative disorders associated with mastocytosis.

Rapamycin may also be a relevant treatment option in relapsed or refractory patients carrying the D816V KIT mutation. We found that in vitro, D816V-mutated MC lines (but not wild-type MC lines) were specifically sensitive to rapamycin⁴⁶. Even though the first-in-human results did not show significant efficacy, our study of a series of 24 patients (including 12 with ISM) highlighted a response rate of 70% (especially for the signs of MC activation), as could be expected from the in vitro data (unpublished data, submitted for publication). Efficacy on MPCM was also observed.

Advanced mastocytosis: the main objective is to prolong overall survival (Table 4 and Figure 4)

Advanced mastocytosis is a spectrum of hematological malignancies with a poor prognosis. In eligible and particularly poor prognosis patients, the aim of the treatment is to induce remission to perform an allogeneic stem cell transplantation (ASCT) that remains the only current treatment with the potential to cure. Until recently, no targeted therapies were available for this difficult-to-treat set of MC diseases (Table 4)^{40,41,44,45,47–50}. Lately, impressive efficacy of midostaurin has been reported in the first large-scale phase II study in advanced mastocytosis, and so it was approved by the FDA in 2017. We will discuss below the main cytoreductive therapies used at our reference center.

Midostaurin. The broad-spectrum tyrosine kinase inhibitor midostaurin has activity against D816V KIT mutations. The results of the first large-scale clinical trial in patients with AdvSM (n = 116) were published in 2016⁴⁹. Overall, 60% of the patients treated with midostaurin exhibited a response. The safety profile was acceptable, and the most frequent adverse events affected the gastrointestinal tract (nausea and diarrhea). The median response duration was 24.1 months, and the median overall survival time was 33.9 months. Interestingly, the midostaurin response rates were similar in all of the subgroups of patients with ASM, including those with AHN. However, histologically complete responses were rarely observed, and treatment had to be maintained. In our opinion, midostaurin is currently the first-line treatment of choice for first-line AdvSM.

Cladribine. Cladribine has been studied to some extent, but it is not considered as the standard of care⁴⁷. In the above-mentioned study by Barete et al., 32 patients received cladribine for AdvSM⁴⁰. The overall response rate was 50%, and the median response durations in ASM and SM-AHN were 30 and 57 months, respectively. However, the median overall survival time was only 2.4 years for ASM. Furthermore, the treatment was not efficient in SM with AHN (particularly associated with myelodysplastic syndrome) and worsened cytopenia. Therefore, cladribine might best be used to treat smoldering forms, chronic MCL and forms associated with myeloproliferative neoplasms, or as a bridge to ASCT transplantation for midostaurin refractory patients.

Allogeneic stem cell transplantation. ASCT remains the only curative treatment for AdvSM and must be considered for all patients. The procedure’s major limitation is eligibility, given the frequency of comorbidities and advanced age in this patient population. Ustun et al. have reported on the largest-yet published series of patients treated with ASCT for AdvSM (n = 57)⁵⁰. Around two-thirds of the patients underwent prior myeloablative conditioning, and the 1-year non-relapse mortality rate was 20%. Strikingly, the overall response rate was 70%, and the complete response rate was 28%. The SM and AHN components were both sensitive to ASCT. The 3-year overall survival rate was 57%. It is noteworthy that most of these patients had not received midostaurin, and so one would expect to see better results in midostaurin-treated individuals. A Europe-wide retrospective analysis is ongoing (the European Society for Blood and Marrow Transplantation registry).

At the CEREMAST, we always consider early ASCT for eligible patients with MCL or high-risk AHN (Figure 4). For other cases, we typically use next-generation sequencing to screen for S/A/R mutations and decide on the optimal time for ASCT. With regard to the poor outcome for patients bearing these mutations, we plan to perform ASCT within a year of diagnosis (i.e. as soon as patients have achieved the best possible response to treatments such as midostaurin).