Treatment of Indolent and Advanced Systemic Mastocytosis.

Management of Indolent and Smoldering SM is focused on preventing anaphylactic reactions and identifying and avoiding symptom triggers. Skin and gastrointestinal symptoms are managed with H1- and H2-antihistamines. When skin symptoms are not adequately controlled, leukotriene antagonists and oral psoralen combined with ultraviolet therapy may be added. Proton pump inhibitors, sodium cromolyn, and oral corticosteroids may be added for gastrointestinal symptoms. Patients should be prescribed self-injectable epinephrine and trained to treat recurrent cardiovascular symptoms or anaphylaxis. Depression and cognitive impairment require a psychiatric evaluation for tailored treatment. Bone involvement is managed with bisphosphonates and eventually interferon. Omalizumab is effective on all vasomotor symptoms, including anaphylaxis, but not on respiratory, musculoskeletal, and neuropsychiatric symptoms. A cytoreductive treatment is not recommended unless anti-mediator therapy has failed. Venom immunotherapy is mandatory for patients with Hymenoptera venom allergy. There is no curative option for patients with advanced SM. The available therapeutic options include tyrosine-kinase inhibitors and cladribine, with variable duration and extent of response. Imatinib mesylate was the first drug approved for SM lacking the cKIT D816V mutation; dasatinib and nilotinib are ineffective. Midostaurin is active on both wild-type and mutant cKIT D816V, while Avapritinib is a selective cKIT D816V inhibitor: they are approved for the treatment of advanced SM. Cladribine is a purine analog with significant activity against monocytes that were thought to have a common progenitor with mast cells. Allogeneic stem cell transplantation is usually performed in younger selected patients.

Introduction

Systemic mastocytosis (SM) is a myeloproliferative neoplasm resulting from a clonal expansion of morphologically and immunophenotypically abnormal mast cells (MCs). A gain-of-function somatic mutation in the KIT gene, which codifies for a tyrosine kinase, is responsible for uncontrolled MC proliferation and survival.1 MCs are effector cells of an immune response, especially involved in parasites infections control and allergic and anaphylactic reactions.

Mastocytosis is characterized by protean clinical manifestations: the release of several mediators and cytokines is responsible for symptoms that involve skin, gastrointestinal tract, cardiovascular system, bone, and neurological and psychological status.

Treatment of Indolent SM and Smoldering SM

Management of Indolent SM (ISM) and Smoldering SM (SSM) is focused on the prevention and treatment of anaphylactic reactions and symptom control (Table 1). In case of severe symptoms refractory to anti-mediator therapy or bone disease unresponsive to bisphosphonates, disease-modifying treatments with cytoreductive agents may be attempted.

Table 1

Treatment of Indolent and Smoldering SM.

Symptoms	First Choice	Second Choice	Third Choice	Fourth Choice
Skin	first and second generation H1-antihistamines escalated up to 4 times their recommended dose	leukotriene antagonists montelukast 10 mg, zafirlukast 20 mg bid	oral psoralen with ultraviolet therapy
Gastrointestinal	H2-antihistamines ranitidine 150 mg bid, famotidine 10 mg bid, cimetidine 400 mg bid	proton pump inhibitors omeprazole 20 mg, pantoprazole 40 mg, rabeprazole 20 mg	sodium cromolyn 800–1200 mg daily divided in 4 doses	oral corticosteroids prednisone 0.5–1 mg/kg/day or equivalent
Cardiovascular	self-injectable epinephrine, antihistamines, Omalizumab, hospital admission
Neurologic	psychiatric evaluation
Osteoporosis	bisphosphonates Os alendronate 70 mg a week, risedronate 35 mg a week; IV pamidronate 90 mg a month zoledronate 5 mg every 12-18 months or 4 mg a month in more severe conditions	interferon α 1–3 MU 3 times per week up to 3–5 MU 3–5 times per week denosumab 60 mg subcutaneously every 6 months		cladribine 5 mg/m2 per 5 days every 4–8 weeks
Recurrent Anaphylaxis		Omalizumab, dosage not defined (150 to 300 mg subcutaneously every 2 weeks to every four week)
Hymenoptera venom allergy	venom immunotherapy	Omalizumab, dosage not defined (150 to 300 mg subcutaneously every 2 weeks to every four week)

The first approach is to identify symptom triggers and suggest avoidance strategies of triggers, such as physical stimuli (heat, change of temperature, pressure, cold, rubbing), exercise, sleep deprivation, emotions, drugs (opiates, contrast media, succinylcholine, nonsteroidal anti-inflammatory drugs, agents with tetrahydroisoquinoline such as quinolones, atracurium, and rocuronium), alcohol, food, and Hymenoptera stings.2,3

Skin

Flushing, urticaria (wheals), itching, angioedema, and dermatographism are the most frequently reported skin symptoms in ISM and SSM. H1-antihistamines are the first-line drugs in this setting: first-generation sedating molecules (diphenhydramine, hydroxyzine, ketotifen, doxepin, cyproheptadine) and second-generation non-sedating molecules (cetirizine, levocetirizine, loratadine, desloratadine, ebastine, rupatadine, bilastine, mozolastine) are available. First-generation antihistamines should be used at bedtime, especially when cutaneous symptoms impair sleeping quality. Dosage of antihistamines (especially second-generation molecules) may be escalated up to 4 times their recommended dose for chronic spontaneous urticaria, with no relevant side effects. A recent review shows that antihistamines can improve patients’ quality of life, reduce wheals and itching on standardized provocation testing, and improve symptoms like itching, flushing, tachycardia, and headache.4

When H1-antihistamines do not adequately control skin symptoms, leukotriene antagonists (montelukast 10 mg, zafirlukast 20 mg bid) may be added. Unfortunately, Zileuton, a 5-lipoxygenase inhibitor, is not available in Europe.

Aspirin can be used as a third-line treatment for skin symptoms, starting from 81 mg bid to 500 mg bid if nonsteroidal anti-inflammatory drugs are tolerated. Its effect should be monitored by measuring prostaglandine2 metabolite excretion. On the other hand, aspirin use may increase cysteinyl leukotrienes, causing/worsening vasoconstriction and bronchospasm.5

Finally, oral psoralen combined with ultraviolet therapy is reserved for patients with cutaneous mastocytosis (urticarial pigmentosa) in case of severe/resistant skin symptoms.6,7

Gastrointestinal tract

Abdominal pain, cramping, nausea, vomiting, heartburn, gastroesophageal reflux, and diarrhea may be present in both ISM and SSM. H2-antagonists (ranitidine 150 mg bid, famotidine 10 mg bid, cimetidine 400 mg bid) are the drug of choice in case of gastrointestinal symptoms.1,3 They inhibit gastric acid secretion via the H2-receptors and, associated with H1-antihistamines, reduce the release of mediators from MCs,8 but they are less effective in controlling diarrhea.9

Proton pump inhibitors (omeprazole 20 mg, pantoprazole 40 mg, rabeprazole 20 mg) are second line drugs in case H2-antihistamines are not effective.1,3

Sodium cromolyn at a dose of 800–1200 mg daily divided into four doses is a third-line treatment. It acts as a stabilizing agent on MC membranes and reduces MC degranulation by interfering with Ca++ influx. In addition, sodium cromolyn has shown to be effective in the management of gastrointestinal symptoms when compared to placebo.10

Oral corticosteroids (prednisone 0.5–1 mg/kg/day or equivalent) are the fourth-line drug for gastrointestinal symptoms. However, because of their side effects, corticosteroids should be tapered as soon as possible based on the patient response.1,6

Cardiovascular symptoms

SM patients may have recurrent presyncope or syncope, hypotension, tachycardia, or anaphylaxis. The prevalence of anaphylaxis in adults with SM ranges from 22 to 49%, about 100 times higher than the general population. Anaphylaxis may be provoked by a concomitant IgE-mediated allergy (especially to Hymenoptera venoms) or may also be spontaneous. Thus, all patients should be prescribed self-injectable epinephrine and should be trained to treat attacks.2,11

Acute episodes of anaphylaxis should be treated according to current guidelines. The drug of choice is intramuscular epinephrine at a dosage of 0.3–0.5 mg, followed by fluid replacement (saline or Ringer lactate), 500–1000 mg of intravenous hydrocortisone and intravenous H1 H2-antihistamines.12 Prevention of new episodes is based on chronic treatment with H1- and H2-antihistamines and leukotriene antagonists, while oral corticosteroids (prednisone 0.5–1 mg/kg/day) should be proposed only in very resistant patients.1,3 Recently, a relevant role has been reported for Omalizumab to resolve cardiovascular symptoms with or without anaphylaxis.13 When this approach is ineffective, a cytoreductive therapy with cladribine or interferon α (IFN α) can be taken into consideration.3

Neurologic symptoms

Depression, headache, cognitive impairment, and sleep disturbance are common. H1-antihistamines showed to be effective on headaches but not on other symptoms. Therefore, these patients should undergo a psychiatric evaluation for a prompt start of tailored treatment.4

Osteoporosis

Bone involvement leading to osteopenia, osteoporosis, and fragility fractures are frequent in SM patients: the reported prevalence ranges from 18 to 31%. It is important to note that an osteoporotic fracture is not considered a sign of aggressive disease, as opposed to the rarely encountered large, osteolytic bone lesions that can sometimes be detected in patients with ASM or MCL and are classified as a C-finding. The pathogenesis of osteoporosis has been attributed to the cytokines and other mediators released from mast cells. Tumor necrosis factor (TNF)-α, interleukin(IL)-1, and IL-6 promote osteoclast activity and inhibit osteoblasts. Moreover, histamine has a stimulatory effect on osteoclasts and their precursors.14

Since there is a relative or absolute prevalence of bone reabsorption, bisphosphonates are the first-line treatment option. Several molecules are available orally (alendronate 70 mg a week, risedronate 35 mg a week) and intravenously administered (pamidronate 90 mg a month; zoledronate 5 mg every day 12–18 months or 4 mg a month in more severe conditions ). They positively affect vertebral bone mineral density (BMD) and less on femoral neck BMD. Zoledronate showed the best positive effect on both vertebral and femoral neck BMD.15

In case of very severe osteoporosis and/or onset of new major fractures, the use of IFN-α should be considered. IFN-α is able to decrease MC burden and MC-related symptoms but may be poorly tolerated for flu-like symptoms, bone pain, fever, cytopenias, depression, and hypothyroidism, leading to poor compliance.1

It is administered subcutaneously from a starting dose of 1–3 million units (MU) three times per week to 3–5 MU 3–5 times per week.

Finally, when bisphosphonates and IFN-α fail, a cytoreductive treatment with the purine nucleoside analog 2-chlorodosxyadenosine (cladribine/2CdA) at a dosage of 5 mg/m2 per 5 days every 4–8 weeks is the third-line treatment. Immunosuppression and myelosuppression are important side effects that may lead to drug discontinuation.16

Denosumab, a monoclonal antibody directed against RANK-ligand(L), has been developed to treat postmenopausal osteoporosis. RANKL, which is expressed by MCs, can activate osteoclast by the RANK pathway. Denosumab, at the dosage of 60 mg subcutaneously every six months, showed to be effective in increasing BMD at both vertebral and femoral neck sites after one year of treatment. Denosumab could be used as a second-line in patients not responding to bisphosphonates or not candidates to bisphosphonates because of renal insufficiency: further studies in larger samples are necessary to assess efficacy.17

Omalizumab

Omalizumab, an anti-IgE humanized monoclonal antibody, is approved to treat chronic spontaneous urticaria and extrinsic bronchial asthma when standard treatments are not effective at maximum doses. At present, the optimal dose and frequency of administration remain to be determined (150 to 300 mg subcutaneously every two weeks to every four weeks).

The largest trial included 55 patients with a mast cell disorder that received Omalizumab. The diagnoses were ISM (29 patients), MC activation syndrome (MCAS), and Cutaneous Mastocytosis (CM). A KIT D816V mutation was found in 27 of 49 patients (particularly those with ISM). The recommended starting dose was 150 mg subcutaneously every two weeks. Omalizumab response was rapid, with a median time to first response of 2 months and the best response after six months. It was effective on all vasomotor symptoms, including those secondary to anaphylaxis, and gastrointestinal and urinary symptoms, with a good safety profile.18

In a smaller trial including 14 patients, the authors showed a significant improvement of vasomotor symptoms and quality of life. However, the treatment was less effective for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms.19 In addition, the Schedule of drug administration (starting and maintenance doses) varied among patients, considering initial symptoms, clinical response, and treatment tolerance.

A recent review showed that omalizumab treatment led to a complete resolution of anaphylaxis episodes in 84% of the patients, while the efficacy on respiratory, musculoskeletal, and neuropsychiatric symptoms was scarce. The authors concluded that a randomized controlled trial is mandatory to demonstrate the usefulness of Omalizumab in SM treatment.13

Cytoreductive Treatment of ISM and SSM

A cytoreductive treatment is not recommended for ISM and SSM unless anti-mediator therapy has failed.20

Midostaurin is a multikinase inhibitor that is able to inhibit the kinase activity of both wild-type and D816V mutated KIT. An open-label, non-randomized phase 2 trial was conducted on 20 patients with ISM and severe mediator symptoms not controlled with standard therapy. After 12 weeks, patients showed a significant reduction in symptom-score and improved quality of life. In addition, tryptase levels showed a significant decrease. All patients stopped midostaurin after 24 weeks, and most of them showed a relapse. Nausea, headache, and diarrhea were the most common side effects. The effect on anaphylaxis-like symptoms was not studied because of the insufficient number of subjects with cardiovascular symptoms.21

Masitinib, an oral tyrosine kinase inhibitor, was used in a randomized, double-blind, placebo-controlled phase 3 trial. One hundred thirty-five adults patients with ISM and SSM were enrolled in the study: 71 received masitinib and 64 placebo. The dosage was 6 mg/kg per day in two doses. The primary endpoint was the cumulative response in at least 1 of 4 severe baseline symptoms (itching, flushing, depression, asthenia). After 24 weeks, masitinib showed a significant cumulative response in the primary endpoint compared to placebo (18.7% vs. 7.4%). The most frequent adverse events in the active group were diarrhea, rash, and asthenia.22

Avapritinib (BLU-285), a multikinase inhibitor, is a second-generation inhibitor of KIT D816V. In a randomized, double-blind, placebo-controlled phase 2 trial (NCT03731260), avapritinib significantly improved mediator symptoms compared to placebo, with a good safety profile. The dosage ranged from 25 to 100 mg in a daily administration.

Cladribine is a synthetic purine analog that inhibits DNA repair, blocks dividing cells, and induces apoptosis in resting cells. It is effective in reducing must cell burden in ASM and SM-AHN patients. Thirty-six subjects with IM (6 CM, 28 ISM, and 2 SSM) were included in the study. Each course of treatment was repeated with a 4 to 12-week interval for a maximum of 9 courses at a dosage of 0.14 mg/kg/day from 1 to 5 days. The treatment showed a significant improvement in flushing, itching, neuropsychiatric and cardiovascular symptoms with a concomitant reduction of tryptase levels. Common side-effects were myelosuppression-related toxicity (47%) and infectious complications (22%).16

Hymenoptera Venom Allergy and Mast Cell Activation Syndromes

There is a frequent association between severe Hymenoptera venom allergy (HVA) and elevated basal serum levels (>11.4 ng/mL). For example, some authors found that 9 out of 137 (6.6%) patients with severe drug or food allergy (6.6%) had a basal tryptase >11.4 ng/mL, and only two (1.5%) were diagnosed with mastocytosis. On the other hand, 13.9% of patients with HVA had elevated tryptase, and 11.1% had a clonal mast cell disorder.23

American authors found a mastocytosis prevalence of 10.1 per 100000 overall and 96.7 per 100000 among HVA patients. Nine out of 161 (5.6%) patients undergoing venom immunotherapy (VIT) had basal tryptase >11.4 ng/mL, and 3 (1.8%) had a clonal mast cell disorder.24

Typically, HVA in mastocytosis patients is characterized by the absence of urticaria/angioedema and the sudden onset of cardiovascular symptoms leading to loss of consciousness. For this reason, these patients should carry with them an emergency kit including two epinephrine autoinjectors and should be trained in their use by the allergist.23

VIT is mandatory since it is the only life-saving treatment for these patients, and it should be prolonged long-life with a 3–4 month-interval, according to European and American guidelines.25 Mastocytosis patients are at higher risk of reactions during build-up and maintenance phases, but some authors recently observed no adverse events in 8 patients undergoing 12 ultra-rush VIT, both in the build-up and maintenance phases. Nevertheless, because of severe reactions, expert personnel should carry out an ultra-rush protocol with the prompt availability of resuscitation equipment.26,27 In addition, some patients may experience recurrent anaphylaxis following Hymenoptera sting and/or extremely invalidating intolerance to VIT. In these cases, Omalizumab has been reported to induce tolerance to VIT and reduce anaphylaxis episodes13 successfully.

Treatment of Advanced Systemic Mastocytosis

The term advanced systemic mastocytosis (advSM) identifies three different diseases, namely aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). These subtypes are characterized by mast cell-related organ damage, for which a cytoreductive treatment is usually required, and a reduced survival.1

Considering the protean clinical manifestations, the evaluation of aggressiveness involves different body systems such as bone marrow, liver, spleen, bones, and gastrointestinal tract, globally classified as C findings. On the other hand, constitutional symptoms may be more invalidating in some patients than the organ damage itself. The complexity of the disease has led to the development of several response evaluation criteria during the last 20 years, updated to include the grading resolution of C findings and constitutional symptoms.28–31

Until now, there is no curative option for patients with AdvSM. The available therapeutic options include tyrosine-kinase inhibitors, interferonα, and cladribine, with variable duration and extent of response (Table 2). Allogeneic stem cell transplantation is usually performed in younger selected patients.

Table 2

Treatment of Advanced SM.

Drugs	Class	Dosage	Efficacy
Imatinib mesylate	tyrosine kinase inhibitor, specific cKIT mutation	100 mg up to 400 mg daily	bone marrow burden, constitutional symptoms
Interferon α	cytokine	3.5–30 MU weekly	skin involvement, osteoporosis, constitutional symptoms
Cladribine	purine nucleoside analogue	0.13–0.17 mg/kg or 5 mg/mq 5 days a week repeated with a minimum interval of 4 weeks (n° of cycles not defined)	bone marrow burden, constitutional symptoms, skin involvement
Midostaurin	tyrosine kinase inhibitor, both wild type and mutant cKIT	100 mg twice daily	C findings, bone marrow burden, constitutional symptoms
Avapritinib	tyrosine kinase inhibitor, selective for cKIT	200 mg once-daily	C findings, bone marrow burden, constitutional symptoms
Allogeneic stem cell transplantation	chemotherapy	myeloablative conditioning and peripheral blood source	Anecdotal (recommended in selected cases)

Imatinib Mesylate

Imatinib mesylate is an in vitro inhibitor of several tyrosine kinases, particularly wild-type and specific mutant ckit.32,33 It was the first drug specifically approved by the FDA for adult patients with SM lacking the cKIT D816V mutation or unknown cKIT mutational status at 400 mg daily dosage. This indication came after a report by Pardanani et al.,34 in which 12 adults with symptomatic SM were treated with imatinib mesylate 100 mg up to 400 mg daily. Three patients with eosinophilia (1 with ISS and 2 with ASM, all cKIT D816V negative) obtained a complete remission, and 2 ASM patients without eosinophilia obtained a bone marrow cytoreduction and improvement of bone pain. However, three patients with ASM were refractory to imatinib mesylate, irrespective of blood eosinophil count; 2 patients with prevalent skin involvement had a progressive decrease of symptoms, and two were not evaluable for response.

A Dutch open-label phase II study reported on the efficacy of imatinib mesylate among 14 patients, mostly with non-advSM.35 The authors found a reduction of hepatosplenomegaly and skin/constitutional symptoms in almost half of the study population, more pronounced in cKIT D816V negative but also detectable in cKIT D816V positive patients. However, the concomitant use of steroids may have contributed to the response.

Another American prospective open-label phase II study recruited 11 patients with ISM and nine patients with AdvSM for treatment with imatinib mesylate at 400 mg daily.36 During a median time on therapy of 9 months, 1 AdvSM patient and 6 ISM patients reported improvement of symptoms; nevertheless, all patients interrupted the treatment for loss of response. The authors concluded that imatinib mesylate might only produce a significant clinical benefit in patients without cKIT D816V mutation.

A monocentric retrospective study published in 2009 reported the outcome of 27 patients with ISM (30%) and AdvSM (70%) treated with imatinib mesylate at a starting dose of 400 mg daily.37 Among 22 evaluable patients, only four responded (18% overall): 1 ISM patient, 2 ASM patients, and 1 SM-AHN patient; the median duration of response was 19.6 months for all patients (range 9–69 months).

More recently, in 2017, a phase IV clinical trial tested the response to imatinib mesylate of 10 patients with CM and SM with cKIT mutation found outside the activation loop-coding region or wild-type cKIT.38 Four patients obtained a complete response in terms of MC burden in the bone marrow, normalization of tryptase level, and resolution of constitutional symptoms; 1 patient obtained a partial response involving both MC burden and symptoms. All five unresponsive patients were wild-type cKIT. The authors concluded that imatinib mesylate is effective among SM patients with specific cKIT mutational status (i.e., mutation involving the extracellular and transmembrane regions) while is less effective than previously reported in true wild type cKIT.

Interferon α

Historically, interferonα was the first treatment of SM, used by analogy with other myeloproliferative neoplasms,39–41 sometimes in combination with steroids.

A prospective multicentre phase II trial reported only 35% partial response and 30% minor response among 13/20 evaluable patients with ISM and ASM.42 In this study, interferon α 3MU/m2 thrice weekly for six months improved both skin involvement and constitutional symptoms while ineffective in organ involvement. However, the authors also reported a discrete rate of withdrawal, mainly because of worsening of cytopenia, and the reappearance of systemic symptoms soon after the interruption of the drug, even for patients who previously responded.

An Austrian study enrolled five patients treated with interferonα and steroids.43 The authors reported two complete resolutions of C findings, one partial improvement of C findings, one stable disease, and one progression to MCL.

A monocentric retrospective study published in 2009 reported the outcome of 47 patients with ISM (23%) and AdvSM (77%) treated with interferonα at a median dosage of 15 MU weekly (range 3.5–30 MU weekly).37 Among 40 evaluable patients, the overall response rate was 53% for all categories, particularly 6 ISM patients, 6 ASM patients, and 9 SM-AHN patients; the median duration of response was 12 months for all patients (range 1–67 months).

The main adverse events of treatment were fatigue, cytopenia, depression, flu-like symptoms, and fever. In most cases, symptoms are easily managed with dose reduction, but some cases of drug interruption for severe cytopenia and/or depression were reported.42,43

Cladribine

2-chlorodeoxyadenosine (2-CdA) is a purine nucleoside analog used in different diseases of hematopoietic origin, with significant activity against monocytes44 that were thought to have a common progenitor with mast cells.45

A cases series of AdvSM patients refractory or intolerant to interferonα reported the outcome of 4 patients after 4–6 cycles of 2-CdA (0.14 mg/kg 5 days a week) given every 1 to 6 months.46 The authors reported a significant improvement of systemic symptoms and skin rash in three cases and persistence of response long after treatment. In another series of 10 patients with ISM and AdvSM treated with six courses of 2-CdA (0.13 mg/kg 5 days a week), the authors concluded that three patients with ASM obtained a response after a median time of 6 months.47 Moreover, skin involvement was reduced at least 50% in all affected patients, and bone marrow involvement was significantly reduced in 8 cases; constitutional symptoms were markedly decreased.

A monocentric retrospective study published in 2009 reported the outcome of 26 patients with ISM (38%) and AdvSM (62%) treated with 2-CdA (0.14 mg/kg 5 days a week) given every 1 to 3 months.37 Among 22 evaluable patients, the overall response rate was 55% for all categories: five ISM patients, one ASM patient, and six SM-AHN patients; the median duration of response was 11 months for all patients (range 3–74 months).

A multicenter French study recruited 68 patients with CM (9%), ISM (44%) and AdvSM (47%) treated with a median of 3 courses (range 1–9) of 2-CdA (0.13–0.17 mg/kg or 5 mg/mq 5 days a week) given every 1 to 3 months.16 The authors reported an overall response rate of 72%, with the highest response rate in cutaneous/indolent form (100% and 89%, respectively) compared to ASM and SM-AHN (43% and 59%, respectively). Although no complete response was reported, the median duration of response was 3.7 years, with no significant difference between ISM and AdvSM.

The main adverse events of treatment were grade 3–4 myelosuppression and infection, which may lead to dose reduction and treatment delay. Herpes reactivation can be managed with antiviral prophylaxis.16,47

Dasatinib

Dasatinib is a tyrosine kinase inhibitor that exerts a potent action on the mutant D816V cKIT in vitro. On this basis, Verstovsek et al. conducted an open-label phase 2 study on 18 ISM and 15 AdvSM patients treated with dasatinib 140 mg daily.48 The authors reported an overall response rate of 33%: only two patients obtained a complete response, lasting for 5 and 16 months, and both were negative for D816V cKIT mutation; the other nine patients achieved an improvement in constitutional symptoms. The authors concluded that dasatinib is ineffective in treating patients with SM carrying D816V cKIT mutation.

Nilotinib

Nilotinib is a tyrosine kinase inhibitor that is also active against the KIT in vitro. Following preliminary results, Hochhaus et al. conducted a multicenter phase-2 registration trial on 61 patients with advSM (69%) and ISM (31%) treated with nilotinib 400 mg twice a day.49 Unfortunately, evaluable responses were available only in the ASM group: the authors reported a minor response in 8/37 patients, while no complete response was documented.

Midostaurin

Midostaurin is a potent multi-target tyrosine kinase inhibitor, active on wild-type and mutant cKIT D816V. Following the preliminary efficacy report, an international multicenter single-group open-label phase-2 study recruited 116 patients with AdvSM for treatment with midostaurin 100 mg twice daily.50 The authors reported an overall response rate of 46% and a median duration of treatment of 11.4 months (range 0.3–51.5). According to WHO categories, the response rates were 75%, 58%, and 50% for patients with ASM, SM-AHN, and MCL. Responses included improved organ function (reduction of bone marrow burden, spleen volume, and normalization of liver enzymes), reduction or interruption of transfusion dependence, improvement of constitutional symptoms and quality of life, and recovery of weight loss. However, the median duration of response was not reached in patients with ASM (95% CI, 24.1 months to not estimated) and with MCL (95% CI, 3.6 months to not estimated), while it was 12.7 months (95% CI, 7.4 to 31.4) in patients with SM-AHN. Similarly, the median overall survival was not reached (95% CI, 28.7 months to not estimated) in patients with ASM, while it was 20.7 months (95% CI, 16.0 to 44.4) and 9.4 months (95% CI, 7.5 to not estimated) in patients with SM-AHN and MCL, respectively. Overall, median progression-free survival was 14.1 months: in ASM patients, it was 28.7 months, 11.0 months higher than SM-AHN, and 11.3 than MCL patients.

Based on this study, in 2017 FDA approved midostaurin for the treatment of AdvSM, regardless of cKIT D816V mutation status.

Another multicenter phase-2 trial reported on the long-term outcome of 26 patients with AdvSM treated with midostaurin 100 mg twice daily for up to 12 cycles and beyond in case of response.51 During the 12-cycle period, the overall response rate was 69%, with a median time to response of 25.5 days (range 4–56) and a median time to best response of 56 days (range 25–229). Five patients reported only stable disease, and three patients progressed. The best rate of response was reported in patients with SM-AHN (76%) and MCL (67%), rather than ASM (33%). After the 12-cycle period, the overall response rate did not change. Median overall survival was not reached for 3 ASM, while it was 40 months (95% CI, 24.2–55.9) for the 17 SM-AHN patients and 18.5 months (95% CI, 0–62.2) for MCL patients. Overall, the median PFS was 41.0 months (4.4–77.6).

A Polish study reported data on the real-world efficacy of midostaurin on 13 patients with AdvSM.52 After a median duration of treatment of 9 months (range 1–21), a clinical benefit was detectable in 77% of patients, and half of the patients with measurable organ damage obtained a response. After a median follow-up of 19 months, the authors reported seven patients with ongoing therapy and three patients died of progressive disease.

The main adverse events of treatment were nausea and vomiting, diarrhea, increased transaminase, and cytopenia. Gastrointestinal symptoms usually improve after the first months of treatment. Cytopenia and abnormal liver function can be managed with drug interruption and dose reduction, according to the toxicity grading.50–52

Brentuximab Vedotin

Brentuximab vedotin (BV) is a chimeric immunoglobulin G1, specific to human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) used mostly in lymphoproliferative diseases expressing surface CD30. After in vitro study on CD30+ human mast cell lines, a phase 2, open-label study was performed, with the primary objective of evaluating the antitumor activity of BV in patients with CD30-positive non-lymphoid malignancies.53 Two patients with ISM and two patients with ASM were included and treated with BV at a dosage of 1.8 mg/kg or 2.4 mg/kg every three weeks. The authors reported one major response, one improvement of constitutional symptoms, and two disease progression.

Another phase 2 open-label, single-group was conducted to determine the efficacy and safety of BV 1.8 mg/kg every three weeks among patients with AdvSM, and at least 20% of surface CD30 expression, assessed by flow cytometry.54 After a median follow-up of 722 days (range 18–1246 days) and a median number of five cycles (range 1–8 cycles), no significant and/or durable response was observed among ten recruited patients, assessed by reduction of tumor burden and constitutional symptoms. The authors concluded that BV has no clinical activity in this setting of patients.

Avapritinib

Avapritinib (BLU-285) is a selective cKIT D816V inhibitor that showed promising results in phase 1 clinical trial.55 The phase-1 trial enrolled 53 patients with AdvSM for treatment with avapritinib: among 32 evaluable patients, the overall response rate was 76% after a median follow-up of 27.3 months. At this time, the median overall survival has not been reached in this population.

The phase-2 registration trial reported the outcome of 32 patients treated with avapritinib 200 mg daily.56 The overall response rate was 75%, specifically 100% for ASM, 81% for SM-AHN, and 25% for MCL. The median time to response was two months, and the median time to best response was 5.6 months; at a median follow-up of 10.4 months, all responses persisted, and median overall survival was not reached.

Based on these data, the FDA approved avapritinib for Adv SM treatment in June 2021.

The main adverse events of treatment were periorbital and peripheral edema, fatigue, gastrointestinal symptoms, cytopenia, and cognitive impairment.55,56

Allogeneic Transplantation

The role of allogeneic stem cell transplantation is still not defined in the treatment of disease: debulk strategy, the timing of the procedure, choice of best conditioning regimen and donor source, and possible maintenance therapy post-transplant are still matter of debate in the clinical practice.57,58

Allogeneic stem cell transplantation has been performed with various outcomes in mast cell disease patients associated with another hematological neoplasm. Some authors reported the disappearance of leukemia-related mast cells clone after allogeneic transplant,59 while others showed neoplastic mast cell persistence despite complete remission of concomitant hematological neoplasm.60 Moreover, evidence of the graft-versus-mast-cells effect implies an immunological mechanism underlying the clearance of neoplastic infiltration.61,62

Literature data about conditioning regimens and donor sources are scarce. Nakamura et al. reported the outcome of 3 patients with MCL and SM-AHN conditioned with a non-myeloablative regimen (cyclophosphamide and fludarabine).63 Engraftment was reached in all 3 cases, and no transplant-related mortality was observed, but all patients relapsed despite a transient graft-versus-mast cell effect after immunosuppression withdrawal. More recently, a retrospective multicenter study reported the outcome of 57 patients with AdvSM transplanted in the United States and Europe: the overall response was about 70% for all categories.57 Considering survival, the OS and PFS differ among the three categories. Particularly, considering ASM, SM-AHN, and MCL, OS at three years was 43%, 74%, and 17%, respectively, while PFS at three years was 43%, 63%, and 17%. Excluding the patients with MCL, which had the worse prognosis, risk factors for reduced survival were diagnosis of ASM and a reduced-intensity conditioning regimen. All three patients who received a transplant from cord blood and HLA-haploidentical relative and all patients with MCL who received RIC died.

As a general recommendation, myeloablative conditioning and peripheral blood source should be considered in younger people with aggressive clinical course.

Conclusions

Mastocytosis is a complex disease for which a multidisciplinary approach is mandatory for a comprehensive evaluation and choice of therapy. In most cases, patients might need a personalized treatment with a specific combination of different drugs, ranging from antihistamines and bisphosphonates to TKI and chemotherapy. In addition, tolerance of treatment, disease symptoms control, and adverse events should be frequently evaluated and carefully balanced in these patients.