Clinical response to omalizumab in patients with hereditary alpha tryptasemia

Hereditary alpha tryptasemia (HαT) is a genetic trait that results from increased TPSAB1 copy number encoding alpha-tryptase and is characterized by elevated basal serum tryptase (BST) levels of ≥8ng/mL with variably expressed clinical symptoms (1). In addition to multisystem complaints involving gastrointestinal, connective tissue, and neurologic systems, many individuals with HαT report symptoms associated with mast cell activation such as chronic spontaneous urticaria (CsU) and less commonly allergic asthma. Increasing alpha-tryptase gene-dosage at TPSAB1 is associated with greater symptom severity (2) and increasing amounts of αβ-tryptase heterotetramers which have unique enzymatic properties that may contribute to these symptoms (3). Multiple individuals in our cohorts with HαT have uncontrolled CsU or asthma symptoms which led to an on-label indication for treatment with the monoclonal anti-IgE antibody, omalizumab, which binds to free IgE reducing the expression of FcεRI on mast cells and basophils (4, 5). Despite the strong effect observed on symptoms of mast cell mediator release among patients with CsU and systemic mastocytosis, a recent open-label cohort study demonstrated only modest benefit in patients identified as having idiopathic mast cell activation syndrome (MCAS) with 6/14 having minimal to no response to omalizumab and 7/14 having no durable response (6). Given that many of the symptoms associated with HαT are often attributed to mast cell activation, we set out to determine which of the symptoms commonly reported in these patients respond to this specific mast cell-targeted therapy, and by inference suggest which symptoms may be more directly related to mast cells bearing heterotetrameric tryptase in these patients.

Comprehensive retrospective chart review was performed and complete medical histories were obtained from a total of thirteen individuals. Twelve individuals with HαT – six individuals from the University of Florida (IRB201702274 or IRB201601800), one individual from the University of Washington and five individuals from the NIH Clinical Center (enrolled on NIAID-approved protocols NCT01164241 and/or NCT00852943) – previously or concurrently treated with omalizumab were identified; one additional individual in New Zealand prospectively underwent unblinded therapy with omalizumab where HαT was the primary indication (state funded under special authority) was also included. Individuals’ weights, basal serum tryptase levels, tryptase genotypes (from both TPSAB1 and TPSB2 loci), total serum IgE levels, as well as symptoms prior, during, and after omalizumab were queried, and dose and duration of omalizumab treatment were recorded.

The median patient weight was 63 kg (range: 35 kg – 122 kg), median total serum IgE level was 93 IU/mL (range: 11 IU/mL – 2,646 IU/mL), and median BST was 18 ng/mL (range: 11 ng/mL – 33 ng/mL). Nine individuals had one additional TPSAB1 copy, while four had two additional copies. The dose and frequency of omalizumab that most individuals received was 300mg subcutaneously every 4 weeks (Table 1). Sixteen symptoms that were documented as present or absent prior omalizumab in all thirteen patients were queried following treatment (Table S1). The median number of symptoms reported as present prior to treatment was 9 per individual (range: 3 – 13).

Table 1.

Patient characteristics and treatment responses to omalizumab in hereditary alpha tryptasemia.

Patient	Weight (kg)	BST level (ng/mL)	Tryptase genotype (copy number)		IgE (IU/mL)	Number of stated symptoms	Number of symptoms responding to omalizumab	Dose (mg/interval)	Time for response/failure
			α	β
1	73	16	3	2	279	8	6	300mg/4weeks	2 weeks
2	122	22	2	3	289	10	7	300mg/2weeks	8 weeks
3	66	18	2	3	11	12	8	300mg/4weeks	12 weeks
4	53	18	4	2	14	10	7	150mg/4weeks	4 weeks
5	59	13	3	2	147	9	4	300mg/4 weeks	4 weeks
6	59	13	3	2	107	3	3	300mg/4weeks	12 weeks
7	73	17	3	2	44	9	1	300mg/3weeks	4 weeks
8	63	11	3	2	2,646	6	1	300mg/4weeks	8 weeks
9	62	24	3	3	93	4	2	150mg/4weeks	8 weeks
10	81	13	4	2	78	9	0	300mg/2weeks	No response*
11	45	18	3	2	63	13	2	150mg/4weeks	8 weeks*
12	77	33	4	2	187	4	1	300mg/4weeks	2 weeks
13	35	21	3	2	74	8	7	300mg/4weeks	2 weeks

^*also reported severe fatigue with omalizumab injections

While individual responses were variable, twelve of thirteen individuals reported some improvement in at least one symptom (Table 2); six individuals reported improvement in more than half of their symptoms, with between 3–8 symptoms being allayed per individual (Table 1). As a cohort, approximately half of reported symptoms (49/105) from the 16 symptoms queried improved with omalizumab. The improvement was reported as early as 2 weeks after initiation of treatment with the median time for response in those who reported improvement being 8 weeks. All individuals with urticaria reported improvement (10/10). The majority of those reporting nausea (6/ 7), flushing (8/11), fatigue (6/9), and abdominal pain (6/9) also described improvement on omalizumab. While six of nine individuals reported improvement in baseline fatigue, two additional individuals (patients 10 and 11) reported developing fatigue immediately following omalizumab injections; one of these individuals also reported no benefit and the injections were stopped after two months. Other responses included improvement in pruritus (2/4), asthma symptoms (2/5), food intolerance (2/5), musculoskeletal pain (3/8), constipation (N = 2/6), sleep disturbance (1/5), and headaches (1/6). None of the individuals reported improvement in symptoms of autonomic dysfunction (N = 5), palpitations (N = 4), diarrhea (N = 5), or joint hypermobility (N = 6).

Table 2.

Symptoms that were responsive or persistent during omalizumab therapy.

Responsive symptoms N, % responding	Persistent symptoms N, % responding
Urticaria 10/10 (100%)	Asthma symptoms 2/5 (40%)
Nausea 6/7 (86%)	Food intolerance 2/5 (40%)
Flushing 8/11 (73%)	Musculoskeletal pain 3/8 (38%)
Fatigue* 6/9 (67%)	Constipation 2/6 (33.3%)
Abdominal pain 6/9 (67%)	Sleep disturbance 1/5 (20%)
Pruritus 2/4 (50%))	Headaches 1/6 (17%)
	Autonomic dysfunction 0/5 (0 %)
	Joint hypermobility 0/6(0%)
	Palpitations 0/4 (0%)
	Diarrhea 0/5 (0%)

^*two individuals who did not report baseline fatigue, developed fatigue while on omalizumab;

Of the two individuals who were treated in whom the calculated dose of omalizumab was below the studied 0.016 mg/kg/IU [IgE/mL] cut-off, there was not a significant difference in average symptomatic improvement compared to those who did achieve this calculated level (Fig. e1A). However, in one individual the dose was 0.015 mg/kg/IU and 6/8 symptoms improved, whereas in the other individual the dose was 0.002 mg/kg/IU and only 1/6 symptoms improved – potentially due to sub-therapeutic dosing in the latter subject. This was not a potential explanation for treatment failure in patient 10, who was the only individua to report no symptomatic response, as the calculated dose for this individual was 0.095 mg/kg/IU on a monthly basis. A weak positive correlation was seen between calculated omalizumab dose and the number of symptoms improving (Fig. e1B), whereas individual BST levels did not appear to correlate with symptomatic responses overall (Fig. e1C). Finally, we did observe a non-significant decrease in the mean percentage of symptoms improving (36% versus 54%) among the four individuals with two extra-allelic TPSAB1 copy number when compared to individuals with duplications (Fig. e1D).

While these findings are preliminary in nature, improvement of some symptoms – such as flushing, urticaria, and asthmatic symptoms – occurred as expected in response to omalizumab therapy. However, improvement of fatigue and some pain symptoms was unexpected. Furthermore, autonomic and gastrointestinal complaints – including constipation and diarrhea – that one might have attributed to mast cell mediator effects were unchanged with omalizumab. Because these symptoms failed to respond to the systemic mast cell targeted therapy omalizumab – despite universal responsiveness of urticaria in this study – it is possible that in this HαT cohort these symptoms are occurring as a result of an as yet unknown mechanisms, other than mast cell activation. It is unclear why some individuals reported substantial benefit, while others reported minimal or no benefit and in some cases were even intolerant of the drug, but this points to potentially distinct mechanisms contributing to some of the phenotypes in these patients that may be modified by HαT. Given the small sample size, as well as the unblinded and retrospective nature of these findings, one must be cautious regarding the generalizability of these results. However, given the difficulties in managing the types of symptoms frequently reported in individuals with HαT, coupled with the severity of their symptoms and their negative impact on quality of life, this report provides initial evidence for a role of omalizumab in management of selected individuals with HαT. This is particularly relevant given the recent in vitro data demonstrating how HαT patient mast cells, and others containing αβ-heterotetrameric tryptase, may enhance vibration-induced urticaria via cleavage of EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) (3). As further mechanisms and biomarkers are established for the clinical phenotypes observed in patients with HαT as well as other disorders associated with non-clonal mast cell activation, future double-blind, placebo-controlled trials are necessary to establish efficacy of mast cell-directed therapies in these patients.