NEW DEVELOPMENTS AND NOVEL THERAPIES FOR THE TREATMENT OF HES. Amy Klion, MD Laboratory of Parasitic Diseases, NIAID, NIH January 25, 2018
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1 NEW DEVELOPMENTS AND NOVEL THERAPIES FOR THE TREATMENT OF HES Amy Klion, MD Laboratory of Parasitic Diseases, NIAID, NIH January 25, 2018
2 Disclosures No financial relationships to disclose None of the drugs that I will be discussing, with the exception of imatinib, are FDA-approved for the treatment of HES. This includes prednisone, hydroxyurea, interferon,alemtuzumab, cyclosporine, mepolizumab, reslizumab, benralizumab, and any other agents that get mentioned in discussion.
3 Learning objectives Compare and contrast the most common agents used to treat hypereosinophilic syndrome (HES) Employ a systematic approach to the treatment of HES Discuss recent advances in targeted therapies for eosinophilic disorders
4 Case 1 A 52 year old Sudanese man presents with bilateral arm and left leg numbness and tingling of 1 day duration PE reveals wheezing and hyperreflexia of the upper extremities Labs are notable for an eosinophil count of 7,540/mm 3
5 What is the best course of action? (A) Withhold treatment until all diagnostic procedures can be completed (B) Prednisone burst taper (C) Prednisone 1 mg/kg (D) Imatinib 400 mg (E) Prednisone 1 mg/kg and ivermectin
6 Suspected HES with potentially lifethreatening manifestations Limited diagnostic evaluation Empiric treatment with high dose steroids (+ ivermectin for Strongyloides if potential exposure) Proceed with evaluation Yes Response? No Add second agent
7 General approach to the patient with suspected HES Potentially life-threatening? Secondary treatable cause? Most likely clinical subtype?
8 Clinical subtypes of HES HE US MYELOID LYMPHOCYTIC OVERLAP ASSOCIATED FAMILIAL IDIOPATHIC NIH COHORT (n=415)
9 Conventional therapy for HES Prednisone Hydroxyurea Interferon-a Imatinib (FDA-approved for HES in 2006) Response at 1 month P HU IFN IMAT (Ogbogu et al 2009 JACI)
10 Use of steroids in HES First line for all patients except PDGFR+ and CEL No consensus regarding most appropriate starting dose, except in EGPA (1 mg/kg x > 1 month) Topical steroids may be sufficient in patients with overlap syndromes (e.g. EGID) Although an initial response is achieved in a high percentage of patients, side effects and resistance occur with long-term use Slow taper is more likely to result in sustained remission If remission cannot be maintained with 10 mg prednisone daily, consider a second agent
11 Imatinib and PDGFRA-associated MPN Imatinib has a rapid (weeks) and dramatic effect on eosinophilia Assess eosinophil counts, signs and symptoms weekly for at least 1 month Consider drug failure if minimal response at 4 weeks on 400 mg daily Acute necrotizing myocarditis has been reported with initiation of treatment in the setting of cardiac involvement Resistance and relapse are rare, but incidence and mechanisms are probably similar to CML Recent data suggest that cure is possible in some patients after >5 years of sustained molecular remission
12 Treatment of imatinib-resistant or intolerant PDGFRA-positive MPN Increase imatinib dose Alternative tyrosine kinase inhibitors Nilotinib and sorafenib are effective against the most common resistance mutation Consider allogeneic BMT
13 Initial treatment algorithm Myeloid features? Y PDGFRApositive? N Imatinib mg daily for 4 weeks* *with steroids if cardiac involvement suspected Y N Corticosteroid N trial Criteria met for CEL-NOS? Y Varied + typing for BM transplant
14 Clinical subtype predicts steroid-responsiveness Retrospective analysis of 164 PDGFRA-negative HES subjects who received steroids for at least 2 weeks as a single agent and for whom response data was available Response was defined as the minimum clinically effective dose of GC for which AEC<1000/mm3 and symptoms improved for at least 1 week A multivariate logistical model was used to determine predictors of responsiveness Single Organ HES HES HES/EGPA LHES MHES Sample Proportions >21 No Resp n=13 n=82 n=36 n=26 n=8 (Khoury et al. JACI:In Pract, 2017)
15 Treatment of steroid-resistant HES Myeloid features? Y Imatinib 400 mg daily for 4 weeks* Y N Lymphocytic variant? N *unless a targetable mutation is present; with steroids if cardiac involvement suspected IFN-a+ steroids IFN-a or hydroxyurea or MTX
16 Imatinib response rates in idiopathic (PDGFRA-negative) HES Outcome* Time frame (months) Response Study C NA 3/5 (60%) Cools 2003 C at 1 month /8 (24%) Pardanani 2004 C at 1 month /36 (14%) all transient C at 1 month NA 10/43 (17%) partial in 4 C at 1 week /8 (50%) transient in 2 Baccarani 2007 Ogbogu 2009 Helbig 2011 *C= resolution of clinical symptoms and eosinophilia, H=normalization of bone marrow, M=molecular remission
17 Myeloid features predict treatment responses in PDGFRA-negative HES Prospective Retrospective 100 n= n=4 % Response 50 0 n=10 n=6 % Response 50 0 n=2 n=11 PDGFRA+ PDGFRA- MYELOID HES PDGFRA- NON-MYELOID HES (Khoury, Desmond et al. Allergy 2016)
18 Treatment of steroid-resistant HES Myeloid features? Y Imatinib 400 mg daily for 4 weeks N Lymphocytic variant? Y Continue imatinib Response? N Y IFN-a +/- steroids N IFN-a or hydroxyurea or MTX
19 Interferon-alpha in HES Some initial efficacy in up to 65% of patients with HES, but takes 2-4 weeks to work and is associated with significant toxicity (black box warning) Response at 1 month Reason for discontinuation P HU IFN IMAT P HU IFN IMAT Side effects include flu-like symptoms, depression, pancytopenia, vasculitis, peripheral neuropathy, thyroid disease, hepatitis, stroke, retinitis, pulmonary complications
20 Interferon-alpha in HES Direct and indirect effects on eosinophilia Second-line agent for lymphocytic variant HES, but should be administered with steroids theoretical risk of expansion of aberrant T cell population based on in vitro data Typical dose: 1-3 mu sc daily; pegylated interferon is also effective with once weekly dosing Contraindicated in pregnancy Monitoring: CBC, liver function, ophthalmologic exam, thyroid function
21 Treatment of steroid-resistant HES Myeloid features? Y Imatinib 400 mg daily for 4 weeks Y N Lymphocytic variant? N *preferred for subjects with autoimmune features, pulmonary involvement or other features suggestive of EGPA IFN-a + steroids IFN-a, hydroxyurea, MTX*
22 Hydroxyurea in HES Oral agent with similar efficacy to interferon in the treatment of HES and predominantly hematologic side effects Requires 2-4 weeks for effect Cytotoxic agent with effects on rapidly dividing cells Second line agent for idiopathic HES, alone or in combination with interferon Typical dose: 1-3 g orally daily (500 mg-1 g daily in combination with interferon) Monitoring: CBC
23 Second line therapy for HES PDGFR mutation-positive MN: second generation TKI or BMT PDGFR mutation-negative myeloid HES: imatinib Lymphocytic variant HES: interferon-alpha Idiopathic HES: interferon-alpha or hydroxyurea HES with features of EGPA: methotrexate, cytoxan What next?
24 Conventional therapy for HES is unsatisfactory Response at 1 month % Affected Discontinuation of Therapy PRED 42% HU 76% IFN 84% P HU IFN Drug No treated P HU IFN IMAT (Ogbogu et al. JACI 2009)
25 Targeted therapies on the horizon CD52 (alemtuzumab) Common b chain GM-CSF IL-2R (daclizumab) IL-4 IL-4R IL-9 IL-13 IL-31 IgE (omalizumab) TSLP Dexpramipexole (Bochner JACI 2012)
26 Targeting IL-5/IL-5R Mepolizumab (SB ; GlaxoSmithKline) Reslizumab (SCH55700; Teva) Target IL-5 IL-5 IL-5Ra Antibody (parent) Status in eosinophilic asthma Status in HES Humanized IgG1k (murine 2B6) Approved 100 mg sc every 4 weeks in 12 years FDA-approved for EGPA Phase 2 completed for EoE and HES Phase 3 ongoing for HES Humanized IgG4k (rat 39D10) Approved 3 mg/kg iv every 4 weeks in adults Phase 2 completed for EoE and HES Benralizumab (MEDI-563; AstraZeneca) Humanized afucosylated IgG1k Approved 30 mg every 4 weeks for 3 doses then every 8 weeks for 12 years Phase 2 completed for HES Phase 2 for EGPA and EGID ongoing
27 HES and mepolizumab Placebo-controlled, randomized, multicenter trial of mepolizumab (750 mg iv monthly) treatment in 85 FIP1L1/PDGFRA-negative patients with stable HES on mg prednisone daily Primary endpoint: prednisone dose 10 mg daily for 8 weeks
28 HES and mepolizumab: outcomes % subjects prednisone-free Entry at stage 1 Entry at stage Weeks on Study (Rothenberg NEJM 2009) (Roufosse JACI 2012)
29 Clinical subgroup may affect response to mepolizumab LHES subgroup analysis Compassionate use analysis % Response * LHES IHES Response PDN 10 for 8 wk Off PDN until study end AEC 600 for 8 wk AEC 600 until study end 0 IHES n=20 MHES n=3 LHES n=6 Non-Responders Partial Complete EGPA OVERLAP n=6 (Roufosse JACI 2010) (Kuang et al. submitted)
30 Anti-IL5 treatment for EoE? Stein JACI 2006 (n=4) Straumann Gut 2010 (n=11) Spergel JACI 2012 (n=226) Assa ad Gastroent 2011 (n=59) Design Open label, phase I/II Randomized, doubleblind, placebocontrolled Multicenter, randomized, double-blind, placebocontrolled Multicenter, randomized, double-blind Subjects adults with active EoE >20 peak eos/hpf + sxs adults with active EoE >20 peak eos/hpf + sxs children with active EoE >24 peak eos/hpf + sxs children with active EoE >20 peak eos/hpf +/- sxs Drug mepolizumab mepolizumab reslizumab mepolizumab Dosing monthly x 3 weekly x 2 (+ monthly x 2 at higher dose if no response) monthly x 4 monthly x 3 Blood eos Suppressed Suppressed Not assessed Suppressed Tissue eos Dramatic decrease, but max eos 20/hpf in all 4 subjects week 20 Dramatic decrease (66% compared to 7% in placebo), but max eos 15/hpf in all subjects at weeks 4 and 13 Dramatic decrease, but >50% with more than 24 eos/hpf at study end Dramatic decrease with 8.8% <5/hpf and 32% <20/hpf at 12 weeks Clinical sxs Improved in 4/4 Improvement in 2 mepo and 2 placebo subjects Improvement in all including placebo No significant effect
31 Incomplete tissue response to anti-il5 antibody treatment in EoE (Reslizumab, Spergel JACI 2012) (Mepolizumab; Stein JACI 2012)
32 Mepolizumab and EGPA (MIRRA) A phase 3 placebocontrolled doubleblind trial of mepolizumab 300 mg sc monthly in 136 adults with probable or definite EGPA and a history of relapsing or refractory disease on stable prednisone ( mg/day) for 4 weeks Remission (BVAS 0 on 4 mg prednisone) at week 36 32% 3% (Wechsler et al. NEJM 2017)
33 Summary: Anti-IL5 antibody and HES Excellent safety profile FDA-approved for EGPA (300 mg sc monthly) 85% efficacy in steroid-sensitive IHES and LHES (750 mg iv monthly) May be less effective in patients with more aggressive, treatment-refractory disease, especially those with MHES (?IL5 refractory eosinophils) or LHES (?high IL5 levels) Failure to meet the clinical trial endpoints in EoE may be due to incomplete depletion of eosinophils, lack of depletion of mast cells or other lineages, or other factors (trial duration, irreversible structural changes in esophagus, )
34 Benralizumab and HES Phase 2 study in 20 subjects with treatment-refractory HES (symptomatic with AEC>1000/mm3 on stable background therapy) Randomized, double-blind trial of benralizumab 30 mg sc vs. placebo every 4 weeks for 12 weeks Open-label trial of benralizumab 30 mg sc every 4 weeks for 12 weeks Open-label extension of benralizumab 30 mg every 4 weeks for 6 months (responders only) Eosinophils blinded Stable HES background therapy Eosinophils unblinded Reduction of HES background therapy as tolerated
35 Study population Gender Median Age (range) 13F/7M 46 (23-74) HES Subtype IHES (30%) LHES (25%) Overlap EGID (25%) Overlap EGPA (10%) MHES (10%) HES Therapy P (60%) IFN (20%) HU (15%) Pulsed cytoxan (5%) No therapy (15%) GM AEC (range) 2617 ( ) Organ Involvement Derm (60%) Pulmonary (60%) GI/Liver (40%) Stroke (20%) Cardiac (15%) Musculoskeletal (10%) Constitutional (100%)
36 Benralizumab was well-tolerated and effective in depleting eosinophils in HES P=0.005 The primary study endpoint was met (proportion of subjects with >50% decrease in AEC at 12 weeks) At week 13, AEC was <50/mm3 in 17/19 evaluable subjects At week 52, AEC remained suppressed in 14 subjects despite reduction or discontinuation of background therapy
37 What is dexpramipexole? A small molecule enantiomer of a drug used to treat Parkinson s disease that was found to be neuroprotective in in vitro assays Unknown target Phase I studies: good safety profile Phase II study in ALS: slowed progression Phase III study in 1000 subjects with ALS did not meet primary endpoint BUT
38 Dexpramipexole lowers eosinophils in peripheral blood Cell Count, x10 3 /µl Eosinophil Count Months Placebo Dexpramipexole ALS patients Minipigs (Dworetsky et al. Blood Cells Mol Dis)
39 Dexpramipexole in HES: proof of concept Patient population: 10 subjects with steroid-responsive HES requiring more than 10 mg prednisone for disease control Study design: MED Corticosteroid tapers I & II MED: Minimal Effective Steroid Dose MEDD: Minimal Effective Steroid Dose on Dexpram. MEDD CS I DEXPRAMIPEXOLE Weeks Primary endpoints: 1) proportion of subjects with MEDD <50% MED, 2) reduction in steroid dose on dexpramipexole CS II
40 Dexpramipexole is well-tolerated and effective as a steroid-sparing agent in HES 35 year old woman with HES/EGPA overlap on 15 mg prednisone equivalent with lung, GI, skin and sinus involvement AEC (X10 3 cells/µl) Subject % Baseline steroid dose Pre Post Months Asymptomatic off prednisone for >2 years
41 Dexpramipexole appears to cause maturational arrest of BM eosinophilpoiesis Baseline 3 months (Panch et al. submitted) Eosinophil precursor
42 Room for more new kids on the block? Target EOS BASOS MAST OTHER IL5 x IL5R x x low Siglec 8 x x high EMR1 x CCR3 x x x T cells, bronchial epithelial CRTh2 x x x multiple CysLT1 x x x multiple
43 Case 3 60 year old farmer with a history of GERD and seasonal allergies is noted to have an AEC of 12,900/mm3 at a routine visit to his primary care physician Retrospective review of his prior labs is notable for AEC 1700/mm3 one year prior Medications: loratadine and esomeprazole magnesium, both for >10 years Evaluation including routine labs, bone marrow, flow cytometry, mutation testing, CT scan, echocardiogram, PFTs, unrevealing
44 What is the most appropriate next step? (A) Trial of high dose prednisone (1 mg/kg) (B) Hydroxyurea (C) Taper off steroids and monitor (D) Interferon alpha (E) Imatinib mesylate Prednisone taper AEC WEEK
45 Conclusions Prednisone remains the first line therapy for PDGFR-negative HES Understanding the clinical subtypes of HES is important in the selection of a therapeutic agent Although eosinophils are the major driver of pathology in HES, other cell lineages may play a significant role, especially in overlap syndromes Long-term reduction/depletion of eosinophils in humans appears to be safe There is hope for patients with HES
46 Thanks
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