Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.

Comprehensive in Vitro Characterization of CXCR4WHIM variants to Decipher Genotype-Phenotype Correlations in WHIM Syndrome

Background: WHIM (Wart, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome is a rare, autosomal-dominant primary immunodeficiency with neutropenia and lymphopenia. The clinical presentation may include recurrent infections, and increased susceptibility to human papillomavirus. In >80% of cases, WHIM syndrome is caused by heterozygous gain-of-function (GOF) mutations in C-X-C chemokine receptor 4 (CXCR4), with >12 variants reported in WHIM syndrome to date (nonsense [NS], frameshift [FS], and missense[MS]) spanning 27 C-terminal amino acids . These mutations cause hyperactivation of downstream signaling and retention of WBC in the bone marrow (McDermott D, et al. Immunol Rev. 2019;287(1):91-102; Beaussant S, et al. Orphanet J Rare Dis. 2012;7(71):1-14). To date, a comprehensive study characterizing the functional abnormalities caused by pathogenic CXCR4 mutations and correlating these measures with clinical presentation in patients has not been conducted. Here, we aimed to establish genotype-phenotype correlations for all known pathogenic variants using in vitro functional assays. These assays characterize CXCR4 receptor trafficking and downstream signaling, which will enable the long-term goal of assessing pathogenicity of novel CXCR4 variants of uncertain significance (VUS). We further aimed to assess the in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. Methods: We used the CXCR4-negative K562 cell line as a model system to express all 14 known CXCR4 variants identified in patients diagnosed with WHIM syndrome (previous reports, ClinVar, and genetic screening initiatives [Invitae PATH4WARD]). The effects of the mutations on CXCR4 receptor trafficking (internalization and degradation), downstream signaling (Ca 2+ mobilization, cAMP inhibition, ERK and AKT activation), and chemotaxis were studied in parallel in a series of assays in cells stimulated with the natural ligand CXCL12. All in vitro functional parameters characterized were investigated for potential correlations with the clinical phenotypes reported for each variant, including disease manifestations and biomarkers. Results: The most conserved feature of the 14 CXCR4 variants was an impaired receptor internalization in response to CXCL12, evidenced by higher percentage of CXCR4 receptors remaining on the cell surface compared to untreated control, with truncated variants showing maximum impairment and the MS variant E343K being least affected. The decreased CXCR4 internalization correlated with both decreased CXCR4 degradation and increased cAMP inhibition. When stimulated with CXCL12, most variants demonstrated a higher amplitude and duration of ERK and AKT activation. Chemotactic responses to CXCL12 were diverse, depending on the variant sequence and subtype. While Ca 2+ mobilization was not enhanced compared to wild-type (WT) CXCR4-expressing cells in this assay, mavorixafor demonstrated inhibition of Ca 2+ mobilization in all CXCR4 mutant cells with a trend toward greater effect in the NS variants. In addition, both ERK and AKT activation decreased with increasing concentration of mavorixafor. Correlation analyses of the functional parameters in cells expressing mutated or WT CXCR4 and clinical manifestations or WBC counts in patients with these mutations revealed that the CXCR4 internalization defect strongly correlated with severity of peripheral blood cytopenias (ie, decreases in absolute neutrophil counts, and in CD3+ and CD4+ T-cell levels), which was paralleled by an increased susceptibility to recurrent infections. In addition, AKT hyperactivation correlated with lower IgA and decreased CD4+ T-cell levels (Figure). Conclusions: In the current study, we performed a detailed functional analysis of the entire spectrum of CXCR4 WHIM mutations known to date. In vitro CXCR4 receptor internalization correlates with WBC cytopenias and an increased susceptibility to recurrent infections in patients with CXCR4 GOF mutations. These data suggest that CXCR4 internalization and AKT activation may be used as key assays for the assessment of CXCR4 variant pathogenicity in vitro and potentially as WHIM-related disease biomarkers. Additionally, all tested CXCR4 variant cell lines were sensitive to mavorixafor at clinically relevant concentrations, rescuing defective GOF signaling toward that of WT CXCR4-expressing cells. Figure 1 Figure 1. Disclosures Zmajkovicova: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Maier-Munsa: X4 Pharmaceuticals: Current Employment. Maierhofer: X4 Pharmaceuticals: Current Employment. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Badarau: X4 Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

CXCR4 Drives Lympho-Myeloid Fate of Hematopoietic Progenitors Via mTOR and Mitochondrial Metabolic Pathways

Blood production is a tightly regulated process that starts with hematopoietic stem cells (HSCs). In adults, HSCs are unique in their capacity to self-renew and replenish the entire blood system through production of a series of increasingly committed progenitor cells within the bone marrow (BM) microenvironment. HSCs form a rare, quiescent population that displays a metabolism skewed towards anaerobic glycolysis at the expense of mitochondrial oxidative phosphorylation (OXPHOS) to preserve its quiescent state and long-term reconstitution capacity. However, when HSCs differentiate, they undergo a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS, a process that is in part mediated by the metabolic sensor mTOR. It is well-established that HSCs in the BM adapt the production of myeloid and lymphoid cells depending on the needs of the body and that metabolic plasticity is a critical driver of HSC fate decisions. This has never been assessed for multipotent progenitors (MPPs) which constitute the stage at which the major divergence of lymphoid and myeloid lineages occurs. In mice, common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) are generated from phenotypically and functionally distinct subpopulations of lineage-biased MPPs, i.e. MPP2 and MPP3 are reported as distinct myeloid-biased MPP subsets that operate together with lymphoid-primed MPP4 to control blood leukocyte production. This question is thus of paramount importance to understand how the lympho-myeloid specification process is regulated. Signaling by the G protein-coupled receptor CXCR4 on MPPs in response to stimulation by its natural ligand, the chemokine CXCL12, produced by BM perivascular stromal cells constitutes a key pathway through which the niches and MPPs communicate. However, the mechanisms whereby CXCR4 signaling regulates MPP specification are still unknown. We addressed this point using BM samples of patients with WHIM Syndrome (WS), a rare immunodeficiency caused by inherited heterozygous autosomal gain-of-CXCR4-function mutations affecting desensitization of CXCR4 and characterized by chronic lympho-neutropenia, as well as a unique WS mouse model which phenocopies severe pan-leukopenia. We unraveled myeloid skewing of the hematopoietic stem and progenitor cell (HSPC) compartment in BM of patients with WS and of WS mice. This relied on CXCR4 signaling strength that controls the output of the lymphoid and myeloid lineages by coordinating the composition and molecular identity of the MPP compartment. The fate of the lymphoid-biased MPP4 subset was central in such a process. Indeed, CXCR4 signaling termination was required for efficient generation and maintenance of the MPP4 pool, while regulating intrinsically their cell cycle status and lymphoid-myeloid gene landscape. In fact, we demonstrated for the first time that enhanced mTOR signaling, accumulation of damaged mitochondria and overactive OXPHOS-driven metabolism promoted cell-autonomous molecular changes that reprogram mutant MPP4 away from lymphoid differentiation. Consistent with this, in vivo chronic treatment with the CXCR4 antagonist AMD3100/Plerixafor or the mTOR inhibitor Rapamycin normalized mitochondrial metabolism and MPP4 differentiation. Thus, our study shows that CXCR4 signaling acts through the mTOR pathway as an essential gatekeeper for integrity of the mitochondrial machinery, which in turn controls lymphoid potential of MPP4. Disclosures No relevant conflicts of interest to declare.

Mavorixafor, an Oral CXCR4 Antagonist, for Treatment of Patients with WHIM Syndrome: Results from the Long-Term Extension of the Open-Label Phase 2 Study

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare, autosomal-dominant primary immunodeficiency. Gain-of-function (GOF) mutations in the CXCR4 gene are the most common cause of WHIM syndrome, manifesting as panleukopenia with severe neutropenia, lymphopenia, and monocytopenia, recurrent bacterial infections, unusual susceptibility to human papillomavirus infections with intractable mucocutaneous warts, and increased risk of malignancy (McDermott DH, et al. Immunol Rev. 2019;2878:91-102). Mavorixafor is an investigational, small-molecule, selective antagonist of the CXCR4 receptor being developed as an oral, once-daily (QD) treatment for patients with WHIM syndrome (Dale DC, et al. Blood. 2020;136(26):2994-3003). Objective: We present an update on the clinical outcomes of patients with WHIM syndrome who continued in the long-term extension of the phase 2 study, highlighting long-term safety and efficacy. Methods: A long-term extension is ongoing as part of the open-label, prospective, dose-escalation, phase 2 study evaluating the safety and efficacy of mavorixafor (NCT03005327) in adults with WHIM syndrome. Individuals with a pathogenic GOF CXCR4 mutation and absolute neutrophil count ≤400/μL and/or absolute lymphocyte count ≤650/μL were included. All provided written informed consent. The primary objectives were to evaluate safety and tolerability and assess safe dosage. Exploratory efficacy end points included changes in infection rates, number of cutaneous warts, and white blood cell counts, compared to baseline. Researchers completed detailed interviews of 4 participants continuing in the study to assess their overall study experience and perceived treatment effects. Results: Five of 8 patients in the dose-finding phase 2 study entered into the long-term extension (LTE); median treatment duration was 148.4 weeks. One patient left the LTE because of study fatigue, and all 5 patients had dose escalation to 400 mg oral QD as of May 2021. As of the November 2020 data cutoff, annualized infection rates decreased from 5.6/year at study baseline to 2.2/year at 40 months' treatment, providing evidence of persistent reduction of infections over time. At doses of 300 and 400mg QD (n=7), the mean time above threshold for ANC and ALC were 12.7 hours (SD ± 9.8) and 16.9 hours (SD ± 5.9) compared to 2.1 hours (SD ± 3.3) and 11.5 hours (SD ± 5.9) at doses ≤200 mg QD, respectively. One patient experienced a 79% reduction in warts. Safety data review at May 2021 showed that there were 12 minor treatment-emergent adverse events (grade 1) with long-term treatment (46 months), no treatment-related infections of grade 3 or higher, no treatment-related serious adverse events, and no clinically significant laboratory abnormalities with mavorixafor treatment. Patient interviews revealed that all 4 LTE participants experienced good tolerability of mavorixafor and decreased frequency, severity, and duration of infections and decreased hospital/doctor visits. Three of 4 participants reported previous need for prophylactic treatment to prevent infection of minor wounds, but with mavorixafor, minor wounds healed without infection or need for prophylaxis. The mechanism of action of mavorixafor was of interest to 3 of 4 participants, who found it important that treatment address the underlying cause of disease, not simply the symptoms. Two participants reported a QOL improvement, and the other 2 reported that WHIM syndrome never affected their QOL Conclusion: Ongoing long-term treatment of adults with WHIM syndrome with mavorixafor 300 to 400mg shows durable increase in neutrophils and lymphocytes and sustained improvements in infections and warts. Detailed patient interviews for patient global impression of changes are consistent with sustained clinical benefit of long-term treatment. Mavorixafor has the potential to be a safe, effective, and long-term therapy targeting the underlying cause of WHIM syndrome. A global phase 3 registrational study is ongoing. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Firkin: X4 Pharmaceuticals: Research Funding. Bolyard: X4 Pharmaceuticals: Research Funding. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hu: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Characterization of a Novel Missense CXCR4 Mutation in a Patient with WHIM-like Syndrome

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome is a rare primary immunodeficiency with a heterogeneous presentation of symptoms defining its acronym as well as panleukopenia. The majority of cases are inherited in an autosomal dominant manner, with gain-of-function mutations in the C-terminus of the C-X-C chemokine receptor 4 (CXCR4) (McDermott D, et al. Immunol Rev. 2019;287:91-102). To our knowledge, there are no literature reports implicating CXCR4WHIM mutations outside the CXCR4 C-terminus. Here we report the clinical presentation of a patient with the novel mutation CXCR4D84H and characterize the functional effects of the mutation on CXCR4 trafficking and chemotaxis in in vitro and ex vivo assays. Further, CXCR4D84H is reported in 3 population genetic databases (average allele frequency 3.8 × 10 -5) and is also found in 5 unrelated patients in another rare disease database (CentoMD). C ase Report: A 40-year-old female presented with a history of recurrent vulvovaginal and anal dysplasia and carcinoma in situ requiring multiple surgeries starting at age 20 years. Cytopenia was first documented at age 15 years in the context of mononucleosis, which resolved, although cytopenias persisted through adulthood. To date, the patient has decreased absolute neutrophil counts (600-1100/mm 3 range), WBC counts ~2000/mm 3, and normal immunoglobulin levels. Bone marrow biopsy revealed bilobed neutrophils and granulocyte precursors. The patient has no history of recurrent infections besides HPV/EBV and no family history of warts, immunodeficiency, or squamous cell carcinoma. Genetic testing revealed a heterozygous mutation in CXCR4 (c.250G>C, D84H) that has not been previously reported. This missense mutation occurs in the transmembrane domain of CXCR4 in proximity of the residues involved in signal initiation, and hence, may alter signaling responses. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from this patient and 2 healthy controls and analyzed for functionality ex vivo including CXCR4 internalization assays and chemotaxis to exogenously added CXCR4-ligand CXCL12. The CXCR4-negative K562 cell line was transiently transfected to express CXCR4D84H, CXCR4WT, and known CXCR4WHIM mutations for further comparison of their functional responses to CXCL12. Results: Flow cytometry data shows abnormal peripheral leukocyte frequency and count. Lymphocyte subpopulations showed 33%-57% reduced CXCR4 internalization in response to CXCL12 compared to controls. Chemotactic response to CXCL12 was increased in PBMC subsets including natural killer T (NKT) cells compared to healthy donor cells. These observations are comparable to previously published responses to pathogenic CXCR4WHIM variants, but, chemotactic responses of NKT cells is a novel finding. In K562-transfected cells, CXCR4D84H demonstrated impaired CXCL12-induced internalization compared to CXCR4WT at a level comparable to the CXCR4E343K variant, the only CXCR4 missense variant known to date to cause WHIM syndrome. Chemotaxis of cells expressing CXCR4D84H in response to CXCL12 is increased by 1.25- to 2.4-fold compared to CXCR4WTdepending on CXCL12 concentration, in line with the observation of increased chemotaxis of cells expressing known CXCR4WHIM variants. Overall, the CXCR4D84H mutation recapitulates the phenotypes exhibited by known CXCR4WHIM variants in both internalization and chemotaxis assays. Conclusions: We show the functional effects of a novel missense mutation CXCR4D84H found in a patient with clinical WHIM syndrome recapitulates the internalization and chemotaxis findings of other CXCR4WHIM mutations. This is the first report of a missense mutation in CXCR4 outside of the C-terminus causing a WHIM phenotype, and additionally highlights defective chemotaxis in NKT cells, which may be relevant in this patient's HPV-associated carcinoma in situ phenotype. Based on an analysis of population databases, and assuming a conservative 5-10% penetrance, there are potentially ~1250-2500 individuals in the United States with disease due to the p.D84H variant alone, highlighting the under-recognition of WHIM syndrome. Patients who have similar clinical presentation as described in this case study should be evaluated for WHIM syndrome and other primary immunodeficiencies by using genetic screening for CXCR4 and diagnostic assays described. Disclosures Pawar: X4 Pharmaceuticals: Current Employment. Zmajkovicova: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wiest: X4 Pharmaceuticals: Current Employment. Nguyen: X4 Pharmaceuticals: Current Employment. Monticelli: X4 Pharmaceuticals: Current Employment. Maier-Munsa: X4 Pharmaceuticals: Current Employment. Sondheimer: X4 Pharmaceuticals: Consultancy. Walter: Octapharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmig: Consultancy, Membership on an entity's Board of Directors or advisory committees. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Badarau: X4 Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Tarrant: ThermoFisher Scientific: Consultancy; X4 Pharmaceuticals: Consultancy, Research Funding; Department of Justice: Consultancy; Abbvie: Research Funding; Viela Bio: Research Funding.

Application of an Artificial Intelligence/Machine Learning Model for Estimating Potential US Prevalence of WHIM Syndrome, a Rare Immunodeficiency, from Insurance Claims Data

Introduction: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an inborn error of immunity characterized as a primary immunodeficiency with neutropenia-but the acronym does not reflect the broad spectrum of disease manifestations that patients may experience. A WHIM syndrome diagnosis may be confirmed clinically by the presence of myelokathexis, the retention of white blood cells in the bone marrow, or by identification of a known pathogenic gain-of-function mutation in the CXCR4 gene coding for the CXCR4 receptor. Diagnosis of WHIM syndrome is thought to be frequently missed because of low disease awareness, missed identification of myelokathexis, and lack of routine genetic testing (Al Ustwani O, et al. Br J Haematol. 2014:164;15-23; Dotta L, et al. Curr Mol Med. 2011;11:317-325; Heusinkveld L, et al. Exp Opin Orphan Drugs. 2017;5(10):813-825). The prevalence of WHIM syndrome has never been systematically studied and is unknown. Determination of prevalence via insurance claims data is hindered by the absence of an International Classification of Diseases (ICD)-10 code for WHIM syndrome as well as inconsistent coding for key symptoms of WHIM syndrome, which are variably penetrant. This study applied an artificial intelligence (AI)/machine learning (ML) model to estimate the potential prevalence of WHIM syndrome using a large US insurance claims database. Methods: A deidentified, longitudinal, patient-level US claims database of >300 million lives was used for this study. Thirty-two patients with genetically confirmed WHIM syndrome were identified from the claims database by linking deidentified patients to known physicians and matching clinical and demographic features. Using this group as a positive training class, an AI/ML model was deployed to identify patients with WHIM look-alike clinical phenotypes in the database. Patients were further filtered based on clinical features to generate low (presence of warts, history of infections, and hypogammaglobulinemia) and high (presence of warts, history of infections, and coding associated with immunodeficiency) prevalence estimates; a final prevalence number for the US was projected to account for incomplete coverage of the US population in the claims database. Finally, insurance codes for disease symptoms, treatments, and management were analyzed to investigate the burden of disease in patients identified by the model. Results: The model showed a high predictive value for distinguishing patients with known WHIM syndrome from a random sample of age-matched patients in the database (area under the curve [AUC] of receiver operating characteristic [ROC] plot, >0.99) as well as a control group of patients with ICD-10 codes defining immunodeficiency conditions (AUC of ROC plot, 0.99). The model generated estimates ranging from 1803 (low) to 3718 (high) patients with WHIM look-alike phenotype in the US. Analysis of medical history in the high-estimate WHIM look-alike group revealed symptomatic and severe disease, as evidenced by ≥1 instance of use of granulocyte colony-stimulating factor (41%) or intravenous immunoglobulin (46%) therapy (both <1% in control group), need for respiratory services (82% vs 8% in control group), presence of hearing loss (18% vs 1% in control group), and high annual utilization of emergency (51%) and hospital (44%) services (vs 8% and 1%, respectively, in control group). Conclusions: The methodology used here provides an approach to explore the prevalence of rare diseases that are often mis- or under-diagnosed and are not captured with a unique ICD-10 code. This study estimates a prevalence of 1803 to 3718 WHIM look-alike patients in the US, supporting the possibility that there may be ≤~3700 patients with either diagnosed or undiagnosed WHIM syndrome in the US. An analysis of the medical history of the WHIM look-alike patients revealed a history of symptomatic and severe disease and a high unmet medical need. Since it is not feasible to definitively confirm a WHIM diagnosis in the look-alike group, it is possible that some of these look-alike patients may have diagnosed or undiagnosed WHIM syndrome, while others may have a clinical phenotype consistent with WHIM syndrome without meeting its classic diagnostic criteria. Disclosures Garabedian: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Neri: X4 Pharmaceuticals: Current Employment. Seng: X4 Pharmaceuticals: Current Employment. Jones: Real Chemistry (Formerly Swoop/IPM): Current Employment, Other: I was paid salary to perform secondary research project work for client "X4" which resulted in this publication.

Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome

Purpose WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published. Methods To summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide. Results All patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms. Conclusion HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts.