CXCR4 antagonist therapy based on a WHIM syndrome

By Warren R. Heymann, MD, FAAD
June 12, 2024
Vol. 6, No. 24

Emelio* had a delightfully whimsical personality that matched his syndrome’s acronym — WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis). His smile was as infectious as his verrucae, and he joyfully accepted whatever destructive or medical modality we could think of (from cryosurgery to field interferon) with unrelenting enthusiasm, always willing to try something new for his recalcitrant disease. He was our patient in the 1990s, shortly after WHIM was recognized as a distinct disease entity (OMIM #193670). After a few years, he was “lost to follow-up;” I wish he had not been. How wonderful it would have been to tell him that in 2003, George Diaz from Mt. Sinai School of Medicine performed gene linkage analysis from WHIM pedigrees and discovered three different causal gain-of-function mutations of CXCR4 [C-X-C chemokine receptor type 4 gene] that have led to mechanism-based therapeutic strategies. (1) (* not his real name)

WHIM syndrome is a rare disease with approximately 70 cases reported in the medical literature. WHIM is an autosomal dominant primary immunodeficiency syndrome. Clinically, patients with WHIM syndrome are more susceptible to human papillomavirus (HPV), causing warts and potentially squamous cell carcinomas; hypogammaglobulinemia; recurrent bacterial infections (such as otitis media, cellulitis, pneumonia, and sinusitis); and bone marrow myelokathexis, characterized by retention and apoptosis of mature neutrophils resulting in neutropenia. Laboratory manifestations also include significant lymphopenia and monocytopenia. (2) WHIM syndrome behaves as a mostly “benign” immunodeficiency with a relatively low mortality risk. Life expectancy may be shortened primarily to excess cancer risk. (1)

Mechanistically, the truncating gain-of-function mutations of CXCR4 on chromosome 2 (2q22.1) result in hyperactive signaling of this G-protein coupled receptor. Merati et al. state, “While not yet fully deciphered, it is postulated that increased CXCR4 receptor activity upon binding of its cognate stromal cell-derived factor-1 (SDF-1; also known as CXCL12) ligand, prevents the release of mature neutrophils and promotes their apoptosis in the marrow. This cellular mechanism drives myelokathexis that is observed clinically in affected patients. The CXCR4 mutations are inherited in autosomal dominant manner. Some patients with WHIM syndrome, however, do not have a detectable CXCR4 gene mutation, suggesting that mutations in other genes may be involved.” (2)

Plerixafor was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. (3) It failed that indication because of its short half-life, parenteral use, and because most strains of HIV could use an alternative chemokine receptor (CCR5) for entry. (1) Plerixafor’s interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), also mobilizes CD34+stem cells from the bone marrow into the peripheral bloodstream. In December 2008, plerixafor was approved by the U.S. FDA for autologous transplantation in patients with non-Hodgkin’s Lymphoma or multiple myeloma. (3)

In 2011, McDermott et al. recognized that plerixafor could potentially treat WHIM syndrome and tested this hypothesis in animal studies expressing CXCR4. (4) A phase 1 study in three WHIM patients demonstrated a diminution of infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. (5) In an open-label study of three severely affected patients with WHIM syndrome who could not receive G-CSF, plerixafor was administered for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. (6)

McDermott et al. performed a single-center, quadruple-masked phase III crossover trial, comparing the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient. Plerixafor was nonsuperior to G-CSF for TISS (P= 0.54) and non-inferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023). Plerixafor was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). A complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with significant wart burdens at baseline. The authors concluded that plerixafor should continue to be studied as a potential treatment for WHIM syndrome. (7)

Marin-Esteban et al. reported the case of a 29-year-old man with WHIM syndrome and an HPV-5-associated perianal squamous cell carcinoma (SCC). After six months of treatment with plerixafor in combination with short-term administration of imiquimod, the SCC completely resolved. Six years after the discontinuation of plerixafor, the patient had a recurrence of HPV5-related squamous-cell carcinoma at the same location as the original lesion in the context of profound panleukopenia. “The beneficial effects of plerixafor, as well as the recurrence of squamous-cell carcinoma within 6 years after discontinuation of treatment, are consistent with the benefits of long-term plerixafor treatment in patients with WHIM syndrome.” (8)

One of the limitations of plerixafor treatment is its parenteral administration. Mavorixafor is a CXCR4 antagonist that is administered orally. (9) Badolato et al investigated the efficacy and safety of mavorixafor in a double-blind, placebo-controlled, phase 3 trial of participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/μL. A total of 31 participants received once-daily mavorixafor (n=17) or placebo (n=14) or 52 weeks. Higher absolute WBC, ANC, and absolute lymphocyte count levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo and total infection scores were 40% lower. Regarding warts, the authors state, “Despite no difference in wart change score, minor improvements in wart change scores were observed in both the mavorixafor and placebo groups. A previous phase 2 trial of mavorixafor showed an average 75% reduction in the number of warts observed up to 18 months on trial. In our trial, wart change up to 52 weeks was assessed by a central review using photographs of targeted regions, which may not have permitted enough time for significant reduction in wart change score or to monitor the effect of treatment on improvement of newly emerged warts. Therefore, longer observation times and an alternative form of wart assessment may be needed.” Treatment with mavorixafor significantly reduced infection frequency, severity, duration, and antibiotic use. Mavorixafor was well tolerated in participants with WHIM syndrome. No serious treatment-emergent adverse events (TEAEs) were observed, nor did any participants discontinue the drug due to TEAEs. (9) On April 29, 2024, the U.S. FDA approved mavorixafor (Xolremdi) capsules for patients with WHIM syndrome 12 years of age and older.

In all probability, most dermatologists will never encounter a patient with WHIM syndrome. What makes this research so intriguing is understanding the role that CXCR4 may play in other disorders, such as keratinocyte carcinomas and cutaneous T-cell lymphoma. (2) Knowing how CXCR4 antagonists may be used specifically for these disorders will assure that we are not just administering them on a whim.

Point to Remember: Advances in understanding the pathomechanisms of WHIM syndrome are the prelude to treating this syndrome — and other diseases — with CXCR4 antagonists.

Our experts’ viewpoint

Philip M. Murphy, MD
David H. McDermott, MD

Laboratory of Molecular Immunology
National Institute of Allergy and Infectious Diseases, NIH

Targeted treatment of WHIM syndrome immunodeficiency: from famine to feast?

Complete resolution of the clinical manifestations of disease by mechanism-based drug treatment is the Holy Grail of personalized medicine, and in-depth study of rare Mendelian conditions to pinpoint mechanisms is an efficient way to attain it. As Dr. Heymann has clearly described, for the ultrarare combined immunodeficiency disease WHIM syndrome, the structurally distinct small molecule CXCR4 antagonists plerixafor (Mozobil; Sanofi-Genzyme) and mavorixafor (Xolremdi; X4 Pharmaceuticals) are two new entrants in the quest, acting by blocking a hyperfunctional mutant receptor encoded by the disease gene CXCR4. WHIM syndrome is of outsized interest to dermatologists because the signature pathogen in the disease is HPV, which may cause extensive refractory skin, oral, and anogenital disease in about half of WHIM patients often starting in childhood. Patients can be infected with multiple types of HPV even in the same lesion, including typical alpha types and atypical beta, gamma, and mu types. In a few patients HPV infections have progressed to squamous cell cancer.

The conventional treatments for WHIM syndrome, G-CSF to correct neutropenia, and immunoglobulin supplementation to correct IgG deficiency, do not have clinically significant effects on HPV disease, leaving a major unmet medical need that the new agents might fill. In Phase 1 and 2 trials, both agents appeared to cause wart regression, and two patients with HPV+ head and neck squamous cell carcinoma given plerixafor had arrest or regression of tumor. Consistent with this, in Phase 3, plerixafor given twice daily for one year induced clinically significant wart regression in the majority of patients; however, not all warts regressed, some patients saw no benefit, and no anogenital warts regressed even with co-administration of the TLR7 agonist imiquimod. In Phase 3 the effect of mavorixafor given once daily on warts did not differ from placebo. Both drugs act similarly to mobilize myeloid and lymphoid cells to blood, so the efficacy difference for wart control may have to do with pharmacokinetic and pharmacodynamic factors. The variability in plerixafor efficacy suggests that HPV lesions even in the same patient may have variable biology, perhaps related to location, antigen presentation, immunologic access, and HPV type-specific differences. Improving on plerixafor’s activity and unleashing mavorixafor’s potential for wart regression may simply require dose escalation and a longer treatment duration and/or provoking inflammation to improve immune cell access to virally infected cells. Toward this end, we have begun testing plerixafor administration by continuous infusion pump with positive preliminary results.

HPV lesion regression is the simplest infectious benefit to demonstrate since HPV is the only chronic infection common to WHIM patients and the lesions are stable without treatment and can be monitored photographically. Control of acute infection by other pathogens is more difficult to assess because of high variability in incidence from year to year, difficulty distinguishing excess infections in WHIM patients relative to healthy control subjects, the rarity of the disease and the need to assess both infection frequency and severity as endpoints. Moreover, the mavorixafor Phase 3 trial was conducted during the COVID-19 pandemic at 20 different international sites, where differences in mask wearing, social distancing, and lockdowns could potentially distort results. Nevertheless, it is clear that these drugs reverse panleukopenia in WHIM syndrome, reduce infection burden to some extent, and are relatively well-tolerated compared to filgrastim (G-CSF). For this, the FDA has approved mavorixafor in WHIM syndrome, marketed as Xolremdi. Plerixafor was already FDA approved for stem cell mobilization marketed as Mozobil and can be prescribed off label for WHIM syndrome with generics currently available. The next challenge is to find the best way to deliver these drugs to fully reverse the clinical manifestations of the disease, i.e. the Holy Grail. Neither drug has been tested yet in young children (< age 10 years), who may benefit the most. Ultimately, the future challenge is cure using gene therapy or safer and more broadly applicable methods of allotransplantation, which has been used to cure 9 WHIM patients to date.

1. Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure. J Clin Immunol. 2019 Aug;39(6):532-556. doi: 10.1007/s10875-019-00665-w. Epub 2019 Jul 16. PMID: 31313072; PMCID: PMC6698215.

2. Merati N, Sivachandran S, Jfri A, Ben-Shoshan M, Vinh DC, Popradi G, Litvinov IV. Plerixafor on a WHIM - Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome? Skin Therapy Lett. 2022 Mar;27(2):1-5. PMID: 35385630.

3. De Clercq E. Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother. 2019 Jan-Dec;27:2040206619829382. doi: 10.1177/2040206619829382. PMID: 30776910; PMCID: PMC6379795.

4. McDermott DH, Lopez J, Deng F, Liu Q, Ojode T, Chen H, Ulrick J, Kwatemaa N, Kelly C, Anaya-O'Brien S, Garofalo M, Marquesen M, Hilligoss D, DeCastro R, Malech HL, Murphy PM. AMD3100 is a potent antagonist at CXCR4(R334X) , a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome. J Cell Mol Med. 2011 Oct;15(10):2071-81. doi: 10.1111/j.1582-4934.2010.01210.x. PMID: 21070597; PMCID: PMC3071896.

5. McDermott DH, Liu Q, Velez D, Lopez L, Anaya-O'Brien S, Ulrick J, Kwatemaa N, Starling J, Fleisher TA, Priel DA, Merideth MA, Giuntoli RL, Evbuomwan MO, Littel P, Marquesen MM, Hilligoss D, DeCastro R, Grimes GJ, Hwang ST, Pittaluga S, Calvo KR, Stratton P, Cowen EW, Kuhns DB, Malech HL, Murphy PM. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr 10;123(15):2308-16. doi: 10.1182/blood-2013-09-527226. Epub 2014 Feb 12. PMID: 24523241; PMCID: PMC3983611.

6. McDermott DH, Pastrana DV, Calvo KR, Pittaluga S, Velez D, Cho E, Liu Q, Trout HH 3rd, Neves JF, Gardner PJ, Bianchi DA, Blair EA, Landon EM, Silva SL, Buck CB, Murphy PM. Plerixafor for the Treatment of WHIM Syndrome. N Engl J Med. 2019 Jan 10;380(2):163-170. doi: 10.1056/NEJMoa1808575. PMID: 30625055; PMCID: PMC6425947.

7. McDermott DH, Velez D, Cho E, Cowen EW, DiGiovanna JJ, Pastrana DV, Buck CB, Calvo KR, Gardner PJ, Rosenzweig SD, Stratton P, Merideth MA, Kim HJ, Brewer C, Katz JD, Kuhns DB, Malech HL, Follmann D, Fay MP, Murphy PM. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome. J Clin Invest. 2023 Oct 2;133(19):e164918. doi: 10.1172/JCI164918. PMID: 37561579; PMCID: PMC10541188.

8. Marin-Esteban V, Molet L, Laganà M, Ciocan D, Dominguez-Lafage C, Alouche N, Nguyen J, Gallego C, Mercier-Nomé F, Jaracz-Ros A, Beaupain B, Bouligand J, Proust A, Habib C, Bonnin RA, Girlich D, Fouyssac F, Schmutz JL, Bursztejn AC, Bellanné-Chantelot C, Bourrat E, Herfs M, Espéli M, Balabanian K, Schlecht-Louf G, Donadieu J, Bachelerie F, Deback C. CXCR4 Antagonist in HPV5-Associated Perianal Squamous-Cell Carcinoma. N Engl J Med. 2024 Apr 11;390(14):1339-1341. doi: 10.1056/NEJMc2213180. PMID: 38598804.

9. Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale DC, Deyà-Martinez À, Dickerson KE, Ezra N, Hasle H, Kang HJ, Kiani-Alikhan S, Kuijpers TW, Kulagin A, Langguth D, Levin C, Neth O, Olbrich P, Peake J, Rodina Y, Rutten CE, Shcherbina A, Tarrant TK, Vossen MG, Wysocki CA, Belschner A, Bridger GJ, Chen K, Dubuc S, Hu Y, Jiang H, Li S, MacLeod R, Stewart M, Taveras AG, Yan T, Donadieu J. Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome. Blood. 2024 Apr 21:blood.2023022658. doi: 10.1182/blood.2023022658. Epub ahead of print. PMID: 38643510.

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