Long-Term Therapeutic Outcomes with Cladribine in Patients with Xanthoma Disseminatum

Abstract

Cladribine (2-chlorodeoxyadenosine or 2CdA) is a purine analogue that has been used in various non-Langerhans cell histiocytosis. We present a case series of six patients with xanthoma disseminatum having systemic involvement, treated with monthly cladribine for three to 12 cycles (median six cycles), leading to 63.3% improvement at the end of treatment, increasing to 75% at the end of 2.1 ± 1.6 years of follow-up. Three patients maintained their response, two continued to improve without further intervention, and one patient relapsed with partial response to reinstitution of therapy. Intracranial lesions improved significantly in all three patients with neurological involvement. One patient with severe laryngeal involvement causing stenosis was able to avoid tracheostomy. Cladribine was largely well tolerated. Half of the patients developed transient leucopenia requiring prophylactic granulocyte colony-stimulating factor, but none of the patients developed any serious infections.

Introduction

Xanthoma disseminatum (XD) is a rare cutaneous and mucocutaneous (C group) non-Langerhans cell histiocytosis (non-LCH) with a major systemic component, most commonly diabetes insipidus (40%).[1] There may be involvement of the central nervous system as well as osteolytic skeletal lesions. Information regarding treatment options and their efficacy is scarce; several agents have been tried, including corticosteroids, cyclophosphamide, thalidomide, doxycycline, high-dose chemotherapeutic agents like vinblastine, carmustine, etoposide, cytarabine, and melphalan, interleukin 1 (IL-1) receptor antagonist anakinra, interferon alpha, rosiglitazone, and simvastatin, yielding variable responses but lacking consistent, reproducible outcomes.[2] Cladribine (2-chlorodeoxyadenosine or 2CdA) is a nucleoside adenosine analogue that has demonstrated good efficacy in patients with XD in several case series and case reports.[3,4,5]

Case Series

This was a retrospective chart review of patients with the diagnosis of XD, based on clinical features and histopathology, who were treated with cladribine [Table 1]. Six patients, including four males and two females, were included. Reports of three patients (Patients 1–3) were previously published with response at the end of treatment cycles.[6,7,8] These patients were actively followed up. The mean age of the patients was 24.7 ± 11.7 years (range nine to 44 years). The median disease duration at presentation was 3.4 ± 2.5 years (range 1.5 to 8 years). All patients presented with skin-colored to yellowish to brown soft to firm papules, plaques, and nodules in periorbital, perioral, and flexural distribution, variable in extent [Figures 1 and 2]. Associated pruritus was seen in three (50%) patients. Mucosal involvement was seen in four (66.6%) patients, with extensive laryngeal involvement in one patient [Patient 5, Supplementary Figure 1 ^{(125.6KB, tif)} ], causing hoarseness of voice and dyspnea. Histopathology was consistent with XD in all cases. On systemic evaluation, 5/6 (83.3%) patients had central diabetes insipidus, clinically manifesting as polyuria and polydipsia and confirmed by plasma hyperosmolality (>295 mOsm/kg), urine hypoosmolality (<300 mOsm/kg), and absent pituitary bright spot on magnetic resonance imaging (MRI) brain (T1W). Three patients (50%) (Patients 2, 4, and 5) also had additional neurological involvement in the form of T2W hyperintense ill-defined intracranial lesions within the brainstem (n = 3), temporal lobes (n = 2), hypothalamus (n = 2), frontal and parietal lobes (n = 1), cerebellum (n = 1), hippocampus (n = 1), and optic chiasma (n = 1) on MRI brain. These caused memory loss, polyphagia, and focal seizures in Patient 4 and visual loss in Patient 2. Three patients (50%) had lytic bony lesions detected on a skeletal survey involving various sites, like the skull, sternum, cervical and lumbar vertebrae, ilium, and femur [Table 1].

Table 1.

Clinical profile of six patients with xanthoma disseminatum and treatment response

Patient	Mucocutaneous	Systemic involvement	Previous treatment taken	Dosage and No. of cycles	Follow-up	Cutaneous PGA (%) (end of treatment cycles)	Cutaneous PGA (%) (end of follow-up)	Cutaneous IGA (%) (end of follow-up)	Response in extracutaneous manifestations	Adverse effects
Patient 1 26/M	Periorbital Forehead Cheek Neck Axillae Chest	Diabetes insipidus Single lytic bony lesion in left parietal bone	None	5.6 mg/d 8 cycles	3 months	70	70 Sustained response	70	Diabetes insipidus maintained on desmopressin	None
Patient 2 16/M	Periorbital Perioral Neck Axillae Trunk Inguinal folds Popliteal fossae Ocular conjunctiva (left)	Diabetes insipidus Multiple intracranial lesions involving the brainstem, cerebellum, hypothalamus, pituitary, optic chiasma, and lateral ventricle Optic atrophy on ophthalmoscopy and visual loss Right eye-2/60 Left eye-6/36	Topical retinoids and topical steroids for three months, alternative medicine for a year	8.4 mg/d 6 cycles	4.75 years	30	60 Further improvement	60	Improvement in visual acuity of right eye- 6/60 50% decrease in size of intracranial lesions on PET-CT Diabetes insipidus maintained on desmopressin	Transient leucopenia—sixth cycle
Patient 3 44/F	Periorbital Forehead Neck Axilla Thighs	None	Three dexamethasone- cyclophosphamide pulses with daily oral prednisolone and cyclophosphamide, intralesional steroids	8.7 mg/d 3 cycles	2.75 years	60	99 Further improvement	95	NA	Transient leucopenia—third cycle Proximal renal tubular acidosis—fourth cycle, leading to discontinuation
Patient 4 23y/F	Periorbital Perioral Axillae Inframammary Trunk Cubital fossae	Diabetes insipidus Multiple intracranial lesions involving medial temporal lobe, hippocampus, hypothalamus, pituitary, parietal lobe, and mid-brain	Oral methotrexate 15 mg/week and azathioprine 100 mg daily for 1.5 years	8.4–10.3 mg/d (wt gain) 12 cycles	1.5 years	90% (first six cycles) 50% (End of 12 cycles)	50 Relapse	55	Cessation of focal seizures and polyphagia, improvement in memory loss 50% decrease in	Transient leucopenia after each cycle
	Inguinal folds Perineum Popliteal fossae Oral mucosa	(Memory loss, polyphagia, focal seizures) Bony lesions in sternum, right ilium, left femur, C4–C5 vertebrae, likely marrow involvement Xanthogranulomatous cholecystitis (diffuse FDG uptake in gall bladder) and increased FDG uptake in stomach							size of intracranial lesions as well as significant decrease in abdominal uptake on PET-CT, resolution of marrow lesions Diabetes insipidus maintained on desmopressin
Patient 5 19y/M	Periorbital Perioral Axillae Inframammary Trunk Cubital fossae Inguinal folds Popliteal fossae Penile shaft Oral and laryngeal mucosa (respiratory distress and hoarseness of voice)	Diabetes insipidus Multiple intracranial lesions including right medial temporal lobe, hypothalamus, pons, compression of pituitary stalk Bony lytic lesions in mastoid, L5 vertebra, SI joint, bilateral femoral shaft, metacarpals	Oral mini-pulse for six months, methotrexate 10 mg/week with azathioprine 100 mg daily for one year, three cycles of interferon alpha	7 mg/d 5 cycles	1.5 years	80	80 Sustained response	85	50% decrease in size of intracranial lesions on PET-CT Significant improvement in respiratory distress and phonation Diabetes insipidus maintained on desmopressin	Fever three to four days after each cycle
Patient 6 30/M	Periorbital Perioral Neck Axillae Trunk Cubital fossae Inguinal folds Buttocks Popliteal fossae Oral mucosa	Diabetes insipidus	Alternative medicine for six months	8.4 mg 6 cycles	1.3 years	90	90 Sustained response	90	Diabetes insipidus maintained on desmopressin	None

FDG: Fluorodeoxyglucose, IGA- Investigator global assessment, L5- Lumbar vertebra 5, PET CT- Positron emission tomography computed tomography, PGA- Patient global assessment, SI- Sacroiliac joint, NA: Not Applicable

Figure 1.

(a) Periorbital, perioral, (b) axillary, and (c) buttock lesions in a 30-year-old man (Patient 6) showing 90% regression after five cycles of cladribine ((d), (e), and (f))

Figure 2.

(a) Forty-four-year-old woman with xanthoma disseminatum (Patient 3) showing (b) 60% improvement in periorbital and neck lesions at the end of three cycles, with (c) follow-up after three years showing near-complete resolution. The patient underwent an adjunctive single session of surgical resection for right-eye infraorbital nodule

All patients were treated with a slow infusion of intravenous (IV) cladribine 0.14 mg/kg/day (dose ranging from 5.6 to 10.3 mg) in 500 ml normal saline over 3–4 hours, for five days every month, for a median of six cycles (range three to 12 cycles). Premedication with injection pheniramine 22.75 mg and injection paracetamol 15 mg/kg was given half an hour prior. Baseline investigations included complete blood count (CBC), liver and kidney function tests including electrolytes, viral markers [hepatitis B surface antigen (HBsAg), anti hepatitis C virus (anti-HCV), human immunodeficiency virus (HIV 1 and 2)], Mantoux test, urine routine microscopy, and a chest X-ray to exclude any infections. Patients were monitored for blood pressure, heart rate, and temperature at the start, during, and end of infusion. CBC was repeated every alternate day of the cladribine cycle during inpatient admission and one week after completion of the cycle on an outpatient basis, which guided the administration of G-CSF.

All but one patient reported cessation of development of new lesions within one to two cycles. The overall mean improvement in cutaneous lesions was 63.3 ± 21.60% as per patient global assessment (PGA) and 63.3 ± 21.83% as per Investigator Global Assessment (IGA) (based on clinical photographs) at the end of treatment cycles [Figures 1–3]. Patients were followed up for a mean of 2.08 ± 1.57 years in total (range three months to 4.75 years), or 1.46 ± 1.6 years after their last treatment cycle. Patient 3 remains under ongoing treatment and follow-up. Three patients (Patients 1, 5, and 6) sustained the improvement they achieved at the end of their treatment cycles. Two patients continued to progressively improve over many years after the cessation of their cladribine cycles, Patient 2 from 30% improvement at the end of the last (sixth) cycle to 60% improvement (PGA) at the end of 4.75 years, and Patient 3 with 60% improvement at the end of her last (third) cycle to 99% PGA after 2.75 years [Figure 2]. However, Patient 4 had a severe relapse in both cutaneous lesions and neurological symptoms (corresponding to relapse of central nervous system (CNS) parenchymal lesions on positron emission tomography- computed tomography (PET CT) back to baseline within three months of stopping monthly cladribine cycles after initially achieving 90% improvement with six cycles. On reinstating monthly cladribine, she was able to achieve 50% improvement after four cycles and continues to be under treatment [Figure 4]. The mean overall improvement at the end of the follow-up period thus increased to 74.8 ± 18.4% as per PGA and 75 ± 17.8% as per IGA. Adjunctive surgical excision and debulking was done in two patients (Patients 1 and 3) for periorbital lesions. Neurological disease also improved significantly in all three patients with neurological involvement, symptomatically as well as on PET-CT (50% decrease in size of intracranial lesions in Patients 2 and 4 and complete resolution in Patient 5) repeated after four to six cycles.[9] Patient 5, having extensive laryngeal involvement at baseline, had been advised tracheostomy but deferred the same and had complete resolution of hoarseness and dyspnea after two cycles. In addition, all patients with central diabetes insipidus received oral desmopressin 0.05-0.2 mg/day, achieving good control of diabetes insipidus.

Figure 3.

(a), (b), and (c) perioral, periocular, axillary, and neck lesions in a 19-year-old man (Patient 5) showing 80% regression after five cycles of cladribine ((d), (e), and (f)). Laryngeal involvement causing hoarseness and severe dyspnea also resolved

Figure 4.

(a) Axillary and genital lesions in a 23-year-old woman of xanthoma disseminatum (Patient 4) showing (b) 90% improvement after six cycles of cladribine. (c) Relapse after three months post-cessation of cladribine, with (d) 50% improvement after another six cycles (total 12 cycles)

Adverse effects were seen in 4/6 (66.6%) patients, all transient. Three (50%) patients had transient asymptomatic leucopenia after one or more cycles, treated with G-CSF (granulocyte colony-stimulating factor). Patients undergoing treatment subsequently received prophylactic G-CSF with cladribine cycles, avoiding this complication. Patient 5 reported a fever three to four days after each cycle. Patient 3 developed proximal renal tubular acidosis during her fourth cycle, necessitating treatment discontinuation. Patients routinely received antimicrobial (sulfamethoxazole 800 mg + trimethoprim 160 mg twice daily, three times a week) and antiviral (oral acyclovir 400 mg twice daily, three times a week) prophylactically and no patient developed serious infections.

Discussion

Cladribine is a purine analogue that is selectively toxic to lymphocytes and monocytes due to high levels of an enzyme deoxycytidine kinase (dCK) within them that converts the drug to its lethal triphosphate form intracellularly, which then interferes with DNA repair.[10] Though the most well-known use of cladribine is in hairy-cell leukemia, there has been an extension of its use in many other hematological malignancies as well as histiocytic group of disorders on the premise that tissue histiocytes are derived from blood monocytes. The long-term efficacy of cladribine, even with a single cycle of five to seven days, has been attributed to its action on both quiescent and proliferating cells, as well as possible epigenetic mechanisms via inhibition of DNA methylation that leads to switching off of oncogenic signaling.[10] It has shown good efficacy in LCH with about 73–86% response rate and durable remissions for about three to four years.[11,12] Cladribine was first used in non-LCH in Rosai–Dorfman and Erdheim–Chester disease involving the eye, with good efficacy.[13,14] Subsequently, Khezri et al.[3] first used it for cutaneous predominant non-LCH in five adult patients with XD for five to eight cycles, with improvement ranging from 50% to complete resolution. Another case series of three patients with XD by Tuan et al.[4] reported significant resolution with five to nine cycles and a sustained remission after four to 5.5 years of follow-up, similar to our results. Patients with severe laryngeal involvement may require tracheostomy for severe dyspnea,[4,5] but we were able to avoid the same in a young patient of 19 years with the use of cladribine alone. DeMoss et al.[15] previously reported complete resolution in intracranial lesions with six cycles of cladribine, similar to our patients. However, we also report a case of extensive involvement with severe relapse within three months of completing six cycles of cladribine. Potential mechanisms of inadequate response to cladribine include decreased expression of intracellular phosphorylating enzyme dCK and increased levels of dephosphorylating nucleotidases, both leading to decreased active triphosphate form of the drug[16], alterations in cell membrane transporters essential for drug influx and alterations in apoptotic pathways.[10] However, reinstitution of therapy was able to reproduce response, albeit to a lesser extent. This is similar to the decreased periods of remission with repeated cycles reported in hairy cell leukemia.[17]

The poor reputation of cladribine regarding its systemic toxicity has been largely derived from data in leukemia and lymphoma, with 68% of 44 patients experiencing a grade 3 or 4 event, largely myelosuppression, and eight (18%) patients suffering from a grade 3 infection.[18] However, data from LCH patients are encouraging. Though grade 3–4 cytopenias requiring dose delays are reported in 5.4%–53.8% of patients, the incidence of infection was minimal, with just one patient in a cohort of 13 developing herpes zoster.[11] Similar data are available from long-term outcomes of multiple sclerosis patients with oral cladribine, with an increased rate of herpetic infections but not other infections.[19] It is possible that the hematological malignancies themselves, as well as adjuvants, are partially responsible for the high rates of infections in leukemia and lymphoma patients. Thus, cladribine is establishing itself as a reliable treatment modality for infiltrative histiocytic disorders with reasonable safety when given with adequate monitoring and prophylaxis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)

There was no use of artificial intelligence in any component of this manuscript.

Supplementary Figure 1

Direct laryngoscopy of Patient 5 showing diffuse yellowish-white plaques in the laryngeal mucosa

Funding Statement

Nil.