Vitiligo Following Autologous Hematopoietic Stem Cell Transplantation

Vitiligo, a depigmenting dermatosis is characterized by the disappearance of melanocytes in the epidermis and thought to be an autoimmune condition¹. While it has been reported in a small number of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and attributed to T-cell deregulation^{2, 3}, its occurrence after autologous HSCT has only been reported twice in the English literature^{4, 5}. Therefore, the etiological correlation remains uncertain. In this report, we describe a case of significant hypopigmentation consistent with vitiligo, developing in a patient with multiple myeloma following autologous HSCT.

A 60-year-old African-American woman presented with progressive fatigue. Initial evaluation revealed marked anemia, and further workup uncovered an IgG lambda monoclonal gammopathy by serum protein electrophoresis. Further investigations established the diagnosis of Durie-Salmon stage III, International Staging System stage II, IgG lambda multiple myeloma. The cytogenetic analysis of bone marrow aspirate revealed hyperploidy and deletion of chromosome 13. The patient initiated induction treatment with lenalidomide and dexamethasone and subsequently underwent autologous HSCT. Three months post-transplantation, she achieved a very good partial response (VGPR) and started maintenance lenalidomide 10 mg daily. Approximately 5 months post-transplantation, the patient reported pruritus involving the face, chest, and upper back, associated with patchy hypopigmentation. Initially, these findings were thought to be consistent with tinea versicolor, but symptoms did not improve and worsened with topical therapy (Figure 1). Skin cultures and stains were negative for fungi while a punch biopsy revealed juxtaposition of pigmented and hypopigmented skin (Figure 2A), with higher magnification showing melanin pigment in basilar keratinocytes and less pigment in the epidermis associated with inflammation (Figure 2B); An immunostain for melan-A documented loss of melanocytes in the hypopigmented epidermis while present in normal number in the pigmented epidermis (Figure 2C); A Fontana Masson stain confirmed the loss of melanin pigment (Figure 2D). Given concerns that the rash could be an unreported toxicity of lenalidomide, the drug was discontinued. The patient’s rash did not significantly change over time. Meanwhile, she continued using topical tacrolimus and received narrowband UV-B phototherapy without improvement. Nineteen months post-transplantation, the patient achieved complete remission of her multiple myeloma. The hypopigmentation has persisted more than six years following the autologous HSCT and 3 years after discontinuation of lenalidomide when disease relapsed and progressed and alternative therapy was administered.

Figure 1:

Frontal view of the patient showing scattered widespread areas of hypopigmented skin on the face and trunk consistent with vitiligo

Figure 2:

(A) Skin punch biopsy reveals juxtaposition of pigmented (thin arrow) and hypopigmented skin (thick arrow); (B) Higher magnification shows melanin pigment in basilar keratinocytes and less pigment in the epidermis associated with inflammation; (C) An immunostain for melan-A documents loss of melanocytes in the hypopigmented epidermis while present in normal number in the pigmented epidermis; (D) Fontana Masson stain highlights melanin pigment.

HSCT (primarily autologous) constitutes a cornerstone of current therapy for multiple myeloma. Even though allogeneic HSCT can produce therapeutically beneficial graft-vs-tumor effects, it also carries a risk of immune complications following transplantation⁶. Vitiligo has rarely been reported following allogeneic HSCT, often in the setting of GVHD^{2, 3}. Two mechanisms have been proposed for the development of this autoimmune manifestation post-allogeneic HSCT. The first invokes a passive transfer of donor immunity. This theory has been surmised based on the transmission of pre-existing donor autoimmune conditions, including vitiligo but also thyroiditis, and other autoimmune diseases, onto the recipient host after allogeneic HSCT. The other mechanism involves a response of the donor T cells to the host environment, most often in the setting of GVHD, mediated by melanocyte-specific T lymphocytes⁷. Claudy and colleagues described the ultrastructural changes of altered melanocytes when they are in close contact with T lymphocytes⁸. They observed that lymphocyte-induced melanocyte degeneration occurred during the early phase of GVHD when the pigmentary alteration is not clinically detectable and continues during the chronic phase of the disease, leading to hypopigmentation.

In the setting of autologous HSCT, we are aware of only two reported cases of vitiligo. Worswick et al. describe a patient who underwent autologous HSCT for scleroderma⁵. However, this case is associated with clinical evidence of GVHD, and is probably a manifestation of this complication as previously described in the setting of allogeneic HSCT. Additionally, Sanli et al. describe one patient who initially had allogeneic HSCT for CML, then developed GVHD and scleroderma; he ultimately underwent salvage autologous HSCT 4 years later, which was followed by the development of vitiligo⁴.

The mechanism underlying the deregulation of autoimmunity following autologous HSCT remains unclear as one would not expect that infusion of autologous hematopoietic cells would trigger an autoimmune response. However, GVHD has been reported after autologous HSCT. Drobyski et al. and Fidler et al. reported 6 patients who developed GVHD following autologous HSCT^{9, 10}. In this context and as pointed out by Worswick et al., vitiligo may represent a cutaneous form of GVHD⁵. In support of this hypothesis, both previously reported patients with vitiligo following autologous HSCT had GVHD and an autoimmune disease (scleroderma, in both cases) prior to the development of vitiligo.

In the patient described in this report, the pathology of the skin biopsy is more in keeping with post-inflammatory hypopigmentation, which may be an early manifestation of vitiligo since the diagnostic criteria are not fully met for the diagnosis of vitiligo. However, the prolonged persistence of unabated clinically significant depigmentation confirms the diagnosis of vitiligo. Notably, the patient described in this report has developed vitiligo following autologous HSCT in the absence of other overt manifestations of GVHD or prior autoimmune disease, raising the possibility that this depigmentation may be unrelated to GVHD. Although initial concerns, in this case, focused on lenalidomide as a possible etiology since the drug is known to modulate the immune response and has been associated with autoimmune complications, such an adverse event has never been reported with lenalidomide. It is worth noting in this context that vitiligo, although not reported with the immunomodulator lenalidomide, has been well described as an immune-related adverse event during treatment with immune checkpoint inhibitors used in Oncology. For example, while the prevalence of vitiligo in the general population is in the order of 1% (although reported to be as high as 8.8% in India) and 2.8% in patients with melanoma, the incidence of this side effect in melanoma patients receiving anti-PD1 therapy has ranged between 9.6 and 25%^11,12,13. It is not excluded that the combination of HSCT followed by lenalidomide may be causative in this patient.

• Vitiligo, a depigmenting dermatosis is characterized by the disappearance of melanocytes in the epidermis and thought to be an autoimmune condition. Its prevalence in the general population is in the order of 1%.

• Vitiligo has been reported in a small number of patients following allogeneic hematopoietic stem cell transplantation (HSCT), mostly in the setting of GVHD. Its occurrence after autologous HSCT has only been reported twice in the English literature. Its mechanism in this setting remains unclear, although GVHD has been reported after autologous HSCT.

• In this report, we describe a case of vitiligo developing in a patient with multiple myeloma following autologous HSCT and lenalidomide maintenance.

• Lenalidomide, although never associated with vitiligo, is an immune modulator with well described autoimmune side effects. Likewise, other drugs harnessing the immune response, like checkpoint inhibitors (anti-PD1 therapy) have resulted in high incidence of vitiligo.

• We postulate that vitiligo may be the result of a combined effect of HSCT and lenalidomide in modulating the patient’s immune response.