Dermatologic complications in transplantation and cellular therapy for acute leukemia

Abstract

Adoptive cellular immunotherapy, mainly hematopoietic stem cell transplant and CAR-T cell therapy have revolutionized treatment of patients with acute leukemia. Indications and inclusion criteria for these treatments have expanded in recent years. While these therapies are associated with significant improvements in disease response and overall survival, patients may experience adverse events from associated chemotherapy conditioning, engraftment, cytokine storm, supportive medications, and post-transplant maintenance targeted therapies. Supportive oncodermatology is a growing specialty to manage cutaneous toxicities resulting from the anti-cancer therapies. In this review, we summarize diagnosis and management of the common cutaneous adverse events including drug eruptions, graft-versus-host disease, neoplastic and paraneoplastic complications in patients undergoing cellular therapies.

Drug Eruptions

CHEMOTHERAPY

Toxic erythema of Chemotherapy

Toxic erythema of chemotherapy (TEC) encompasses a wide array of non-allergic cutaneous eruptions to chemotherapeutic drugs. Historically, these eruptions went by many, often redundant, names, based primarily on clinical or histologic features. Some examples include hand foot syndrome (HFS), palmar plantar erythema/erythrodysesthesia, intertriginous eruptions associated with chemotherapy, and intertrigo dermatitis. TEC is a new term that broadly encompasses these, such that confusion among patients and providers is minimized [1].

TEC presents classically with painful erythema and edema, sometimes with a bullous component, and most often affects the hands, feet, and intertriginous zones and less frequently the elbows, knees, and ears [1, 2] (FIGURE 1). Atypical presentations may occur, especially in skin of color, and can manifest as hyperpigmentation [3]. A localized form at injection sites appears to be more likely when small distal vessels are used for chemotherapy [4]. In some cases, TEC may generalize and clinically mimic toxic epidermal necrolysis [5]. The mechanism behind TEC eruptions is not clearly elucidated but may relate to the accumulation of chemotherapy in eccrine glands, leading to local toxic effects [2].

Figure 1:

Toxic erythema of chemotherapy (TEC) in the groin.

TEC eruptions typically occur 2–3 weeks after administration of chemotherapy, although some may experience a delayed form months after chemotherapy initiation [1, 2]. In patients with AML, thiotepa, daunorubicin, cytarabine, and busulfan/fludarabine are often implicated in these eruptions [2, 6]. Eruptions are typically self-limited and resolve with desquamation and post inflammatory hyperpigmentation. Symptomatic treatment may be given including topical steroids, emollients, analgesics, topical antibiotics, and cold compresses [2].

Azacytidine

Azacytidine is a nucleoside inhibitor and hypomethylating agent with two forms – injectable, for the treatment of MDS and oral, which is approved for the treatment of AML after achieving first complete remission. One study assessing all adverse events to injectable azacytidine found that among AML patients, 7.2% and 19.9% experienced primarily low-grade skin/mucosal infections and injection site reactions, respectively [7]. Excessive bleeding at injection sites may also occur as azacytidine induced thrombocytopenia is common [8]. Azacytidine has been reported to precipitate Sweet syndrome. [9, 10].

Busulfan

Busulfan is an alkylating agent that is often used in combination with cyclophosphamide or fludarabine/clofarabine for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHCT). Dermatologic adverse events (dAEs) are common with this medication, with rash and pruritus occurring in 57% and 28% of patients in clinical trials, respectively. In addition, busulfan can cause generalized skin darkening which may involve the mucosal surfaces [11]. The use of busulfan as part of the conditioning regimen has also been identified as one of the primary risk factors for the development of post alloHCT permanent chemotherapy induced alopecia, which is defined as hair loss that persists for longer than 6 months [12, 13].

Cyclophosphamide

Cyclophosphamide is an alkylating agent that has many uses in the treatment of acute leukemias, including cytoreduction, conditioning prior to alloHCT, and prophylaxis against graft vs host disease (GvHD) [14]. Hyperpigmentation is the primary cutaneous toxicity and often presents on the palms, soles, and oral mucosa but may also affect the nails [15]. Cyclophosphamide can also induce hair loss or changes to hair texture or quality and may play a role in the development of late chemotherapy induced alopecia [16]. Hypersensitivity reactions may also occur and can manifest as urticaria, angioedema, or vasculitis [17]. These reactions typically begin shortly after cyclophosphamide infusion is begun, but may also have a delayed presentation if hypersensitivity is due to a cyclophosphamide metabolite [17].

Cyclosporine

Cyclosporine is a calcineurin inhibitor with immunosuppressive effects, most often given for GvHD prophylaxis. Most dAEs associated with this medication involve the pilosebaceous unit, including hypertrichosis, sebaceous hyperplasia, acne, folliculitis, epidermal cysts, and pilar keratosis [15]. Hypertrichosis is one of the most common dAEs, affecting up to 70% of patients, and is believed to be due to cyclosporine induction of the anagen phase of hair growth [18, 19].

Cytarabine and Daunorubicin

Cytarabine, a pyrimidine nucleoside analog, and daunorubicin, an anthracycline, are both cytotoxic chemotherapies used in the treatment of AML frequently as part of a “7+3” regimen [20]. Daunorubicin is often implicated in the development of TEC. Morbilliform eruptions or acral erythema, can occur in 50% of patients taking high-dose cytarabine [21] (FIGURE 2). Edema, rash, mucositis and pruritus have been reported in 60%, 52%, 46%, and 9% of patients on the “7+3” regimen, respectively [20].

Figure 2:

Painful rash secondary to cytarabine.

CPX-351 (Vyxeos^®)

CPX-351 (Vyxeos^®) is FDA approved for therapy related AML and AML with myelodysplasia related changes. This medication is a liposomal encapsulation of cytarabine and daunorubicin that is designed to deliver a synergistic 5:1 drug ratio [20]. DAEs to this therapy are common – clinical trials report rash, mucositis and pruritus with frequencies of 54%, 44%, and 15%, respectively [20]. In a study further characterizing these toxicities, investigators found that CPX-351 rash commonly presents as a purpuric maculopapular/papulonodular eruption [22]. Twenty-three percent developed this morphology of rash and of these, 35% had a high-grade form. Clinically, this is best categorized as a subtype of toxic erythema of chemotherapy. Fortunately, the rash appears to have a benign course and resolves spontaneously in most patients. Histology is nonspecific, most often showing superficial perivascular lymphocytic infiltrate and/or red blood extravasation. Notably, all patients in this study did not develop rash until after CPX-351 completion [22]. The mechanism of dAE development is not entirely clear, but may be due to the prolonged effects of the liposomal formulation of cytarabine and daunorubicin on the epidermis through upregulation of the CD95 and TNFαR cytotoxic receptors [23].

Decitabine

Decitabine, a nucleoside synthesis inhibitor and hypomethylating agent, which is often used for AML treatment off label in elderly patients. Decitabine has been considered a post alloHCT maintenance therapy option [24]. Common dAEs, include ecchymosis (22%), non-specific rash (19%), erythema (14%), petechiae of the oral mucosa (13%), stomatitis (12%), non-specified skin lesions (11%), pruritus (11%), alopecia (8%), urticaria (6%), and swelling of the face (6%) [25].

Fludarabine

In the context of alloHCT, fludarabine, a purine analogue, is most frequently used as part of the conditioning regimen [26]. Skin toxicity may occur and most often manifests as rash, including generalized maculopapular eruptions [15]. Less commonly, cases of erythema multiforme, Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TENS), and pemphigus have also been reported [27]. In addition, fludarabine has been associated with acceleration of both BCC and SCC growth; although the mechanism is not entirely clear, this may relate to its immunosuppressive effects [28, 29].

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is an inosine monophosphate dehydrogenase inhibitor that is used as an immunosuppressive. Like the calcineurin inhibitors, this medication is used primarily for GvHD prophylaxis in patients undergoing alloHCT with acute leukemias. Cutaneous toxicities are fairly limited with mycophenolate mofetil. Patients may experience aphthous stomatitis, acne, edema, and worsening of dyshidrotic eczema [19]. While MMF use also appears to increase the risk of skin cancer [30], one study found that converting from calcineurin inhibitors to MMF as the maintenance immunosuppressant following alloHCT decreased non melanoma skin cancer risk [31].

Tacrolimus

Tacrolimus, a calcineurin inhibitor, has similar clinical effects and indications as cyclosporine. Compared to cyclosporine, tacrolimus has a relatively mild cutaneous toxicity profile. Telogen effluvium can occur frequently and is believed to be secondary to tacrolimus induced vasoconstriction of vessels supplying the hair follicles [32]. Increased risk of skin cancer has been well substantiated in the literature; as such, the FDA issued a black box warning for tacrolimus in 2005 [30, 33]. This risk of skin carcinoma appears to be increased with greater cumulative exposure to tacrolimus [34, 35].

Thiotepa

Thiotepa is an alkylating agent that is often used as part of the conditioning regimen prior to alloHCT. Development of dAEs is common – in one pediatric study, all patients developed skin reactions (TEC) to high-dose thiotepa. Morphologies included desquamation (97%), erythema (95%), hyperpigmentation (84%), and pruritus (68%), primarily in the intertriginous areas [36]. Thiotepa associated hair loss also occurs often, and increased exposure to thiotepa has been shown to increase risk of permanent chemotherapy induced alopecia [37].

TARGETED THERAPIES

Alemtuzumab

Alemtuzumab is a monoclonal antibody that binds to CD52, an antigen that can be found on both normal and malignant mature lymphocytes. It is currently FDA approved for the treatment of chronic lymphocytic leukemia and has been used in some protocols as part of the preparative regimen for alloHCT. DAEs occur frequently among patients taking this medication – in clinical trials, patients experienced rash (52%), urticaria (16%), pruritus (14%), flushing (10%), dermatitis (8%), erythema (5%), and peripheral edema (5%) [38]. Anaphylactic infusion reactions may also occur [39].

Anti-thymocyte globulin

Anti-thymocyte globulin (ATG) is an equine or rabbit derived antibody that targets T cells and thymocytes, often used as GvHD prophylaxis in patients undergoing HCT. In clinical trials, dAEs reported by patients included rash (11%), edema (6%), pruritus (6%), and herpes simplex reactivation (4%) [40]. In addition, type III hypersensitivity reactions (serum sickness) are a well-recognized complication – these present in 0.25–8.5% of patients and typically begin one or two weeks after ATG infusion [41]. Rarely, immediate type I reactions including anaphylaxis may also occur [42].

Blinatumomab

Blinatumomab is used in relapsed and refractory ALL. Blinatumomab is a bispecific T cell antibody that engages CD19, which is expressed on over 90% of B cell precursor ALL blasts, and CD3 positive cytotoxic T cells. This interaction activates cytotoxic T cell driven lysis of CD19 positive ALL blasts [43, 44]. However, dermatologic toxicities occur frequently, with clinical trials reporting rash in 21–36%, edema in 30%, and stomatitis in 18.5% [43, 45] Fortunately, most cases of dAEs appear low grade, with only 1–2% of patients experiencing a high-grade form. Medium vessel vasculitis, possible secondary to blinatumomab induction of a type III hypersensitivity state, has also been described [46].

FLT3 inhibitors

Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in about 35% of patients with AML [47]. Patients with these mutations are more likely to experience relapse of their disease. In recent years, therapies designed to target this mutation have been approved for usage in various cancers. There are several drugs in this class. Two commonly used ones, midostaurin and gilteritinib are used in the newly diagnosed and the relapsed/refractory setting, respectively. Clinical trials have shown that patients treated with these experienced greater overall and event free survival [48, 49]. Different FLT3 Inhibitors have been tried or are under trial for maintenance therapy after alloHCT [50].

DAEs occur frequently in these patients, although they have not been well characterized in the literature. Among patients on gilteritinib in clinical trials, edema, mucositis, and rash occurred in 41%, 40%, and 36% of patients, respectively. Cellulitis and skin infection were also reported, but less frequently [51]. Mucositis (66%), petechiae (36%), hyperhidrosis (14%), and rash (14%) were the most common dAEs among patients on midostaurin [52]. Cellulitis and skin infection were also reported, but less frequently [51].

In addition, cases of neutrophilic dermatoses, including Sweet syndrome and panniculitis, have been reported with these therapies [53, 54]. FLT3 inhibitors work by inducing terminal differentiation of myeloblasts and as a result may lead to differentiation syndrome and its associated neutrophilic dermatoses. If patients develop these toxicities, they made need to reduce, interrupt, or discontinue their therapeutic regimen.

IDH inhibitors

Mutations in isocitrate dehydrogenase (IDH) genes 1 and 2 occur in up to 30% of AML cases and lead to disruptions in epigenetic regulation, ultimately disrupting differentiation [55]. IDH1/2 inhibitors, including FDA approved medications enasidenib and ivosidenib, are a new class of therapies for use in patients with these mutations. They have demonstrated impressive efficacy, leading to complete remission in approximately 20% of patients [56, 57]. Enasidenib safety has been shown for maintenance therapy after alloHCT [58]. DAEs are common. In clinical trials, edema, rash, and pruritus were reported in 32%, 19–26% and 9–14% of patients, respectively [59, 60]. In one study, 32% of patients on enasidenib or ivosidenib experienced a dAE, with over 15% reporting high grade symptoms. Enasidenib associated toxicities occurred more frequently and tended to be higher grade. The most common dAEs were inflammatory dermatoses, with maculopapular rash occurring the most frequently. Infection, most frequently cellulitis, and vascular changes, most frequently edema, were also common in this cohort. Fortunately, dAEs appeared to be tolerable or manageable, with only 2 patients who experienced dAEs requiring interruption or discontinuation of their IDH inhibitor therapy [61].

Venetoclax

Venetoclax is an oral BCL2 inhibitor that is FDA approved for the treatment of AML in patients who are ≥ 75 years old or cannot undergo intensive chemotherapy due to comorbidities. Venetoclax has been tried as post-transplant maintenance therapy in AML patients at high relapse risk [62]. DAEs to this therapy have not been well characterized, but clinical trials reported rash in 13–18% and edema in 13–34% of patients [63, 64]. There are also cases in the literature of venetoclax induced vitiligo and venetoclax induced geographic tongue [65, 66]. These dAEs, while common, tend to be low grade [67].

TOTAL BODY IRRADIATION

Total body irradiation (TBI) is often given to patients undergoing HCT as part of the preparatory regimen. Administration of TBI can potentially treat malignancy in sites not penetrable by chemotherapy. TBI has been associated with numerous dAEs. In one single center analysis, 20% and 53% of patients experienced alopecia and oral mucositis, respectively [68]. These typically began within 90 days of undergoing TBI treatment. Permanent alopecia has also been reported [12, 69]. Dermatitis is well described in patients undergoing radiotherapy but occurs rarely in patients undergoing TBI due to lower and more fractionated doses [68]. An increased risk of basal cell carcinoma in alloHCT recipients with TBI exposure has been detected in some studies [70].

ANTIBIOTICS

Patients with acute leukemia have an increased risk for infection. The malignancy itself can lead to the production of defective lymphocytes with impaired cell-mediated immunity, and prolonged treatment with chemotherapy can cause severe neutropenia, ultimately increasing the risk of fungal, bacterial, and viral infections [41]. Oftentimes, antimicrobials are given prophylactically to these patients to prevent the development of severe infections. As a result, patients with acute leukemia are exposed to a wide array of antibiotics and other antimicrobials. This frequent use of antimicrobials carries a multitude of risks, including the development of cutaneous toxicities.

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX) is often used to prevent infection in alloHCT recipients [71]. TMP-SMX is commonly implicated in the development of drug hypersensitivity reactions; the active metabolites of sulfamethoxazole (SMX) are generally thought to be the causative agents [72]. Skin reactions occur in roughly 3–4% of patients receiving the medication and can vary in morphology – maculopapular eruptions, diffuse erythema, urticaria, erythema multiforme and purpura have all been reported [73]. Patients may also notice increased photosensitivity. Severe hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), and anaphylaxis may also occur. These severe reactions occur rarely, but the SMX moiety and other sulfonamides appear to disproportionately increase risk of their development relative to other antibiotics [74]. In patients who develop hypersensitivity reactions (excluding SJS/TEN/DRESS) desensitization may allow for continued treatment with TMP-SMX and is generally quite successful [75].

Voriconazole

Voriconazole is an antifungal used to treat numerous fungal infections, including aspergillosis and candidiasis. It is commonly given prophylactically to patients who undergo alloHCT, as they are more predisposed to developing these fungal infections. Although effective, voriconazole has also been associated with a wide array of adverse effects, including visual changes, hallucinations and hepatic enzyme abnormalities [76]. Dermatologic toxicities have also been reported.

Phototoxicity occurs in approximately 8% of patients on voriconazole and often presents about 120 days following initiation of treatment [77]. Up to one third of children treated with voriconazole are affected [78]. Morphologies of these eruptions include cheilitis, exfoliative dermatitis, and pseudoporphyria [77]. Patients may also experience hypersensitivity to voriconazole, including severe reactions such as anaphylaxis and SJS/TEN [79, 80]. In addition, patients can develop chronic phototoxicity and accelerated photoaging, which often manifest as lentigines or actinic keratoses [81]. These symptoms possibly develop due to the generation of reactive oxygen species by voriconazole and its metabolite voriconazole N oxide, which leads to sensitization of keratinocytes to UVA light and resultant DNA damage [82].

By a similar mechanism of action, voriconazole also increases risk of squamous cell carcinoma. A systematic review found that patients were almost twice as likely to develop SCC if they had previously used voriconazole [83]. This relationship also appears to be dose dependent – one study reported that every 60-day exposure at standard dosing of 200 mg BID resulting in a 6% increased risk of developing SCC [84]. HPV may also be implicated in the pathogenesis, as many patients, regardless of immunosuppression status, have detectable HPV DNA within their voriconazole associated SCCs [85]. Cases of melanoma development following photosensitive reactions to voriconazole have also been reported, but the relationship between the two has not been well investigated [86]. Voriconazole does not display the same relationship with basal cell carcinoma [83].

Chimeric antigen receptor T cell therapy (CAR-T)

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment modality with broadening scope due to its efficacy in the treatment of hematological malignancies. The CAR T-cell therapy is based on genetically engineering of T cells with selective targeting of tumor specific antigens which result in immune mediated destruction of tumor cells [87]. Given the expansion of CAR-T cell therapy indications, more patients will experience toxicities associated with these cytotoxic therapies due to the release of pro-inflammatory cytokines [88]. The cutaneous toxicities of various grade reported for FDA approved CAR T-cell products ranges from 9–31% with less than 5% of grade 3 or higher adverse events (AEs) [89–91]. The dAEs include erythematous maculopapular exanthemas as the most common one, petechial, pustular and bullous eruptions. The histopathology findings vary in correlation with etiopathogenesis and morphology. These include dermal infiltration by lymphocytes compatible with eruption of lymphocyte recovery, vacuolar interface changes and subepidermal bullae, papillary edema in conjunction with dense CD8+ and CD3+ CAR T cells predominance in the bulla in blistering reactions [92, 93]. The latency period for development of cutaneous toxicities with CAR T-cell therapy is highly variable and reported from day 1 to 19 months after CAR T-cell infusion. Clinicians should keep in mind the higher-than-expected short time frames of immunologic reactions when evaluating the patients with history of CAR-T therapy for a new eruption. Most of the dermatological toxicities associated with CAR T therapy are minor and resolve spontaneously with conservative management or topical steroids. Grade 3 or higher dermatological toxicities like blistering dermatoses occur less frequently, but may need prompt topical and systemic steroid therapy [94].

Graft-versus-Host Disease (GVHD)

GVHD is an immune mediated multisystem disorder seen in 30–70% of patients who undergo allogenic HCT (alloHCT) [95]. It is associated with significant morbidity and mortality. Early recognition and management is important for improving quality of life and overall survival [96]. Acute GVHD is characterized by the activation of donor T cells with targeting of recipient tissues – mainly skin, liver and the gastrointestinal system [97]. Skin is the most frequently affected organ. GVHD is broadly classified into acute GVHD (aGVHD) and chronic GVHD (cGVHD) based on the timing of onset, using a cutoff of 100 days traditionally; however, the signs and symptoms of both aGVHD and cGVHD may overlap and can be seen outside the cutoff period. The clinical findings are predominantly used to distinguish and treat the two entities. Clinical manifestations of aGVHD of skin usually include a maculopapular rash which can accompany other organs involvement with persistent abdominal pain, diarrhea, and liver dysfunction with rising serum bilirubin [98]. The staging of skin aGVHD is based on the involvement of body surface area (BSA). Stage 1 with rash <25% of BSA, stage 2 with 25–50% of BSA, stage 3 > 50% of BSA and stage 4 having generalized erythroderma with bullae and/or desquamation [99]. The rash usually starts around the time of white blood cell engraftment and frequently involves the areas around the nape of the neck, ears, shoulders, and the palmar and plantar skin [100]. It is usually a pruritic maculopapular eruption (FIGURE 3) which is occasionally painful like sunburn. In severe cases, lesions can be more widespread with generalized erythroderma, bullae, and skin sloughing [101]. The skin biopsy has limited diagnostic utility for aGVHD due to histopathological similarities between the lesions related to aGVHD, drug eruption and viral exanthems [102]. The histopathological findings suggestive of aGVHD include dyskeratosis, interface dermatitis, vacuolar degeneration of basal layers and superficial infiltrates [103]. These histological findings are not specific to aGVHD and decision for diagnosis and treatment should be based mainly on the clinical judgement [104, 105]. A careful history, examination, investigation for extracutaneous organ involvement, and biopsies can aid in the diagnosis. The treatment of cutaneous aGVHD depends upon extent and severity of skin eruptions and other organ involvement. Topical steroids should be considered for stage 1–2 cutaneous aGVHD. For the trunk and extremities, moderate to high potency topical corticosteroids can be used. In patients with involvement of the face, groin and skin folds, low potency topical steroids and topical calcineurin inhibitors should be considered [106]. The patients with higher grade lesions (stage 3–4) should be treated with systemic steroids (prednisone 1–2 mg/kg) along with the support of topical corticosteroids. There is need for multi-disciplinary care in high grade skin lesions with involvement of the wound care team and aggressive skin care with application of burn sheets, topical and antibacterial emollients, non-adherent and impregnated dressings with regular gentle cleansing [107]. In the setting of refractory widespread disease, adding oral Janus Kinase 1/2 inhibitor ruxolitinib) should be considered [108]. There are other non-standard options available in steroid refractory disease which can be considered in a case-by case basis. These include clinical trials, extracorporeal photopheresis (ECP), tumor necrosis factor (TNF) antagonists (infliximab, etanercept), mycophenolate mofetil (MMF), antithymocyte globulin therapy (ATG), sirolimus (mTOR inhibitor) and pentostatin [109–114].

Figure 3:

Acute GVHD following alloSCT for AML.

Of note, some patients can present with aGVHD pictures outside of expected timeframe. Most notably, tapering immunosuppression which is routinely performed to prevent or treatment of relapse, elicits GVHD [115]. Donor lymphocyte infusion (DLI) which is used as a rescue ro treat the relapse or prevent it in stem-cell transplantation provokes GVHD [116].

cGVHD usually affects 30–50% of alloHCT patients with approximately 30% of cases occurring de-novo without any previous history of aGVHD. It is the leading cause of non-relapse mortality in patients otherwise cured of their underlying primary malignant disease [117, 118]. The development of cGVHD is characterized by chronic inflammation in the setting of repeated tissue injury with loss of central immune tolerance and aberrant tissue repair mechanisms [119]. cGVHD is characterized by skin involvement with lichen planus or scleroderma like cutaneous lesions, dry oral mucosa, oral ulcerations with sclerosis of gastrointestinal tract and liver dysfunction with elevated serum bilirubin level [120]. The most common non-sclerotic cutaneous features in cGVHD are lichen planus or poikiloderma-like cGVHD [121]. The lichen planus lesions are flat-topped erythematous papules or plaques mainly on the dorsal aspects of hands, feet, forearms and trunk. Poikiloderma like GVHD is characterized by skin atrophy and pigmentary and telangiectatic changes [100]. Sclerotic cGVHD usually develops in the later stage of disease and can affect the skin areas similar to lichen planus-like lesions. It can present as a firm skin-colored, shiny, hyper- or hypo-pigmented plaques, hair loss, lichen sclerosis-like white plaques, scleroderma-like lesions with contractures, progressive loss of range of motion and joint dysfunction. In some cases, chronic sclerotic changes and skin atrophy due to prolonged steroids can lead to chronic non-healing ulcers (FIGURE 4) [122, 123]. The 2014 NIH cGVHD consensus criteria and scoring system is the most commonly used method for evaluating the severity of mucocutaneous cGVHD [124]. The skin lesions are scored from 1 to 3 based on the degree of skin involvement with 1–18%, 19–50% and >50% BSA, respectively. A sclerosis severity score of 2 is given for superficial sclerotic features (no hidebound, lesion able to pinch) and a score of 3 is given for deep sclerotic features (hidebound, unable to pinch) or impaired mobility and ulceration. Oral disease is recorded with presence or absence of lichen planus like features and scored based on the severity of symptoms and limitation in oral intake from 1 to 3 for no, partial, or major limitations, respectively [124]. The diagnosis is usually made by 4-mm punch biopsy in sclerotic cGVHD. [125]. The mainstay of therapy for cutaneous cGVHD is the use of medium-to-high-potency corticosteroids, topical calcineurin inhibitors (pimecrolimus, tacrolimus) and ultraviolet (UV) phototherapy. Given the chronic nature of cutaneous changes, the combination of topical and systemic therapy is usually administrated in moderate to severe cases for accelerated response and to prevent irreversible effects. Similar to aGVHD, the choice and strength of topical corticosteroids or calcineurin inhibitors depend upon the involved area of skin. The standard first-line systematic therapy is prednisone (1mg/kg daily) [126]. In steroid-refractory disease, oral ruxolitinib, oral rho-kinase inhibitor belumosudil, and/or Bruton’s tyrosine kinase inhibitor (BTK) ibrutinib are approved as a subsequent line of therapy [127]. For cases refractory to initial FDA-approved therapies, clinical trials, ECP, MMF, rituximab, methotrexate (MTX), pentostatin, sirolimus, imatinib and hydroxychloroquine have been used with variable efficacy [128–134].

Figure 4:

Early inflammatory phase of sclerodermoid GVHD (left), fully developed sclerodermoid GVHD complicated by progressive ulceration (right, top and bottom).

Paraneoplastic Dermatological Manifestations

Paraneoplastic skin lesions are sometimes the first manifestation of underlying occult disease or disease recurrence in which prompt recognition and diagnosis can help in the early diagnosis of the primary malignant process [135, 136]. The most common cutaneous paraneoplastic diseases seen in patients with leukemia are neutrophilic dermatoses including Sweet syndrome and pyoderma gangrenosum, paraneoplastic pemphigus and vasculitis [137].

Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by the abrupt onset of painful erythematous papules, plaques or nodules along with fever and leukocytosis. Malignancy-associated Sweet syndrome is most often hematological and is most commonly seen alongside AML followed by MDS [138, 139]. The underlying pathogenesis may be related to a hypersensitivity reaction to cancer antigens and/or cytokine dysregulation. The inflammatory process leads to dermal edema, pustule formation and development of targetoid lesion [139]. The upper extremity is usually the most common site of involvement (FIGURE 5), followed by the trunk, lower extremities, and head and neck. In bullous Sweet syndrome, there are vesicles and flaccid bullae along with erythematous to violaceous plaques with occasional ulceration [140]. In a less common variant, subcutaneous Sweet syndrome, there is neutrophilic infiltration of subcutaneous fat rather than dermis with development of subcutaneous nodules without significant dermal changes [141]. The diagnosis of Sweet syndrome is based on an abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate with two minor criteria including fever, underlying malignancy, abnormal laboratory values at presentation (elevated ESR, CRP) and excellent response to therapy with systemic steroids or potassium iodide [142, 143]. Topical and systemic steroids are the first line of therapy for patients with Sweet syndrome. Topical corticosteroids are preferable for patients with localized skin involvement. Systemic steroids usually start at a dose of 0.5–1 mg/kg per day and usually taper over the period of 4–6 weeks after clinical response [144]. In patients with a contraindication to systematic glucocorticoids, colchicine, dapsone and potassium iodide are some of the options [145]. In selected case of severe disease, pulse high dose IV steroids can be used for 3–5 days followed oral steroid therapy with a gradual taper [144, 146]. If refractory to first line agents, patients can be treated with cyclosporine, methotrexate, oral retinoids such as etretinate, anakinra and TNF antagonists on a case-by-case basis [147–153].

Figure 5:

Sweet’s syndrome in an AML patient on induction chemotherapy.

Pyoderma gangerosum (PG) is another neutrophilic dermatosis associated with underlying hematological malignancy [154]. It is an ulcerative disorder with formation of inflammatory papules or pustules that progress to a painful ulcer (FIGURE 6) with a violaceous undermined border and a purulent base [155]. PG has four major subtypes: ulcerative (classic), bullous, pustular and vegetative [156]. The development of lesions is usually rapid, and patients’ reported pain score is much higher than expected based on the degree of skin lesion [157]. The most common site of skin involvement is the lower extremities, but lesions can occur in any other area of body. Bullous PG is the less common form and commonly seen in patients with hematological malignancy. The diagnosis of PG requires detailed history and physical examination along with skin biopsy for histopathological confirmation and to rule out other more common etiology of skin lesions like infection. The biopsy should include both the inflamed border and ulcer area along with subcutaneous fat [158]. Overall, PG is a diagnosis of exclusion and can be challenging [159]. The multi-disciplinary approach with local wound care and in some cases plastic surgery is very important for wound healing [160]. The initial therapy in patients with mild and localized PG is usually high potency topical steroids (e.g., clobetasol) and topical calcineurin inhibitors (tacrolimus 0.1%) [161]. The initial clinical improvement can be seen within a couple of days to weeks of treatment, but wound healing of ulcerated lesion may take several weeks to months. In cases of extensive or rapidly progressive disease, systemic corticosteroids (prednisone 0.5 to 1.5 mg/kg per day) can be used as initial therapy. After initial clinical response, steroids can be tapered in 4–10 weeks with close monitoring. In patients with intolerance or lack of response to glucocorticoids, cyclosporine, TNF antagonists, MMF, azathioprine, MTX, and dapsone are some of the options [160, 162, 163].

Figure 6:

Early stage of pyoderma gangrenosum (biopsy proven prior to deep ulceration) in a MDS patient on azacytdine (left) with relatively rapid resolution after 2 weeks on systemic steroid (right).

Infections

Skin infections are seen in about 8–10 % of patients with acute leukemia due to the impaired immune responses related to disease itself and associated treatments [164]. However, infections in the setting of HCT occur in the context of multiple interplaying factors including but not limited to the conditioning regimen, GVHD status and use of immunosuppressive regimens [165]. Invasive fungal infections with cutaneous manifestations are a major cause of morbidity and mortality in acute leukemia and alloHCT patients, in particular with a history of prolonged neutropenia. Aspergillus, Fusarium and Zygomycetes are some notable examples [166]. Herpes simplex virus (HSV) commonly affects the mucocutaneous orofacial region (85–90%) and genital areas (10–15%). Primary infection is not common and the majority of lesions are associated with reactivation of latent virus [167]. Varicella-zoster virus (VZV) causes varicella (chickenpox) and reactivation results in herpes zoster (shingles) which appear as grouped painful, pruritic, vesicular lesions in a dermatomal distribution [167]. Demodex folliculorum has recently been more scrutinized in hematological malignancies and alloHCT patients. It usually presents as an itching, redness and inflammation of affected area [168]. Facial involvement is the most common site and can easily be diagnosed as GVHD. Cutoff sign on the scalp described as a sharp demarcation between erythematous skin and spared scalp at the frontal and temporal hairline is one of the differentiating features [169]. A notable cutaneous bacterial infection in immunocompromised patients is ecthyma, associated with Pseudomonas aeruginosa, staphylococci, or group A beta-hemolytic streptococci and usually presents as a deep, painful erythematous or hemorrhagic nodules or vesicles that can progress to ulcers and crusty sores [170].

Leukemia Cutis

Leukemia cutis (LC), also known as cutaneous myeloid sarcoma, is most common in AML although it can be seen in other types of leukemia. It has been associated with an unfavorable prognosis. The morphology varies and includes classic papules (FIGURE 7), nodules, plaques or rare manifestations with erythroderma, blistering or ulceration [171].

Figure 7:

Leukemia cutis as the first presenation in aucte monocytic leukemia.

Although LC is not a direct complication of cellular therapy, it demands high attention in HCT candidates. LC can develop anytime in the course of the disease including- in the author’s experience-immediately pre-HCT. The chemotherapy that can induce sustainable marrow remission and prepares the patient for HCT may not eliminate the LC component. Indeed, skin can become a sanctuary for leukemia cells [172]. If missed prior to the HCT, the patient would undergo HCT while not in remission.

Skin cancers

HCT survivors have an increased risk of UV-induced skin cancers including squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Male sex, clinically photodamaged skin, history of skin cancer, history of chronic lymphocytic leukemia, and acute and chronic GVHD are risk factors for cutaneous SCC post alloHCT [173, 174]. Total-body irradiation is a major contributor to BCC development [175]. Some of the medications used in the setting of HCT including voriconazole and lenalidomide increase the risk of developing skin cancers. (Refs) Sun protection measures and early detection of precancerous and cancerous lesions with regular periodic surveillance are recommended. Annual dermatologic exams generally are appropriate; however, among patients with cGVHD or a history of skin cancer, surveillance every 6 months is preferred [176].

Practice Points

Becoming familiar with acute cutaneous complications of cellular therapies in patients with acute leukemia.

Early diagnosis of the skin toxicities to intervene at earlier stages.

Preventive measures regarding increased risk of future cutaneous malignancies in patients

Research Agenda

Review Article; Regarding the broad nature of the topic, the authors tried to provide a concise and at the same time comprehensive coverage for the readers regarding the most important and widely seen cutaneous complications of cellular therapies.