A recent retrospective review concluded that drug hypersensitivity could be excluded with certainty in post-HSCT patients who develop a morbilliform eruption if concurrent hyperbilirubinemia and diarrhea are present [12]. The distribution and onset of the cutaneous eruption in drug hypersensitivity often spares acral sites, particularly the palms and soles, and lacks the folliculocentric erythema of aGVHD eruptions (Fig. 6.4) [12].

This diagnosis is suggested by blanching erythema that is painful and limited to palms and soles (most common) or flexural sites (Fig. 6.5). The pathophysiology is hypothesized to be a result of toxic metabolite accumulation in eccrine-rich sites [13].

Engraftment syndrome (ES) may be favored in patients who received an autologous transplant and develop symptoms reminiscent of capillary leak syndrome with cytokine storm [14, 15]. ES has also been described in allogeneic HSCT [16]. Clinical findings include non-infectious fever (persistently negative culture data and no response to empiric antibiotics), hypoxemia, diarrhea, weight gain, anasarca, and a morbilliform cutaneous eruption (Fig. 6.6). Timing of onset is, by definition, in the peri-engrafment period. ES is remarkably responsive to systemic corticosteroids, and in a recent retrospective review, 41 of 42 patients with ES showed rapid symptoms resolution leading to hospital discharge in a median of 10 days [15]. The same review found excellent correlation between markedly elevated C-reactive protein (CRP) and ES diagnosis (Table 6.2) [15].

Many studies have investigated the utility of a diagnostic skin biopsy for aGVHD. The histological findings are often non-specific and do not reliably improve diagnostic distinction between aGVHD and drug hypersensitivity, particularly in early GVHD [17–19]. The results of a decision analysis showed that a skin biopsy should be performed only in cases in which the pretest probability for aGVHD is exceptionally low [20, 21].

A noteworthy area of research revolves around the use of mammalian target of rapamycin (mTOR) inhibitors instead of calcineurin inhibitors after allogeneic HSCT for GVHD prophylaxis. In 2002, Hoffmann et al. [25] showed that transfer of donor CD4+ CD25+ regulatory T Cells (Tregs) after allogeneic HSCT can prevent severe aGVHD while maintaining graft-versus-leukemia effect in mice. More recent work by Satake et al. [26] showed (in mice) that the mTOR inhibitor sirolimus in combination with low dose IL-2 showed Treg expansion and decreased risk of aGVHD. Peccatori et al. [27] showed that use of sirolimus prophylaxis led to a much lower than expected incidence of GVHD in patients receiving high GVHD risk transplants (peripheral blood stem cell grafts from partially HLA-matched family donors). Prophylactic use of mTOR inhibitors in combination of Tregs modulation is a very active area of research with multiple ongoing trials (NCT02528877, NCT01795573, NCT02118311, NCT00105001, NCT01251575, NCT01903473, NCT00406393, NCT00993343, NCT00602693).

General consensus guidelines from the BCSH, BSBMT, and ASBMT recommend management of grade I aGVHD (<50 % body surface area involvement) with topical therapies in addition to optimization of prophylactic immunosuppression [8, 9, 28]. The most common approach to grade I aGVHD includes topical corticosteroids and/or topical calcineurin inhibitors (CNIs). However, for cases in which 25–50 % of body surface area is involved, progression must be monitored closely and early initiation of first-line systemic therapy should be considered. Additionally, patients who have a clinical grade of I, although an Ann Arbor risk score of 3, are at a significantly increased risk for aGVHD to involve more organs and should be considered for systemic therapy [22]. It is foreseeable that the Ann Arbor score will play a larger role in early grade aGVHD management, particularly for cases with clinical and biomarker discordance.

High-potency topical corticosteroids (class 1 or 2), the cornerstone for therapy on the extremities and trunk, can be considered for short periods of time on the face, major body folds, and genital region with close monitoring. Topical CNIs, such as tacrolimus or pimecrolimus, provide benefits equivalent to class 4 or class 5 topical corticosteroids and they should be employed in tandem, especially to the face and genital region (Table 6.6) [29].

In addition to topical corticosteroids and CNIs, clinicians should stress skin hygiene and sun-safe practices. Excellent skin hygiene (i.e. use of emollients at least once per day) will optimize skin barrier function and minimize transepidermal water loss; recommendations include: minimize the duration of showers, minimize the use of soaps or other skin cleansers, favor skin care products that are unscented, and use thick emollients immediately after showers plus at least one other time per day. Regular use of sun protection factor creams and appropriate clothing, in addition to avoidance of high-intensity sun exposure will minimize the potential for additional keratinocyte damage.