Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria

Abstract

Aggressive systemic mastocytosis (ASM) is a clonal mast cell disease characterized by progressive growth of neoplastic cells in diverse organs leading to organopathy. The organ-systems most frequently affected are the bone marrow, skeletal system, liver, spleen, and the gastrointestinal tract. Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption. During the past decade several treatment strategies for ASM have been proposed. One promising approach may be combination treatment with interferon-α (IFN-α) and glucocorticoids. This concept has been based on the notion that systemic mastocytosis involves multilineage hematopoietic progenitors indicating a relationship with myeloproliferative disorders. However, relatively little is known about the quality of responses to IFN-α in ASM and the actual response rates. This may be due in part to the fact that disease criteria for ASM have only recently been established, and no response criteria are available. In the current article, we propose surrogate markers and treatment response criteria for patients with ASM. In addition, we have applied these criteria retrospectively to ASM patients described in the available literature. In these analyses, the calculated rate of major response (=complete resolution of C-Findings) in patients treated with IFN-α (with or without additional glucocorticoids) amounts to approximately 21%. This confirms clinical activity in some patients for this drug-combination, but also points to the need to search for more effective strategies in the treatment of patients with aggressive mast cell disorders.

Introduction

Systemic mastocytosis (SM) is a clonal disease of myelomastocytic progenitors. The clinical picture in SM is variable ranging from an asymptomatic (indolent) course to highly aggressive courses with a short survival [1], [2], [3], [4], [5]. Most patients with SM are adults, although the disease can occur at any age. Clinical symptoms result from mast cell (MC)—derived chemical mediators or/and infiltration of diverse organs by neoplastic cells [1], [2], [3], [4], [5]. Recent data suggest that SM behaves like a myeloproliferative disease process involving multipotent hematopoietic progenitors. The notion of recurrent c-kit mutations at codon 816 detectable in patients with SM has supported this novel concept. Notably, in patients with SM, codon 816-mutations have not only been detected in MCs, but also in other myeloid cells and even in B-lymphocytes [6], [7], [8], [9], [10]. Moreover, SM patients are at a certain risk to develop secondary leukemias similar to those with other myeloproliferative diseases [11], [12], [13].

Based on clinical findings and symptoms, four major groups of patients with SM have been defined: indolent systemic mastocytosis (ISM), mastocytosis with an associated clonal hematologic non-MC-lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL) [2], [3], [14]. Patients with ISM have a favorable prognosis. These patients may suffer from mediator-related symptoms, but do not suffer from significant organopathy caused by MC-infiltration. Typical cases present with maculopapular skin lesions of mastocytosis [2], [3], [14].

In patients with ASM, significant organopathy due to MC-infiltration is found (C-Findings). Almost any organ can be involved [14], [15], [16], [17], [18], [19], [20]. The organ-systems most frequently affected are the bone marrow, skeletal system, liver, spleen, and the gastrointestinal tract. Respective clinical findings (so called C-Findings) include cytopenias, osteolysis (or osteoporosis) with pathologic fractures, hepatosplenomegaly with impaired liver function and ascites, and malabsorption [14], [15], [16], [17], [18], [19], [20]. In some cases, eosinophilia and lymphadenopathy are prominent clinical features [2]. In contrast to ISM, patients with ASM often present without maculopapular skin lesions [1], [2], [3], [14]. MCL is a rare systemic MC disease characterized by (rapidly) progressive C-Findings, a high proportion of MCs in bone marrow smears (≥20%), circulating MCs, and a short survival in most cases [2], [3], [14].

Patients with ASM can show a slowly progressing or a rapid clinical course. Rapidly progressing ASM may also shift into another category of SM, i.e. MCL or (A)SM-AHNMD within short time [1], [2], [3], [4], [14], [21], [22]. Irrespective of the clinical course, no curative therapy for ASM and MCL has become available to date. Rather, the primary goal for treatment is the amelioration of symptoms and pharmacologic control of growth of neoplastic cells. Because of clinical disease heterogeneity, the treatment has to be adjusted to the individual situation of the patient [2], [3], [14], [23], [24]. In each case, several specific questions should be asked: The first is whether at all the overall situation requires the use of any cytoreductive drug (diagnosis ASM definitively confirmed, C-Findings documented). The second question is: what type(s) of drug would be appropriate. Although this question has no clear answer, and no standard therapy for ASM has become available, some promising effects with interferon-alpha (IFN-α) and other drugs have been reported [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].

In the following sections, we consider treatment options for ASM based on the current literature, and propose follow up markers and treatment response criteria. Using these criteria it should be possible in future clinical trials to identify responding groups of patients, to define response rates and the quality of responses, and to search for effective drugs and drug combinations that may lead to an improvement in the overall survival of patients with aggressive mast cell disorders.