Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria
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.
Section snippets
Selection of patients for cytoreductive drugs
Cytoreductive drugs have multiple side effects and most of them are considered to be mutagenic thereby increasing the risk of disease progression and the development of (secondary) leukemias. Therefore, these drugs should be administered with great caution in patients with ‘low grade’ hematopoietic malignancies, and IFN-α may be considered preferable when compared to other drugs in this respect. With regard to SM, cytoreductive drugs should only be offered to those patients who show clear signs
Treatment options and selection of cytoreductive drugs
Once the diagnosis ASM has been established, patients should be considered for treatment with cytoreductive drugs. As mentioned above, all drugs are experimental in nature. However, some promising results have been reported using IFN-α [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. In fact, recent data suggest that a group of patients with ASM benefits from this agent [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. In most cases, IFNα2b was used.
Mediator-targeting drugs as important adjuncts to cytoreductive treatment
Patients with aggressive mastocytosis often exhibit an extensive burden of neoplastic MCs. As a result, MC activation with consecutive mediator release and respective clinical symptoms may occur and may represent a serious (sometimes life-threatening) event. Therefore, all patients with ASM should receive prophylactic H1- and H2-receptor antagonists [23], [24]. Especially during the initiation of cytoreductive drugs, MC-mediator release can cause significant symptoms. Therefore, these patients
Disease monitoring and follow up
During treatment with cytoreductive drugs, patients with ASM should be monitored by employing a number of disease-related parameters. These markers can be divided into those reflecting the recorded C-Findings (such as elevated liver enzymes, elevated serum calcium, or decreased hemoglobin, others) and those reflecting the burden of neoplastic MCs (bone marrow histology, serum tryptase levels, soluble kit and CD25 [44], [45], [46], [47], [48]). During therapy, only the C-Finding-related
Proposed response criteria
Based on recently established criteria to diagnose ASM and respective C-Findings [14], we now propose treatment response criteria for these patients. In this proposal, a major response, a partial response, and no response (treatment failure), are described. These criteria may also be applied to patients with MCL or ASM-AHNMD (to document response of ASM). Table 2 shows a summary of proposed response criteria.
Reported treatment results in patients receiving IFN-α
Unfortunately, only little is known about responses to IFN-α or other drugs in patients with ASM. In a review of the available literature, we were able to identify 14 well documented patients with aggressive MC disease receiving IFN-α with or without prednisolone [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. Of these 14 cases, three (21.4%) showed a major response with dissolution of C-Findings. In five patients (35.7%), a partial response was obtained, and 42.9% of
Associated hematologic neoplasms (AHNMD)
In approximately 15–30% of all patients with SM, an AHNMD is observed [1], [2], [3], [11], [12], [13], [14]. In most of these patients, myeloid malignancies such as a myeloproliferative disorder, myelodysplastic syndrome, or acute myeloid leukemia, occur. It is thus of great importance to establish the exact diagnosis for both the AHNMD and the SM, and to figure out which of the conditions are causative in the development of symptoms and laboratory abnormalities. Sometimes, it may be very
Mast cell leukemia
Mast cell leukemia is a rare disease characterized by a rapid expansion of mast cells in the bone marrow, blood, and other organs with consecutive organopathy [22], [42], [43]. The prognosis is grave and the survival appears to be poor [42]. No effective treatment is available for these patients. In those who have been treated with IFN-α alone, no long term remission was observed. Conventional chemotherapy was also without any long lasting effect in these patients [42]. Nevertheless, in some
Final comments and future perspectives
The treatment of aggressive mast cell diseases remains a challenge for the clinician and sometimes may be a quite difficult task. Mediator-related symptoms can be controlled in most cases. However the uncontrolled proliferation of MCs is often resistant to therapy. In a group of patients with ASM, IFN-α2b plus prednisolone may work although the responses are often minor or only transient. In rapidly progressing ASM and MCL, more aggressive therapy (chemotherapy) should be considered. In some
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