NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-007-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until June 10, 2025. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94849; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: June 10, 2024; Expiration date: June 10, 2025
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Systemic Mastocytosis
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Systemic Mastocytosis
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Mary Anne Bergman, Guidelines Coordinator, NCCN
Cindy Hochstetler, PhD, Oncology Scientist/Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Jason Gotlib, MD, MS, Panel Vice Chair, has disclosed receiving grant/research support from AbbVie, Inc., Blueprint Medicines, Bristol Myers Squibb, Cogent Biosciences, Incyte Corporation, Merck & Co., Inc., Protagonist Therapeutics, Inc., and Telios Pharma, Inc.; and receiving honoraria from AbbVie, Inc., Blueprint Medicines, Cogent Biosciences, Inctye Corporation, and Protagonist Therapeutics.
Aaron T. Gerds, MD, MS, Panel Chair, has disclosed serving as a consultant for AbbVie, Inc., GSK, Kartos Therapuetics, Inc., and MorphoSys AG.
To view disclosures of external relationships for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Bristol Myers Squibb; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Seagen. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc., Rahway, NJ, USA.
Overview
Mastocytosis is a group of heterogeneous disorders resulting from the clonal growth of abnormal mast cells and their accumulation in the skin and/or in extracutaneous organs.1 In the revised 2017 WHO classification, mastocytosis was removed as one of the subtypes of myeloproliferative neoplasms and has since been listed as a separate disease entity with its own distinctive clinical and pathologic features.2 Systemic mastocytosis (SM) is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The comprehensive care of patients with mastocytosis requires a multidisciplinary team approach. Referral to centers with expertise in mastocytosis is strongly recommended.
Diagnostic Classification and Criteria
In 2022, the International Consensus Classification (ICC)3 and the 5th edition of the WHO Classification4 generated modifications to the diagnostic criteria for SM. Diagnostic criteria include 1 major diagnostic criterion (multifocal, dense infiltrates of tryptase and/or CD117-positive mast cells [≥15 mast cells in aggregates] detected in the biopsy sections of bone marrow and/or extracutaneous organs) and 4 minor diagnostic criteria (the presence of >25% of mast cells with atypical morphology in lesional tissues; the presence of KIT D816V or other activating KIT mutation; the aberrant expression of CD2, CD25, and/or CD30 on neoplastic mast cells; and a serum tryptase level >20 ng/mL) in the absence of an associated myeloid neoplasm. In the ICC, in cases where an aspirate is a dry tap and unevaluable, mast cell leukemia (MCL) may be diagnosed on a core biopsy if a diffuse mast cell infiltrate is present.
In the WHO diagnostic criteria, the diagnosis of SM is established when 1 major criterion and at least 1 minor criterion are present, or when at least 3 minor criteria are present.5 This is similar for the ICC diagnostic criteria; however, the presence of 1 major criterion is enough for a diagnosis of SM. If the major criterion is not met, then at least 3 minor criteria are required.3 In the 2022 WHO classification, SM is further divided into 6 different subvariants (based on the mast cell burden, organ involvement, and SM-related organ damage): indolent SM (ISM), bone marrow mastocytosis, smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and MCL.4 Following the publication of the 2022 WHO and ICC classifications, the panel added tables for the 2022 classification of mastocytosis (see Figure 1) and for the 2022 diagnostic criteria for SM (see Figure 2).
SM-A. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
SM-C. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
Cytoreductive Therapy Recommendations
In the NCCN Guidelines, regimens for cytoreductive therapy are stratified into 3 categories (based on the evidence, efficacy, toxicity, and, in some cases, access to certain agents): preferred regimens, other recommended regimens, and useful in certain circumstances.
The management of mast cell activation symptoms with antimediator drug therapy is recommended for symptomatic ISM or SSM (see Figure 3). Enrollment in a clinical trial is a preferred option for these patients. Avapritinib (if platelet counts are ≥50 × 109/L)6 is also a preferred option for symptomatic ISM. Additionally, for symptomatic ISM or SSM, cladribine7–9 or peginterferon alfa-2a10–13 may be useful in certain circumstances for select patients with severe, refractory mediator symptoms or bone disease not responsive to antimediator therapy or bisphosphonates.14
SM-4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
Enrollment in a clinical trial, avapritinib (if platelet counts are ≥50 × 109/L),15,16 and midostaurin17–19 are preferred regimens and cladribine7–9 and peginterferon alfa-2a (± prednisone)10–13 are other recommended regimens for patients with ASM (see Figure 4), SM-AHN (when the SM component requires prioritization over the AHN component) (see Figure 5), and MCL (with or without an AHN; with the exception of peginterferon alfa-2a ± prednisone) (see Figure 6). Imatinib is included as a treatment option that is useful in certain circumstances for the rare patients with ASM (for KIT D816V mutation–negative after testing with a high-sensitivity assay or unknown; well-differentiated SM; or if eosinophilia is present with FIP1L1::PDGFRA gene fusion, which operationally redefines the patients as having a myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions as defined by the WHO and ICC) (see Figure 4).20–27
SM-5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
SM-7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
SM-8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Systemic Mastocytosis, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0030
Avapritinib
Avapritinib, a potent and selective inhibitor of KIT D816V, has demonstrated activity in patients with ISM and advanced SM,6,16 and is FDA-approved for the treatment of adult patients with ISM and advanced SM, including ASM, SM-AHN, and MCL.
Indolent SM
In the phase II PIONEER trial, patients with moderate to severe ISM despite prior use of ≥2 best supportive care medications were randomized 2:1 to receive avapritinib (25 mg daily) or placebo.6 At 24 weeks, a reduction of 15.6 points (95% CI, −18.6 to −12.6) from baseline in the total symptom score was reported in patients treated with avapritinib compared with a reduction of 9.2 points (95% CI, −13.1 to −5.2; P=.003) in those treated with placebo. Compared with patients treated with placebo, those treated with avapritinib also achieved a ≥50% decrease in serum tryptase level (54% vs 0%; P<.001), KIT D816V variant allele frequency in peripheral blood (68% vs 6%; P<.001), total symptom score (25% vs 10%; P=.005), and bone marrow mast cell burden (53% vs 23%; P<.001). Grade ≥3 adverse events occurred at similar rates in both groups. The most common adverse events that occurred in the avapritinib group at a rate of ≥2 times that of the placebo group included flushing (9.2% vs 4.2%), peripheral edema (8.5% vs 4.2%), face edema (7.1% vs 1.4%), elevated blood alkaline phosphatase (ALP) (6.4% vs 1.4%), periorbital edema (6.4% vs 2.8%), and insomnia (5.7% vs 2.8%). The number of anaphylactic events in both groups were low and the trial was not powered to determine a difference in the frequency of anaphylaxis between the 2 groups.
Advanced SM
Data from the phase I EXPLORER trial, which consisted of 53 evaluable patients with advanced SM (ASM, n=3; SM-AHN, n=37; MCL, n=13) treated with a dose of 30 to 400 mg once daily (dose escalation and expansion stages) revealed an overall response rate (ORR) of 75% (95% CI, 62%–86%) (100% [95% CI, 29%–100%] for ASM; 76% [95% CI, 59%–88%] for SM-AHN; and 69% [95% CI, 39%–91%] for MCL), per the modified International Working Group-Myeloproliferative Neoplasms Research and Treatment & European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria.15 A total of 92%, 80%, and 99% of patients reported a ≥50% decrease from baseline in bone marrow mast cells, KIT D816V variant allele fraction, and serum tryptase, respectively. A decrease of ≥35% in spleen volume from baseline was obtained in 82% of patients. Across all patients (n=86), the most common grade ≥3 nonhematologic adverse events were fatigue (9%) and vomiting (5%), while the most common grade ≥3 hematologic adverse events were thrombocytopenia (34%), anemia (30%), and neutropenia (15%). There were 9 cases of intracranial bleeding (ICB) in patients with advanced SM (13% of 69 patients in the advanced SM safety population), 7 of which were associated with antecedent severe thrombocytopenia.
A prespecified interim analysis of the phase II PATHFINDER trial, which comprised 32 evaluable patients with advanced SM (ASM, n=2; SM-AHN, n=26; MCL, n=4) treated with avapritinib at a starting dose of 200 mg once daily, reported an ORR of 75% (95% CI, 57%–89%), as assessed by the mIWG-MRT-ECNM response criteria.16 The ORR was 100% (95% CI, 16%–100%), 81% (95% CI, 61%–93%), and 25% (1%–81%) in patients with ASM, SM-AHN, and MCL, respectively. The safety population (n=62) was used to assess secondary endpoints. Patients experienced reductions in objective measures of mast cell disease burden. The percentages of patients who achieved a ≥50% decrease from baseline in bone marrow mast cells, KIT D816V variant allele fraction, and serum tryptase were 88%, 60%, and 93%, respectively. A decrease of ≥35% in spleen volume from baseline was obtained in 66% of patients. An amelioration in patient-reported symptoms, as assessed by the advanced SM symptom assessment form total symptom score, was also reported (P<.001). The most common grade ≥3 hematologic adverse events were neutropenia, thrombocytopenia, and anemia, and occurred in 24%, 16%, and 16% of patients, respectively. The most common grade ≥3 nonhematologic adverse events were increased blood ALP (5%), peripheral edema (3%), periorbital edema (3%), and fatigue (3%). The study reported one instance (1.6%) of ICB in a patient with severe thrombocytopenia at baseline. As patients with severe thrombocytopenia at baseline had an increased risk of ICB, the study protocols for both the EXPLORER and PATHFINDER trials were amended to exclude patients with platelet counts <50 × 109/L as part of the mitigation strategies to reduce ICB.15,16
Comparison between avapritinib and best available therapy was performed in one retrospective study that pooled data from a multicenter study in which patients with advanced SM were treated with best available therapy and data from the EXPLORER and PATHFINDER trials.28 Median overall survival (OS) was significantly improved in patients treated with avapritinib (49.0 months [95% CI, 46.9 months–not estimable] vs 26.8 months [95% CI, 18.2 to 39.7 months]; adjusted hazard ratio [HR], 0.48; 95% CI, 0.29 to 0.79; P=.004). Data further demonstrated that avapritinib treatment was associated with improved OS compared with midostaurin (HR, 0.59; 95% CI, 0.36 to 0.97; P<.001) and cladribine (HR, 0.32; 95% CI, 0.15 to 0.67; P=.003).29 OS was also improved in patients with SM-AHN treated with avapritinib compared with best available therapy.30 The duration of treatment (HR, 0.36; 95% CI, 0.26 to 0.51; P<.001) and the maximum decrease in serum tryptase level (mean difference of −60.3%; 95% CI, −72.8% to −47.9%; P<.001) were significantly higher in patients with advanced SM treated with avapritinib.28 The efficacy of avapritinib in patients with advanced SM was established irrespective of prior therapies or SRSF2/ASXL1/RUNX1 (S/A/R) mutation status.31
Following external requests for the inclusion of avapritinib in the NCCN Guidelines and based on the FDA approval of avapritinib and a review of the data, the panel voted to add avapritinib as a preferred treatment option for symptomatic ISM and advanced SM for patients with platelets ≥50 × 109/L (see Figures 3–6). Like the FDA label, the panel clarified that avapritinib is not recommended for the treatment of patients with platelet counts <50 × 109/L due to the risk of increased bleeding events noted in the clinical trials.15,16 During an annual panel meeting, the panel acknowledged that the PIONEER trial specifically randomized patients with ISM with moderate to severe symptoms on ≥2 best supportive care regimens compared with placebo,6 but given the broader FDA label, the panel deemed it important to provide guidance while not limiting therapies. The rationale to recommend avapritinib is to control symptoms and improve quality of life.
Midostaurin
Midostaurin, an oral multikinase inhibitor with activity against D816V-mutated KIT, has demonstrated activity for the treatment of advanced SM17–19 and is FDA-approved only for patients with a diagnosis of ASM, SM-AHN, or MCL, although it has also been shown to be effective for patients with ISM and severe symptoms related to mast cell mediator release or skin infiltration in a small phase II clinical trial.32
In an open-label study of 116 patients with advanced SM, 89 patients had evaluable mastocytosis-related organ damage: 16 patients with ASM, 57 patients with SM-AHN, and 16 patients with MCL. Using modified Valent and Cheson response criteria, treatment with midostaurin (100 mg twice daily) resulted in an ORR of 60% (45% of the patients had a major response, defined as complete resolution of at least one type of mastocytosis-related organ damage).17 Response rates were similar across all subtypes of advanced SM, KIT mutation status (63% for patients who were KIT D816V mutation–positive and 44% for those who were KIT D816V mutation–negative or had unknown mutation status), or exposure to previous therapy. The median OS and progression-free survival (PFS) were 29 and 14 months, respectively. The median OS and PFS were longer for patients with ASM (not reached and 29 months, respectively) than for patients with SM-AHN (21 and 11 months, respectively) and MCL (9 and 11 months, respectively). In a multivariate analysis, a subtype of advanced SM other than MCL and ≥50% reduction of bone marrow mast cell burden were identified as independent predictors of longer OS. Low-grade nausea, vomiting, and diarrhea were the most frequent adverse events. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of patients, respectively, and were more common in patients with preexisting cytopenias.
A study that evaluated the impact of KIT D816V mutation and other molecular markers on the clinical outcome of 38 patients with advanced SM treated with midostaurin found that the ORR, median duration of midostaurin treatment, and OS were significantly higher in patients with an S/A/R–negative (vs S/A/R–positive) mutation profile and in patients with a ≥25% (vs <25%) reduction in the RNA expressed allele burden.33 The acquisition of additional mutations in KRAS, NRAS, RUNX1, IDH2, or NPM1 genes was identified in patients with disease progression. Another study reported an amelioration in the mast cell mediator–related symptoms in patients with advanced SM who were treated with midostaurin.34
Cladribine
Cladribine (2-chlorodeoxyadenosine) is not approved by the FDA for SM, but is used on an off-label basis because of its activity across all subtypes of SM, including MCL refractory to prior cytoreductive therapy.7–9 Cladribine may be particularly useful for patients with advanced SM when rapid debulking of disease is required.
In an analysis, treatment with cladribine resulted in an ORR of 56%, 50%, and 55% in patients with ISM, ASM, and SM-AHN, respectively.8 The presence of circulating immature myeloid cells was a predictor of inferior response. In a study that reported the long-term safety and efficacy of cladribine in 68 patients with SM, the ORR was 72%, split between 92% for patients with ISM (major/partial 56%/36%) and 50% for those with advanced SM (major/partial 38%/13%).9 The median duration of response was 4 years and 3 years for ISM and ASM, respectively. In a multivariate analysis, only mastocytosis subtypes (SM-AHN vs ISM; P=.02 and ASM vs ISM; P=.006) and age >50 years at diagnosis were independently associated with mortality. Lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%) were the most frequent grade 3 or 4 toxicities.
Peginterferon alfa-2a With or Without Prednisone
Interferon alfa (with or without prednisone) carries the potential to induce a marked reduction in serum and urine metabolites of mast cell activation, reduce symptoms related to mast cell mediator release, resolve cutaneous lesions, improve skeletal disease, and improve both bone marrow mast cell burden and C-findings, across all subtypes of SM.10–13 However, because of their cytostatic mechanism of action, responses may take longer to emerge, and the use of interferons may be more suitable for patients with slowly progressive disease without the need for rapid cytoreduction. In the current era of KIT inhibitors, the therapeutic value of interferon therapy is less clear.
The panel clarified that although cladribine and peginterferon alfa-2a are generally recommended only for advanced SM, these agents may also be useful in certain circumstances for select patients with ISM or SSM with severe, refractory mediator symptoms or bone disease not responsive to antimediator therapy or bisphosphonates (see Figure 3).
Imatinib
Imatinib is FDA-approved for the treatment of adult patients with ASM without the KIT D816V mutation or with unknown KIT mutational status and is very effective in the treatment of patients with eosinophilia-associated myeloid neoplasms characterized by the FIP1L1::PDGFRA gene fusion.35,36 It has also shown activity against the KIT F522C transmembrane mutation, V560G juxtamembrane mutation, germline K509I mutation, deletion of codon 419 in exon 8, and p.A502_Y503dup mutation in exon 9.20–27 In a study that evaluated the efficacy of imatinib in 10 patients with SM lacking the KIT D816V mutation and meeting criteria for well-differentiated SM (including 3 patients with ISM and 3 patients with MCL), imatinib resulted in an ORR of 50%, including early and sustained complete response in 4 patients and partial response in 1 patient with wild-type KIT.27
Allogeneic Hematopoietic Cell Transplantation
Allogeneic hematopoietic cell transplantation (HCT) has been evaluated in patients with advanced SM, and the outcomes are significantly affected by the subtype of SM and the type of conditioning regimen.37–40 Data from transplant series are largely derived from the pre-KIT inhibitor era. Reduced-intensity conditioning regimens were associated with lower survival than myeloablative conditioning regimens. In the largest retrospective analysis that included 57 patients with advanced SM (median age, 46 years; SM-AHN, n=38; MCL, n=12; ASM, n=7), allogeneic HCT was associated with a 70% response rate (28% complete response; 21% stable disease) and the 3-year OS rate was 57% for all patients (74%, 43%, and 17% for patients with SM-AHN, ASM, and MCL, respectively).39 MCL subtype was the strongest risk factor for poor OS.
Evaluation for allogeneic HCT is a consideration for patients with advanced SM after adequate response to prior treatment. Following a discussion at the annual panel meeting, the panel clarified that for patients with advanced SM with inadequate response or loss of response to prior treatment, second-line therapy and allogeneic HCT should be considered after restaging (see Figures 4–6). Among patients with SM-AHN, allogeneic HCT should also be considered as part of initial treatment when the AHN component requires HCT or if the AHN component progresses. Prophylactic antimediator drug therapy (corticosteroids, antihistamines, anti-IgE antibody, and epinephrine) should be used as needed with the conditioning regimen.41 The role of KIT inhibitors in the posttransplant setting to minimize relapse has not been formally studied.
Conclusions
The comprehensive care of patients with mastocytosis requires a multidisciplinary team approach (involving dermatologists, hematologists, pathologists, gastroenterologists, allergists, and immunologists), preferably in specialized centers with expertise in the treatment of patients with mast cell disorders. Although the identification of KIT D816V mutation and the emergence of new targeted therapies have significantly improved the diagnosis and treatment of SM, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mast cell activation symptoms, continue to present challenges. Enrollment in well-designed clinical trials investigating state-of-the-art therapeutic strategies (eg, highly selective KIT D816 inhibitors) is encouraged to enable further advances.
References
- 1.↑
Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603–625.
- 2.↑
Swerdlow SH, Campo E, Harris NL, et al. eds, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th ed. International Agency for Research on Cancer; 2017.
- 3.↑
Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 2022;140:1200–1228.
- 4.↑
Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703–1719.
- 5.↑
El Hussein S, Chifotides HT, Khoury JD, et al. Systemic mastocytosis and other entities involving mast cells: a practical review and update. Cancers (Basel) 2022;14:3474.
- 6.↑
Gotlib J, Castells M, Oude Elberink H, et al. Avapritinib versus placebo in indolent systemic mastocytosis. NEJM Evid 2023;2:EVIDoa2200339.
- 7.↑
Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, et al. Cladribine therapy for systemic mastocytosis. Blood 2003;102:4270–4276.
- 8.↑
Lim KH, Pardanani A, Butterfield JH, et al. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol 2009;84:790–794.
- 9.↑
Barete S, Lortholary O, Damaj G, et al. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood 2015;126:1009–1016; quiz 1050.
- 10.↑
Delaporte E, Piérard E, Wolthers BG, et al. Interferon-alpha in combination with corticosteroids improves systemic mast cell disease. Br J Dermatol 1995;132:479–482.
- 11.↑
Casassus P, Caillat-Vigneron N, Martin A, et al. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol 2002;119:1090–1097.
- 12.↑
Hauswirth AW, Simonitsch-Klupp I, Uffmann M, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 2004;28:249–257.
- 13.↑
Simon J, Lortholary O, Caillat-Vigneron N, et al. Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature. Pathol Biol (Paris) 2004;52:294–299.
- 14.↑
Castells M, Butterfield J. Mast cell activation syndrome and mastocytosis: initial treatment options and long-term management. J Allergy Clin Immunol Pract 2019;7:1097–1106.
- 15.↑
DeAngelo DJ, Radia DH, George TI, et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med 2021;27:2183–2191.
- 16.↑
Gotlib J, Reiter A, Radia DH, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med 2021;27:2192–2199.
- 17.↑
Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 2016;374:2530–2541.
- 18.↑
Chandesris MO, Damaj G, Canioni D, et al. Midostaurin in advanced systemic mastocytosis. N Engl J Med 2016;374:2605–2607.
- 19.↑
DeAngelo DJ, George TI, Linder A, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia 2018;32:470–478.
- 20.↑
Frost MJ, Ferrao PT, Hughes TP, et al. Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther 2002;1:1115–1124.
- 21.↑
Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 2003;31:686–692.
- 22.↑
Akin C, Fumo G, Yavuz AS, et al. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 2004;103:3222–3225.
- 23.↑
Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk Res 2006;30:373–378.
- 24.↑
Heinrich MC, Joensuu H, Demetri GD, et al. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res 2008;14:2717–2725.
- 25.↑
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res 2009;33:1481–1484.
- 26.↑
Mital A, Piskorz A, Lewandowski K, et al. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur J Haematol 2011;86:531–535.
- 27.↑
Alvarez-Twose I, Matito A, Morgado JM, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget 2016;8:68950–68963.
- 28.↑
Reiter A, Gotlib J, Álvarez-Twose I, et al. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia 2022;36:2108–2120.
- 29.↑
Reiter A, Gotlib J, Alvarez Twose I, et al. Overall survival in patients with advanced systemic mastocytosis receiving avapritinib versus midostaurin or cladribine. Hemasphere 2022;6(Suppl):Abstract P1014.
- 30.↑
Reiter A, Gotlib J, Alvarez Twose I, et al. Overall survival in patients with systemic mastocytosis with associated hematologic neoplasm treated with avapritinib versus best available therapy. Hemasphere 2022;6(Suppl):Abstract P1013.
- 31.↑
Reiter A, Schwaab J, DeAngelo DJ, et al. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv 2022;6:5750–5762.
- 32.↑
van Anrooij B, Oude Elberink JN, Span LFR, et al. Midostaurin in patients with indolent systemic mastocytosis: an open-label phase 2 trial. J Allergy Clin Immunol 2018;142:1006–1008.e7.
- 33.↑
Jawhar M, Schwaab J, Naumann N, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood 2017;130:137–145.
- 34.↑
Hartmann K, Gotlib J, Akin C, et al. Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis. J Allergy Clin Immunol 2020;146:356–366.e4.
- 35.↑
Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003;102:3093–3096.
- 36.↑
Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038–3045.
- 37.↑
Przepiorka D, Giralt S, Khouri I, et al. Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: review of forty cases. Am J Hematol 1998;57:24–28.
- 38.↑
Nakamura R, Chakrabarti S, Akin C, et al. A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis. Bone Marrow Transplant 2006;37:353–358.
- 39.↑
Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol 2014;32:3264–3274.
- 40.↑
McLornan DP, Czerw T, Damaj G, et al. Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee. Leukemia 2024;38:699–711.
- 41.↑
Ustun C, Gotlib J, Popat U, et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant 2016;22:1348–1356.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN CATEGORIES OF PREFERENCE
Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation).
All recommendations are considered appropriate.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
The NCCN Guidelines® Insights highlight important changes in the NCCN Guidelines® recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding the content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
