Gotlib, Jason

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.

Abstract Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by red blood cell overproduction. In the phase 2 REVIVE study (NCT04057040), rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for therapeutic phlebotomy (PHL) in patients (pts) with PV who were PHL dependent prior to study entry (Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35). During the open-label extension portion of REVIVE (Part 3), combining rusfertide and PHL with or without cytoreductive therapy (CRT) controlled erythrocytosis, provided long-term control of Hct, and was associated with a greater than 8-fold reduction in the estimated annual PHL rate (Gerds AT, et al. Blood. 2024;144(Suppl. 1):4559). Pts who participated in REVIVE Part 3 were eligible to transition to the open-label phase 2 THRIVE extension study (NCT06033586) and receive up to 2 additional years of rusfertide treatment. Our objective is to present initial results describing the long-term durability of response and safety profile of rusfertide in pts with PV who participated in REVIVE and transitioned to THRIVE. Methods Pts with PV who participated in REVIVE, completed ≥12 months of rusfertide therapy, and had an end-of-treatment visit were eligible to transition to THRIVE. Pts who enrolled in THRIVE continued to receive subcutaneous rusfertide once weekly with or without CRT. Median Hct and the number of PHLs each pt received were assessed in all pts who received ≥1 dose of rusfertide and had ≥1 efficacy assessment on study. Safety data were also collected, including treatment-emergent adverse events (AEs), serious adverse events (SAEs), non-PV malignancies, and thromboembolic events (TEs). New-onset AEs (ie, AEs that were reported in THRIVE but not REVIVE) were also recorded. Results: Forty-six/58 pts (79%) who enrolled in Part 3 of REVIVE transitioned to THRIVE. At the data cutoff date (27 May 2025), 44 of the 46 pts (96%) who enrolled in THRIVE remained on study. Median (range) age was 58 (27-77), and the majority were male (74%). More than half (57%) had high-risk PV; 54% of pts were on concurrent CRT. Median (range) treatment duration in THRIVE was 48 (22-66) weeks; median (range) treatment duration in REVIVE and THRIVE combined was 198 (154-267) weeks, or 3.8 (3.0-5.1) years. At baseline, mean (standard deviation [SD]) Hct was 42.3% (3.7) in THRIVE. At Week 60, mean (SD) Hct was 43.0% (4.2). In addition, mean hemoglobin and erythrocyte levels remained stable throughout THRIVE. Prior to study entry in REVIVE, the mean (SD) annualized PHL rate (ie, PHL/year) for the 46 pts who eventually rolled over to THRIVE was 9.2 (5.2) PHL/year. The mean (SD) annualized PHL rate during REVIVE Part 3 and THRIVE was 0.6 (0.8) and 0.7 (1.1) PHL/year, respectively. Overall, the most common AEs in the pts who participated in REVIVE and THRIVE were Grade 1-2 injection site reactions (87%), fatigue (59%), COVID-19 (50%), pruritus (44%), arthralgia (39%), dizziness (35%), anemia (30%), paresthesia (28%), headache (26%), abdominal pain and nausea (24% each), and diarrhea, dyspnea, and upper respiratory tract infection (22% each). In THRIVE, the most common new-onset AEs were anemia (20%) and fatigue (15%). Twelve pts (26%) had a prior history of non-PV cancer. Six pts (13%) had a new-onset cancer event, including basal cell carcinoma (n=3; 7%), squamous cell carcinoma (n=2, 4%), non-invasive bladder cancer (n=1, 2%), and multiple myeloma (n=1; 2%). Of these 6 pts, 5 (83%) had a prior history of non-PV cancer. Nine pts (20%) had a history of TEs prior to enrolling in REVIVE. One patient with cardiovascular risk factors and a TE prior to enrollment in REVIVE had a new-onset TE of cerebrovascular accident in THRIVE. Overall, there were no TEs in pts with low-risk PV in either REVIVE or THRIVE. Conclusions: After transitioning to THRIVE, continued treatment with rusfertide with or without CRT demonstrated consistent, long-term Hct control with reduced therapeutic PHLs compared to baseline. With a median of 3.8 years of treatment, rusfertide's safety profile was consistent with prior observations. Support Protagonist Therapeutics, Inc.

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in >1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Summary We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty‐seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM‐AHN, 70%), received peripheral blood grafts (89%) and non‐myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post‐transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre‐alloHCT to 1.5% (range 0–8) at 1 year post‐alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3–400 ng/mL) pre‐alloHCT to 18 ng/mL (range 0–481 ng/mL) at 1 year post‐alloHCT. At 1 year, progression‐free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%–77%) and 74% (95% CI, 56%–89%) respectively. In the subset of patients with SM‐AHN, 1‐year PFS and OS were 74% (52%–91%) and 79% (95% CI, 58%–94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM ( n = 27) was 4% (95% CI, 0–14) at 100 days and 15% (95% CI, 4–31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1–28) at 100 days and 21% (95% CI, 6–42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre‐ and post‐ alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Background: PV is a myeloproliferative neoplasm that leads to excessive production of erythrocytes and increased platelet and leukocyte counts. The current standard of care is to use therapeutic phlebotomy (TP) with or without cytoreductive therapy (CRT) to treat PV. Over time, the CRT dose often needs to be increased to treat PV progression. Preliminary results from the phase 2 REVIVE study (NCT04057040) demonstrated that rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for TP in patients who were phlebotomy-dependent prior to study entry (Kremyanskaya et al. EHA2023. [Abstract LB2710]; Kremyanskaya et al. New Engl J Med 2024;390:723-35).Final data from REVIVE will be presented. Methods: In Part 1 (Weeks 1-29), subcutaneous rusfertide (starting dose: 20 mg q1w) was initiated and titrated to control Hct to <45%. In Part 2 (Weeks 29-41; blinded randomized withdrawal phase), patients were randomized to receive rusfertide or placebo. Randomized patients were eligible to participate in the open-label extension (OLE) portion of the study (Part 3), in which all patients could receive rusfertide and investigators could make CRT dose adjustments. Results: In Part 1, 70 patients were enrolled; 59 were randomized in Part 2. Fifty-eight patients continued to Part 3. As of 9 July 2024, 50 (71.4%), 37 (52.9%), and 17 (24.3%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.Overall, median (range) patient age was 57.5 years (27-77); the majority were male (70%) and had high-risk disease (55.7%). Overall, 52.9% and 47.1% of patients were treated with TP alone or TP plus CRT, respectively. Prior to enrollment, the estimated average (mean) phlebotomy rate (EAPR) in patients who enrolled on study was 8.5/year, which was reduced to <1.0/year in Part 1. In Part 2, the EAPR was <1.0/year and 6.6/year in the rusfertide and placebo groups, respectively. For patients who continued onto Part 3 and received rusfertide, the EAPR remained at <1.0/year. In Parts 1, 2, and 3, the mean (SD) weekly average rusfertide dose was 30.7 mg (12.2), 38.5 mg (21.3), and 44.9 mg (20.3), respectively. Rusfertide consistently maintained Hct <45%, including in patients receiving therapy for ≥3 years. Platelets increased following initiation of rusfertide therapy and stabilized over time; mean leukocyte counts remained stable. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency. Throughout the study, rusfertide resulted in the normalization of mean serum ferritin levels, increased mean transferrin saturation, and increased mean serum iron levels. Overall, mean corpuscular volume increased slightly over the duration of the study. Throughout the study, there was no evidence of increased markers of inflammation (eg, C-reactive protein or interleukin 6). The most common (≥20%) treatment-emergent adverse events (TEAEs) were injection site reactions (85.7%), fatigue (38.6%), COVID-19 (32.9%), pruritus (34.3%), arthralgia (30.0%), dizziness (30.0%), nausea (24.3%), headache (24.3%), and anemia (21.4%). Grade 3 TEAEs occurred in 25.7% of patients.There were no Grade 4 or 5 TEAEs. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies (most of which were skin cancers) were reported in 11 patients (all had risk factors that may have contributed to the development of these malignancies). There was no obvious correlation between increasing exposure to rusfertide and malignancies reported. Six thrombotic events (5 arterial and 1 venous) occurred in 5 patients with high-risk PV. Conclusions: In REVIVE, rusfertide added to TP with or without CRT provided long-term durable control of Hct and decreased the need for TP. Patients are eligible to roll over to the phase 2 THRIVE OLE study (NCT06033586), which will continue to assess the long-term safety and efficacy of rusfertide for a total period of up to 5.8 years. The randomized phase 3 VERIFY study (NCT05210790) is ongoing and will evaluate rusfertide vs placebo in PV patients.

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN (Gotlib et al. Nature Medicine, 2021; DeAngelo et al., Nature Medicine, 2021). However, despite showing prolonged OS and low risk of progression of the SM component, some patients (20%) exhibit progression of the AHN component, including transformation to AML. In some patients, combination therapy with avapritinib and AHN-directed therapy may therefore be necessary for optimal control of SM-AHN. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN); hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design and Methods: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria (Gotlib et al., J Allergy Clin Immunol Pract, 2022) and incidence/frequency of adverse events. Exploratory endpoints include patient reported outcomes, PFS, OS, and correlative biomarkers linked to mast cell disease or AHN. Pts with a diagnosis of SM-AHN by the WHO 2022 criteria will be eligible for inclusion. Pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, CMML, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN-NOS. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 109/L and ≥ 25 x 109/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively. Key exclusion criteria include a diagnosis of AML, history of intracranial hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 109/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 109/L and < 75 x 109/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. Planned correlative studies include serial single-cell multi-omics utilizing scDNA-seq and immunophenotyping to assess impact of combination treatment on a molecularly complex disease state. This study is currently open to accrual (NCT06327685).

Background and Significance: Systemic mastocytosis (SM) is a rare heterogeneous disease characterized by the aberrant accumulation of neoplastic mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Despite improvement in disease control with approval of tyrosine kinase inhibitors (TKIs), there is still unmet need for improved tolerability and efficacy in AdvSM treatments. Bezuclastinib, an oral and selective type 1 TKI that potently inhibits KIT D816V, is being studied in patients diagnosed with AdvSM in the Apex study (NCT04996875). Results from the Part 1 dose optimization portion of Apex were presented previously. Part 1 randomized 32 patients 1:1:1:1 to receive bezuclastinib at 50, 100, or 200 mg BID or 400 mg QD. Initial results from the Part 1 dose optimization portion of the Apex trial in patients with AdvSM demonstrated encouraging safety profile and signs of clinical activity, as well as deep reductions across biomarkers of MC burden including bone marrow MC burden, serum tryptase levels, and KIT D816V variant allele fraction (VAF). In addition, 94%, 93%, and 100% of patients demonstrated ≥50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively. Exposure achieved with 100 mg BID of bezuclastinib original formulation resulted in optimal efficacy and safety outcomes. 150 mg QD of an optimized formulation is expected to deliver bezuclastinib exposures consistent with the 100 mg BID of the original formulation. Part 2 is further evaluating the efficacy and safety of bezuclastinib in patients with AdvSM at the selected Part 2 dose of 150mg QD of the optimized formulation. Study Design and Methods: Apex is a multicenter, Phase 2 open-label study of bezuclastinib in patients with AdvSM as defined per the WHO criteria. Enrollment includes previously treated and treatment-naïve patients. Part 2 is enrolling approximately 65 patients including up to 15 patients without measurable mIWG C-findings. The Part 2 expansion portion of the Apex study is designed to evaluate the efficacy and safety of bezuclastinib in patients with AdvSM, including ASM, SM-AHN, or MCL. Key eligibility criteria include measurable disease (centrally adjudicated) according to modified IWG-MRT-ECNM criteria and clinically acceptable laboratory values including platelet count ≥50,000/µL. The primary efficacy endpoint of Part 2 is overall response rate (ORR = complete response [CR] + complete remission with partial hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) per mIWG-MRT-ECNM criteria according to mIWG-MRT-ECNM response criteria and will be confirmed by a Central Response Review Committee. Secondary endpoints include further characterization of safety and tolerability, pure pathologic response, biomarker response (including changes in bone marrow MC burden, serum tryptase level, and KIT D816V mutational burden), duration of response, time to response, progression-free survival, and overall survival (OS). Apex Part 2 is actively enrolling. Study sites are enrolling in North America, Asia-Pacific, and Europe. In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.

Abstract With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group–European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.