La mastocitosi è una malattia rara ed eterogenea definita dall’espansione e accumulo di mastociti clonali nella cute e in altri organi; nella maggior parte dei pazienti adulti si presenta come forma sistemica della malattia. In presenza di un sospetto clinico di malattia il livello sierico di triptasi è un utile parametro per lo screening cosi come la ricerca della mutazione D816V sul sangue periferico. Un esame del midollo osseo e i successivi esami di stadiazione sono tuttavia necessari per stabilire la diagnosi, definire la variante e la relativa prognosi. La diagnosi e il trattamento della mastocitosi devono, quindi basarsi su un approccio multidisciplinare che si avvalga della collaborazione di diversi specialisti.
Negli ultimi anni, anche grazie alla messa a punto di nuove opzioni terapeutiche, l’accresciuto interesse della comunità scientifica per questa complessa patologia ha condotto a una maggiore produzione di letteratura specialistica. In occasione dell’ultima edizione del Congresso ASH, ad esempio , sono stati presentati numerosi studi concernenti eziologia, presentazione clinica, marker prognostici e scenari terapeutici.
Di seguito una selezione dei contributi di maggior interesse.
ASH 2021
Efficacy of avapritinib in patients with advanced systemic mastocytosis: hematologic and bone marrow responses from the phase 2 open-label, single-arm, Pathfinder Study
Methods: Patients aged ≥18 years with centrally confirmed AdvSM were treated with avapritinib 200 mg once daily. Peripheral blood smears, bone marrow biopsies (BMBs), and aspirates (BMAs) were obtained at screening, and after 8 and 24 weeks. Evaluations of morphology were performed using standard Wright-Giemsa and H&E staining, while immunohistochemistry was performed on formalin-fixed EDTA-decalcified BM sections using standard techniques for tryptase, CD117, CD25, and CD30. Staining was also performed to detect reticulin and collagen fibrosis. Complete blood counts and differentials were performed at screening, and after 8 and 24 weeks.
Results: In an interim analysis of PATHFINDER, the overall response rate (per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis response) was 75% in 32 evaluable patients with AdvSM who received avapritinib. Reductions of ≥50% in BM MCs were observed in 88% (44/50) of patients and 60% of patients (30/50) had elimination of BM MC aggregates. Following treatment with avapritinib, an overall decrease in MC burden was observed in BMBs with a mean decrease of 64% at Week 8 (n=47) and 73% at Week 24 (n=24), and was associated with a decrease in the percentage of MC aggregates. Avapritinib treatment also resulted in reductions of the proportion of CD25+ and CD30+ MCs in BMBs by Week 8 and Week 24 (Table). In BMAs, avapritinib reduced the mean MC burden from 11% (out of total nucleated cells; n=47; range 0–72) at screening to 3% (range 0–47) by Week 8 (n=43) and 3% (range 0–30) at Week 24 (n=24), with decreases in immature and spindle-shaped MCs (Table). Of 5 patients with circulating MCs at screening and post-screening sample measurements (all with SM with associated hematologic neoplasm diagnoses), all had no detectable MCs by Week 8. Cellularity in BMBs decreased from a mean of 86% at screening to 68% at Week 8 and 59% by Week 24. Fibrosis was present in BMBs in 58 of 59 patients (98%) at screening, 40/44 (91%) at Week 8, and 22/25 (88%) at Week 24; reticulin fibrosis (MF score) and collagen fibrosis (Grade) was reduced during avapritinib treatment in those patients presenting with increased fibrosis. However, no significant changes in osteosclerosis scores were noted. In peripheral blood, a marked decrease in mean eosinophil counts and reductions in white blood cell, neutrophil, monocyte counts were also observed. Platelet counts decreased while hemoglobin levels remained relatively consistent through Week 24 (Table).
Conclusions: Avapritinib demonstrated rapid (Week 8) and profound (Week 24) reductions in neoplastic MC burden characterized by a reduction of the total MC burden in BMBs and BMAs with return to a normal morphologic appearance and normal immunophenotype, usually over 6 cycles. This was accompanied by a normalization of BM cellularity, as well as a decrease in fibrosis and marked improvement in hematologic parameters. These improvements in disease histopathology, along with known deep molecular remission of KIT D816V, suggest the potential for modification of AdvSM disease natural history.
Bibliografia. George TI, Karner KH, Karen A. Moser KA, et al. ASH Meeting 2021; abstract #2565.
Effective control of advance systemic mastocytosis with avapritinib: mutational analysis from the Explorer Clinical Study
Introduction: Systemic mastocytosis (SM) is a rare, hematologic neoplasm driven by KIT D816V mutations in ~95% of patients. Outcomes remain poor for patients with advanced SM (AdvSM), which comprises aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Molecular subtyping reveals a heterogeneous genetic landscape, particularly in patients with an AHN component. The KIT D816V mutation is invariably found in and considered a primary driver of the neoplastic mast cell component, while its role in the AHN component is less clear. Clinical progression (CP) can occur in the SM and/or AHN components and may be associated with outgrowth of clones with distinct mutation patterns. Avapritinib, a selective and potent inhibitor of the KIT D816V–mutant kinase, induced rapid (median time to response ~2 months), deep, and durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies of patients with AdvSM. In these studies, responses to avapritinib treatment were observed regardless of AdvSM subtype, prior therapy, or presence of SRSF2, ASXL1, and RUNX1 (S/A/R) co-mutations that are associated with high risk. Here, we report results from an exploratory mutational analysis in patients with AdvSM enrolled in EXPLORER.
Methods: Peripheral blood (PB) and bone marrow (BM) samples were collected at baseline, during treatment, and at CP, as determined by the local investigator, for biomarker analyses and assessment of disease response to treatment. Serial samples from baseline, on study, and at end-of-treatment (when available) were evaluated centrally by droplet digital polymerase chain reaction (ddPCR) assay for detection of KIT D816V. Central next-generation sequencing (NGS; TruSight™ Myeloid Panel) of KIT and other genes mutated in myeloid malignancies was performed at baseline and on study (in a subset of patients with CP). Mutation-adjusted risk score (MARS; Jawhar et al. J Clin Oncol 2019;37:2846–2856) was used for evaluation of progression-free survival (PFS) and overall survival (OS).
Results: Among 69 patients with AdvSM in the EXPLORER study, 93% had detectable KIT D816V mutations at baseline, 3% had KIT D816Y, and 52% were positive for S/A/R co-mutations. Of patients with baseline and post-baseline assessments, 88% had a ≥50% reduction in KIT D816V variant allele fraction (VAF), with KIT D816V becoming undetectable (limit of detection <0.17%) in PB in 24 of 56 (43%) after a median of 15.4 months. Fourteen (20%) patients (SH-AHN, n=12; MCL, n=2) had documented CP on avapritinib, 6 with acute myeloid leukemia (AML), 4 with worsening AHN, 2 with SM progressions, and 2 undetermined. At the time of CP, most patients still had significant reductions in mast cell and KIT D816V clonal burden: BM mast cells (6/12 with ≥50% reduction; median 46%), PB KIT D816V VAF (10/12 with ≥50% reduction; median 83%), and serum tryptase (10/14 with ≥50% reduction; median 71%) with last assessment within 2.5 months of end of treatment. No on-target KIT resistance mutations were identified. Eight patients with CP had ≥1 S/A/R mutation at baseline. Patients with CP had a median (range) of 6 (3–9) mutations at baseline and 8 (3–12) overall, while patients without CP had 4 (1–14) mutations at baseline and 4 (1–17) overall. In patients with CP, emergent mutations occurred in NRAS, JAK2, CBL, GATA2, CUX1, SRSF2, NPM1, and SETBP1, while mutations in TET2, DNMT3A, and ASXL1 were common at baseline and retained at CP. No recurrent pattern of emergent mutations was observed. Most of these mutations had known associations with the pathogenesis of AML or myeloid AHN subtypes. MARS predicted both PFS (P=0.0126) and OS (P=0.0015), with a MARS ≥2 being associated with higher risk.
Conclusions: In EXPLORER, treatment with avapritinib in patients with AdvSM profoundly reduced KIT D816V disease burden in the majority of patients, consistent with anti-KIT D816V activity in either the SM or AHN component. Progression of the SM component was infrequent and re-emergence of KIT D816V was rare. Outcomes were more favorable in patients with low versus higher baseline MARS scores. These data suggest that avapritinib maintained control of AdvSM disease features, with low rates of CP driven primarily by progression of KIT D816V–negative AHN, and provides a rationale for future study of avapritinib in combination with AHN-directed therapy.
Bibliografia.Deininger MW, DeAngelo DJ, Gotlib J, et al. ASH Meeting 2021; abstract #318.
Screening for hereditary alpha-tryptasemia in subjects with systemic mastocytosis (SM) and non-SM mast cell activation symptoms clinically relevant
Introduction: Hereditary alpha-Tryptasemia (HαT) is a group of genetically defined traits that share increased copy number of TPSAB1 gene encoding for both the α- and β-alleles (Lyons et al 2018). Increased copy number (CN) of the α-tryptase coding sequence in TPSAB1 on one or both alleles represents the genetic base of HαT (Lyons et al 2016). HαT is characterized by mild elevation in serum tryptase levels and a variety of mast cell (MC) activation symptoms, including recurrent anaphylaxis. Prevalence in the general population is up to 5%, that increases up to 20% in systemic mastocytosis (SM); it has been suggested that HαT might be a germline variant predisposing to SM development. In SM, HαT correlated with higher incidence of mediator-related symptoms (Greiner G et al, Blood 2021). Due to its complexity, the assay for TPSAB1 CN is performed in few centers and the actual prevalence of HαT in selected subsets is still to be elucidated. To this end, we screened for HαT 2 groups of subjects, the first with MC activation symptoms and no evidence of SM, the second with diagnosis of SM according to WHO-2016.
Methods: Droplet digital PCR (ddPCR) was used to measure CN variation (CNV) in TPSAB1 by adapting standard CNV ddPCR protocol to genotype for both TPSAB1 and TPSB2 (Fig.1A). The high homology between α and β encoding isoforms and the presence of paralogous genes in a single locus makes TPSAB1 CNV detection very challenging. ddPCR was performed on genomic DNA with/without BamHI, using the PrimePCR ddPCR Copy Number reference AP3B1 (BioRad). Accuracy and precision of the ddPCR protocol was assessed by analyzing 10 samples in triplicate in 3 separate experiments.
Results: We studied 41 subjects with mediator-related symptoms and augmented basal serum tryptase (BST) (cohort 1) and 150 patients with ascertained diagnosis of mastocytosis (cohort 2). The BST threshold established for cohort 1 was equal or higher than 11 mcg/L. Median age was 64.7 yr, males 54%; median BST levels was 15.3 (range 12.3-21 mcg/L); 29% of the pts had history of anaphylaxis. In cohort 2, 134/150 (89.3%) pts had a diagnosis of SM, whereas 13/150 (8,6%) were Cutaneous Mastocytosis (CM). Among SM patients, 113(84.3%) presented with non-advanced SM variants. Advanced forms including aggressive SM (ASM) and SM with an associated hematological neoplasm (SM-AHN) were diagnosed in 6 (4.5%) and 8 (6%) respectively. In 3 pts, SM subtype was not available. Median age was 49 yr, males 55%; 41.7% of the pts had history of anaphylaxis. HαT was documented in 27 (65.9%) subjects in cohort 1, and 14 (9.3%) in cohort 2. In cohort 1, 3 α-tryptase (3α) copy number was observed more frequently (59.2% of HαT+ pts); conversely 3α and 2α-tryptase copy number were observed at a similar rate (42,8%) in cohort 2. HαT+ pts in cohort 1 presented significantly higher BST (17.1 vs 12.05 mgc/L, P<0.001), as previously reported (Greiner G et al, Blood 2021); however, occurrence of mediator related symptoms was comparable to HαT wt, 72% vs 71.4% , respectively; likewise for anaphylaxis (28% in HαT+ vs 33%).In cohort 2, BST levels were similar in HαT+ and HαT wt pts (24.6 and 24.3 mcg/L), as were anaphylaxis episodes (50% and 41%, respectively). A trend for lower MC burden in HαT+ as assessed by flow cytometry was demonstrated (% of bone marrow MC: 0.01% in HαT+ vs 0.07%) whereas no meaningful differences emerged regarding the symptom burden. In addition, a lower prevalence of KIT 816V mutation was observed in HαT+ (71.4% vs 89.5%; p=0.073).
Conclusions: In our study HαT+ was observed in around 10% of patients with SM, a prevalence lower than previously reported (Greiner et al, Blood 2021) and remarkably lower than in a selected cohort of subjects with raised BTL and history of mediator-released symptoms (66%). ddPCR represents a suitable method to investigate the presence of CNV in the α-tryptase coding sequence. Genetic testing for HαT+ should be considered in the diagnostic workout of patients presenting with anaphylaxis or MC mediator-related symptoms and no suspicion/evidence of SM. The clinical correlates of HαT in SM remain to be fully ascertained.
Bibliografia. Irushani Vanderwert FI, Vannucchi A, Sordi B, Mannelli F, et al. ASH Meeting 2021;abstract #1500.
Organ damage at initial presentation across the spectrum of advanced systemic mastocytosis variants clinically relevant
Methods: Among 251 pts with mast cell disorders in our Stanford IRB-approved MPN registry, we identified 87 AdvSM pts between October 1999 and September 2020. Thirteen pts (15%) had ASM, 63 (72%) had SM-AHN, and 11 (13%) had MCL. Comparisons between continuous and categorial variables were performed using the Kruskal-Wallis test and the Fisher’s exact test, respectively. We defined IWG/mIWG liver-associated organ damage as a composite of ascites/pleural effusions requiring diuretics or drainage, liver function abnormalities, and/or hypoalbuminemia.
Results: Median age at diagnosis was 64 years (range 24-88) and 55 pts (63%) were male. The median number of prior treatments was 1 (range, 0-4). Forty-six pts (53%) were enrolled on clinical trials, and they had a median of 2 organ damage findings by WHO or IWG/mIWG criteria. ASM, MCL, and SM-AHN pts had significantly different WBC, ANC, and monocyte counts; pts with SM-AHN had the highest median white blood cell count (11.4 x 109/L), absolute neutrophil count (5.69 x 109/L), and monocytosis (1.58 x 109/L). Pts with SM-AHN exhibited a trend towards a higher absolute eosinophil count compared to ASM pts (p = 0.06). There was a significant difference in IWG/mIWG-defined RBC and platelet transfusion dependence in the 12 weeks prior to initial presentation. Pts with MCL had the highest transfusion requirement, with 55% and 27% of pts requiring red blood cell and platelet transfusions, respectively. There were no differences in median hemoglobin, platelet count, liver function tests, serum albumin, pleural effusions/ascites, and liver or spleen size by palpation or volumetric imaging. Across the 3 AdvSM subtypes, a significant difference was observed between the # of pts fulfilling IWG/mIWG criteria for liver-related organ damage (p = 0.044). Pts with SM-AHN (p = 0.071) and MCL (p = 0.013) fulfilled more IWG/mIWG liver criteria compared to ASM pts. While the absolute number of IWG/mIWG non-hematologic organ damage findings was not different across the 3 subtypes, a pairwise comparison revealed a statistically higher number of IWG non-hematologic organ damage findings in MCL vs. ASM. Irrespective of the criteria, there were no significant differences in organ damage between pts receiving 0, 1, or ≥2 prior therapies.
Conclusion: We provide a preliminary snapshot of the patterns of WHO and IWG/mIWG-defined organ damage at initial presentation across a spectrum of AdvSM pts. Pts with MCL had the highest transfusion requirements, and liver-associated organ damage appears to be more frequent in SM-AHN and MCL pts compared to ASM. We next plan to study the profile of organ damage using WHO, IWG, and mIWG criteria in AdvSM patients who enrolled on the phase I (NCT02561988) and phase II (NCT03580655) studies of avapritinib. These analyses will include clinicopathologic and genetic correlates of organ damage, including # prior therapies, KIT D816V variant allele frequency, and myeloid mutation profile.
Bibliografia. Liang EC, Perkins C, Gotlib J, et al. ASH Meeting 2021; abstract #2567.
Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases
Background: Systemic mastocytosis (SM) is formally classified as advanced, smoldering (SSM), or indolent (ISM). Advanced SM indicates the presence of an associated non-mast cell lineage hematologic neoplasm (SM-AHN) or at least one “C finding” (i.e. features of organopathy from mast cell infiltration); the latter defines aggressive SM (ASM). Both advanced SM and ISM might be associated with MC mediator symptoms (MC-MSs) or urticaria pigmentosa (UP). Current drug therapy for SM is primarily directed at reversing C findings or alleviating symptoms/UP, and includes cladribine, midostaurin, and avapritinib. The former has a long track-record of safety while the latter two are recent additions that target the associated KIT mutation, but with concerning gastrointestinal and neurological side effects. We retrospectively reviewed our experience with cladribine therapy in SM, in order to maintain a proper perspective in making treatment choices.
Methods: The current study includes 42 patients with SM (22 advanced and 20 indolent/smoldering), recruited from the Mayo Clinic SM database, based on documentation of treatment with cladribine. Conventional criteria were used for diagnosis and classification (Blood 2016;127:2391) and definitions of response (Eur J Clin Invest. 2007 Jun;37(6):435); in the latter regard, we utilized modified Valent criteria that incorporated a minimum of one-month duration to qualify as response.
Results Advanced SM: 22 patients (median age 65 years, range 48-80; males 68%) had advanced SM, including 13 SM-AHN, 8 ASM, and 1 mast cell leukemia. Median (range) BM MC burden was 30% (10%-90%), serum tryptase 193 ng/ml (21-1370), hemoglobin 10.6 g/dL (7-15), leukocytes 6 x 10(9)/L (0.5-63), and platelets 115 x 10(9)/L (8-320). KITD816V was detected in 86% of 19 evaluated and abnormal karyotype in 14% of 21 evaluated. 50% of patients had palpable hepatomegaly, 59% palpable splenomegaly, 100% MC-MSs, and 14% UP; 87% displayed at least one C finding.
Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 1.5 months (range 0.1-17). 55% of patients received at least 3 cycles of treatment. Overall response (OR) was documented in 17 (77%) patients with similar OR rates in ASM (88%) vs SM-AHN (69%; p=0.32), with median time to response of 3.7 months (range 0.4-9). OR included 45% major response (MR) and 32% partial response (PR). 17 patients were evaluated for BM MC response with 44% showing >50% reduction, in MCs, including 19% with complete resolution. Organomegaly response was complete in 36% and partial in 27%. Tryptase response of >50% was documented in 32%. Cladribine side effects were limited to cytopenias with 36% showing grade 3 or 4 myeloid cytopenia. Median duration of response was 6 months (range 1-67). Six patients, including 5 with SM-AHN, progressed to either AML or MCL. Among the 5 patients who did not respond to cladribine, one with ASM was successfully treated with midostaurin.
Indolent or smoldering SM: 20 patients (median age 56 years, range 36-73; males 45%) had ISM (n=17) or SSM (n=3). Median (range) BM MC burden was 13% (5%-60%) and serum tryptase level 49 ng/ml (14-1630). KITD816V was detected in 95% of 19 evaluated patients and abnormal karyotype in 12% of 17 evaluated. All patients displayed MC-MSs and 46% UP. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 4 months (range 0-92). 85% of patients received at least 3 cycles of cladribine therapy. OR was documented in 14 (70%) patients, including 60% complete or major regression of symptoms or UP, with median time to maximal response of 8.5 months (range 1-98); response rates in patients with UP were similar with 57% complete or major regression; 10 patients were evaluable for BM MC response with 50% showing >50% reduction in MC burden. Serum tryptase response was evaluated in 13 patients with 46% showing >50% reduction in levels. Treatment-emergent cladribine side effects were limited to cytopenias with only 3 (15%) patients experiencing grade 3 or 4 myeloid cytopenia and (n=3; 15%) and 6 (30%) experiencing grade 3 or 4 lymphopenia.
Conclusions: The current study confirms the favorable side effect profile and long-term safety of cladribine as a first-line drug of choice for both indolent and advanced SM. Response to cladribine therapy was evident in all aspects of the disease, including MC-associated organopathy, UP, MC-MSs, serum tryptase level and bone marrow MC burden.
Bibliografia.Deininger MW, DeAngelo DJ, Gotlib J, et al. ASH Meeting 2021; abstract #318.
Application of prognostic scoring in systemic mastocytosis patients within a UK centre of excellence: Guys and St Thomas’ NHS Foundation Trust
Methods: We performed a retrospective study of 192 adult patients diagnosed with SM between 2009 and 2021 including demographics, clinical data, as well as next generation sequencing (NGS) based myeloid gene panels carried out in advanced SM patients (AdvSM) where available. Prognosis for all patients was calculated based on IPSM (Sperr et al. [2019]) in all our SM patients and MARS scores in those with AdvSM (Jawhar et al. [2019]).
Results: There was no gender bias in our cohort with 87 (46%) males and 105 (54%) females. Median age at diagnosis was 52 years (range 5-84) and majority of patients had indolent SM (ISM; 129/192 [67%]), 8/192 (4%) smouldering SM (SSM) and 55/192 (29%) advanced SM (AdvSM). In those with AdvSM, 43/55 (78%) had an associated haematological neoplasm (SM-AHN); 9/55 (17%) aggressive SM (ASM) and 3/55 (5%) mast cell leukaemia. As expected, AHN sub-types were myeloid with majority being CMML (16/55; 29%) [Table 1]. Median tryptase at diagnosis in ISM patients was 41ug/L (range 3-351ug/L), while in SSM it was 494ug/L (range 174-682ug/L) and in AdvSM it was 155ug/L (range 10-1551). Most patients were positive for the KIT D816V mutation (131/192; 68%). As expected, ISM and SSM (non-AdvSM) patients had better prognosis compared to those with AdvSM [Figure 1a], with median overall survival (OS) not reached in the former and 12 months in the latter with 11-year follow-up. We next applied the IPSM score to the AdvSM cohort, with the largest proportion categorised as AdvSM-3 (25/55; 45%) while 10/55 (18%) were AdvSM-4 [Table 1]. Survival outcome was notably higher in the AdvSM-1 group (4/55; 7%) with no deaths recorded, while 6/25 (24%) and 4/10 (40%) deaths were reported in AdvSM-3 and AdvSM-4 groups respectively. SM patients are known to carry somatic mutations in addition to KIT, in particular SRSF2, ASXL1 and RUNX1 (S/A/R) which are associated with adverse outcome. In our AdvSM cohort, 10/55 (18%) of patients were positive for one of these mutations on NGS-based myeloid gene panel and 8/55 (15%) carried ≥2. We next examined the MARS score; most of our AdvSM patients categorised as low-risk (28/55, 51%), 21/55 (38%) were intermediate-risk and 6/55 (13%) high-risk [Table 1]. Survival outcome as expected in the low-risk group was higher compared to the intermediate- and high-risk groups, with 10-year OS of 87% versus 35% and 30% respectively.
On reviewing our AdvSM cohort, 6/55 (11%) had progressive disease: 5 transforming to acute myeloid leukaemia (AML) and 1 to mast cell leukaemia (MCL). Interestingly, when reviewing cause of death, the highest proportion were due to AHN progression (6/16; 38%) while 2/16 (13%) were from transformation to AML.
As expected within our cohort, there was a discrepancy between the IPSM and MARS scores as the latter includes the presence of S/A/R mutations. 2 patients diagnosed with MCL in 2016 and 2019 respectively, were categorised high risk based on both scores. Both are alive to date having received the KIT inhibitor avapritinib, with one continuing on this treatment. The other progressed to AML and underwent allogeneic stem cell transplant, with ongoing complete remission. Other treatments received by our AdvSM patients are summarised in Table 1.
Conclusion: Application of the IPSM and MARS prognostic scores to our data reflects findings of other groups with better outcomes seen in non-AdvSM compared to AdvSM patients. Furthermore, although our AdvSM cohort is small, the presence of adverse risk factors could be overcome through recent advances in treatments and consolidation with stem cell transplant. Hence, identification of high-risk patients using these prognostic scores can direct targeted first-line therapy and improve outcomes.
Bibliografia. Sriskandarajah P, Oni C, Woodley C, et al. ASH Meeting 2021; abstract #3625.
Whole genome sequencing identifies non-KIT mutations and cytogenetic aberrations in systemic mastocytosis but has limited sensitivity for detection of KIT D816V
Aim: To assess the ability of WGS/WTS to detect cytogenetic aberrations and recurrent somatic mutations in SM.
Methods: 120 patients (51 female, 69 male) diagnosed with SM were analyzed with WGS/WTS and results were compared with orthogonal data of KIT D816V PCR, targeted sequencing, and cytogenetics. 47 patients (39%) were diagnosed with advanced SM (1 mast cell leukemia, 3 aggressive SM, 43 SM with associated hematologic neoplasm). For WGS, 2x151bp paired-end reads were generated on NovaSeq 6000 and HiSeqX machines (Illumina, San Diego, CA). BaseSpace’s Tumor/Normal app v3 was used to call variants with Strelka Somatic Variant Caller v2.4.7 and structural variants (aberrations with >50bp in size) with Manta (v0.28.0). Genomic DNA from a mixture of multiple anonymous donors (Promega, Fitchburg, WI, USA) was used as normal. For WTS, 2×101 bp paired-end reads were produced with a median of 50 mio. reads per sample, aligned with STAR v2.5.0, and variants were called using Isaac Variant Caller v2.3.13.
Results: WGS/WTS detected cytogenetic aberrations in 21% of patients: 2 patients displayed a complex aberrant karyotype, 3 balanced structural aberrations, 16 copy number alterations, and 6 copy number neutral losses of heterozygosity. Aberrations detected by chromosome banding analysis were also found by WGS in all but three patients (small clones with aberrations present in ≤20% of metaphases and <10% of interphase nuclei as determined by FISH). In contrast, WGS/WTS detected additional aberrations in 16 patients. The frequency of chromosomal aberrations detected by WGS/WTS was higher in advanced compared to non-advanced SM (34% vs. 12%, p<0.05). KIT D816V was detected by PCR in 98%, by WGS in 21% and by WTS in 46% of patients. The detection rate by WGS was significantly higher in advanced (36%) compared to non-advanced SM (12%, p<0.05) while no difference was observed for WTS (45% vs. 47%). Somatic mutations outside of KIT were analyzed within a subset of 121 genes recurrently mutated in hematologic neoplasms. 46% of patients showed non-KIT mutations with a median of 2 mutations per patient. Both frequency of non-KIT mutations as well as the median number of mutations per patient was higher in advanced (83%; n=3) compared to non-advanced SM (22%, n=1, p<0.05). Finally, we analyzed the impact of genetic aberrations on survival in our SM cohort. Patients were grouped according to the presence of chromosomal aberrations and gene mutations (non-KIT) as assessed by WGS/WTS. SM patients with both types of aberrations (n=16), one type of aberration (n=47; gene mutations only n=38; chromosomal aberrations only n=8), or no aberration but KIT D816V (n=57) showed significant differences in overall survival (p<0.05, Figure 1).
Conclusions: WGS/WTS has limited sensitivity for detection of KIT D816V in SM. This finding can be explained by the low KIT D816V mutation burden typically found in bone marrow aspirates of SM patients. In line, we observed a slightly higher detection rate in advanced SM and in RNA-based WTS analysis. As WGS/WTS will be applied for the diagnostic workup of myeloid malignancies in the future and SM associated with other hematologic neoplasms may be overlooked if not specifically investigated, additional PCR-based techniques are still mandatory to rule out KIT D816V as a diagnostic criterion for SM. In contrast, WGS/WTS detects both chromosomal aberrations and additional gene mutations in patients with SM and can be used as an alternative to cytogenetics and targeted sequencing for risk assessment. In particular, the absence of genetic aberrations in WGS/WTS identifies SM patients with indolent course of the disease and favorable prognosis.
Bibliografia. Hoermann G, Meggendorfer M, Baer C, et al. ASH Meeting 2021; abstract #1495.
Healthcare resource utilization and costs of Medicare fee for service beneficiaries newly diagnosed with moderate to severe non-advanced systemic mastocytosis
Systemic mastocytosis (SM) is a rare mast cell disease driven by the KIT D816V mutation in which mast cells accumulate in ≥1 tissues or organs resulting from clonal proliferation of abnormal mast cells in one or more extracutaneous organs. Most forms of SM are non-advanced (non-AdvSM). To date, the economic burden of non-AdvSM has not been well-studied among Medicare patients. This study compared direct healthcare resource utilization (HCRU) and healthcare costs in Medicare beneficiaries with non-AdvSM and a matched cohort without SM.
This study used Centers for Medicare and Medicaid Services-sourced 100% Medicare Fee for Service (FFS) claims (Parts A/B/D) and identified newly diagnosed non-AdvSM patients who had ≥2 medical claims for SM (ICD-10-CM Dx codes: D47.02 OR C94.30 OR C94.31 OR C94.32 OR C96.21) between 1/1/2017 and 12/31/2018. Patients were classified as non-AdvSM using a claims-based algorithm. The index date was the date of first observed SM diagnosis. Continuous enrollment in Medicare Parts A/B/D for 12 months pre- and post-index was required. Non-AdvSM patients were direct matched (1:1) on age, sex, race, index year, Medicare-Medicaid dual eligibility, and Charlson Comorbidity Index score to a non-SM control cohort. HCRU and costs were assessed during the 12 months pre- and post-index. Medical costs are reported in 2021 US dollars.
Post match, there were 333 non-AdvSM and 333 non-SM patients. Mean [SD] age of the non-AdvSM cohort was 67.3 [11.7] and 67.8 [13.3] years for the control cohort. Over 25% of patients were <65 years of age at index and originally qualified for Medicare with a disability. Most (76%) patients were female, and 94% were White. During the 12-month pre-index period, non-AdvSM patients had more specialist physician office visits per patient (mean [SD]: 15 [15]) compared to non-SM patients (10 [13]; p<0.01). Non-AdvSM patients vs. controls had higher prevalence of asthma (29% vs. 15%, p<0.0001) and any malignancy (43% vs. 15%, p<0.0001) and lower prevalence of hypertension (58% vs. 68%, p=0.0103), diabetes with and without complications (19% vs. 34%; 8% vs. 15%; both p<0.0001), and renal disease (7% vs. 11%, p=0.0439). Non-AdvSM patients were also higher utilizers of corticosteroids (64% vs. 54%, p=0.0094), epinephrine auto-injectors (31% vs. 1%, p<0.0001), and omalizumab (6% vs. 0%, p<0.0001) compared to non-SM patients.
Total (Parts A/B/D) healthcare costs in the 12-month follow up period were almost one-third higher for non-AdvSM patients than for non-SM controls (mean [SD]: $40,250, [$54,563] vs. $30,013 [$51,235]; p=0.0128). Pharmacy (Part D only) expenditures were also significantly higher ($13,938[$38,367] vs. $5,745 [$17,213], p=0.0004) and accounted for a greater proportion (34.6% vs. 19.1%) of total costs for non-AdvSM patients vs. non-SM patients. Non-AdvSM patients were high utilizers of physician office visits post-index compared to non-SM controls; more non-AdvSM patients had ≥1 oncology/hematology visit (36.9% vs. 12.9%; p<0.0001), or allergy/immunology visit (47.2% vs. 3.9%; p<0.0001) and mean [SD] visits per patient were higher among non-AdvSM patients (3.4 [11.8] vs. 1.3 [6.4] oncology/hematology, p=0.0049; 3.3 [9.5] vs. 0.2 [1.7] allergy/immunology, p<0.0001). Approximately 40% of non-AdvSM patients filled ≥1 prescription for an epinephrine auto-injector compared with <3% in non-SM patients (p<0.0001). More non-AdvSM patients had prescriptions for H1 antihistamines (13.8% vs. 5.4%, p=0.0002), oral and systemic corticosteroids (39.0% vs. 27.9%, p<0.0001; 51.7% vs. 32.1%, p=0.0079, respectively), leukotriene antagonists (40.5% vs. 8.7%; p<0.0001), and omalizumab (6.9% vs. 0.0%, p<0.0001).
Compared to a matched cohort of non-SM Medicare FFS patients, non-AdvSM Medicare patients had 30% higher mean per patient total healthcare expenditures ($40,250 vs. $30,013), driven by more prescription drug use and higher utilization of outpatient resources, specifically visits to oncologists/hematologists and allergists/immunologists. Notably, this analysis does not represent the HCRU and costs of the most severe SM patients. Further research to understand the basis of the higher proportion of non-AdvSM patient in this analysis who were <65 years and qualified for Medicare with a disability (vs. 14% in all of Medicare), and the corresponding long-term medical costs among these patients is warranted.
Bibliografia. Sullivan EM, Cohen J, Norregaard C, et al. ASH Meeting 2021; abstract #4049.
Healthcare resource utilization and costs of advanced systemic mastocytosis among Medicare fee for service beneficiaries
This study used Centers for Medicare and Medicaid Services-sourced 100% Medicare Fee for Service (FFS) claims (Parts A/B/D) to identify newly diagnosed SM patients with >2 medical claims for SM (ICD-10-CM Dx codes: D47.02 OR C94.30 OR C94.31 OR C94.32 OR C96.21) between 01/01/2017 and 12/31/2018. The index date was the date of first observed SM diagnosis code. A claims-based algorithm was used to determine AdvSM subtype. Patients were required to have continuous enrollment in Medicare Parts A/B/D for 12 months pre- and post-index. AdvSM patients were direct matched (1:1) to a non-SM control cohort on age, sex, race, index year, Medicare-Medicaid dual eligibility, and Charlson Comorbidity Index score. HCRU and costs were assessed pre- and post-index. Chi-square and t-tests were used to evaluate differences in outcomes between AdvSM and non-SM patients. Medical costs are reported in 2021 USD.
After matching, there were 339 AdvSM and 339 non-SM patients. Mean [SD] age was 68.2 [13.2] among AdvSM and 68.5 [13.9] among non-SM patients. More than 25% of patients were <65 years old at index and qualified for Medicare due to a preexisting disability. Majority of patients were female (59%) and White (91%). Compared to non-SM patients, AdvSM patients had more specialist and emergency department (ED) visits during the baseline period. Baseline prevalence of asthma (26% vs. 16%, p=0.0009) and any malignancy (60% vs. 23%, p<0.0001) was higher among AdvSM patients compared to controls, and lower for hypertension (70% vs. 81%, p=0.0006), and diabetes with and without complications (28% vs. 52%; 16% vs. 33%; both p<0.0001).
During the 12 months post-index, all cause total healthcare expenditures (Parts A/B/D) were significantly higher for AdvSM patients than for non-SM comparator patients (mean [SD]: $123,412 [$180,386] vs. $47,988 [$64,693]; p<0.0001). Pharmacy costs (Part D) were a key driver of the total, accounting for 41% ($50,494 [$140,561]) of the total costs for AdvSM patients and 19% ($9,221 [$22,270]) of the total for non-SM patients. Inpatient hospital stays made up 24% of AdvSM patient costs and 26% of non-SM patient costs. More AdvSM than non-SM patients had ≥1 inpatient hospitalization (58% vs. 42%; p=0.0001), and length of hospital stay was significantly longer for AdvSM patients (13.1 [26.95] days) than for comparator patients (5.22 [12.66]; p<0.0001). Mean [SD] number of ED visits per patient was over twice as high for AdvSM than for non-SM patients (3.7 [12.0] vs. 1.6 [3.6]; p=0.0026). AdvSM patients had more than 5 times as many oncology/hematology and allergy/immunology physician office visits per patient versus non-SM controls (10.9 [21.5] vs. 2.0 [7.2]; 2.3 [7.4] vs. 0.1 [0.7]; both p<0.0001). AdvSM patients were higher utilizers of epinephrine (29.2% vs. <3% non-SM patients; p<0.0001), oral and systemic corticosteroids (54.0% vs. 38.1%, p<0.0001; 51.9% vs. 41.6%, p=0.0071), chemotherapy (12.09% vs. 6.78%; p=0.0181), and omalizumab (4.7% vs. 0.0%, p<0.0001).
AdvSM Medicare FFS patients were more resource intensive and had 2.5 times higher per-patient healthcare costs in the 12 months following SM diagnosis compared to a matched cohort of non-SM patients. These costs were driven by significantly higher rates of inpatient stays, more frequent ED and physician outpatient visits, and higher utilization of multiple medications. Notably, AdvSM patients in this analysis included a larger proportion of patients <65 years old with preexisting disability compared to the broader Medicare population (~25% vs. 14%), suggesting that AdvSM patients may be more likely to qualify for Medicare due to disability rather than age compared to the overall Medicare population. Further research in this area is warranted.
Bibliografia. Sullivan EM, Cohen J, Norregaard C, et al. ASH Meeting 2021; abstract #4048.
A phase 2 Study of bezuclastinib (CGT9486), an oral, selective, and potent KIT D816V inhibitor, in adult patients with advanced Systemic Mastocytosis (AdvSM)
This study used Centers for Medicare and Medicaid Services-sourced 100% Medicare Fee for Service (FFS) claims (Parts A/B/D) to identify newly diagnosed SM patients with >2 medical claims for SM (ICD-10-CM Dx codes: D47.02 OR C94.30 OR C94.31 OR C94.32 OR C96.21) between 01/01/2017 and 12/31/2018. The index date was the date of first observed SM diagnosis code. A claims-based algorithm was used to determine AdvSM subtype. Patients were required to have continuous enrollment in Medicare Parts A/B/D for 12 months pre- and post-index. AdvSM patients were direct matched (1:1) to a non-SM control cohort on age, sex, race, index year, Medicare-Medicaid dual eligibility, and Charlson Comorbidity Index score. HCRU and costs were assessed pre- and post-index. Chi-square and t-tests were used to evaluate differences in outcomes between AdvSM and non-SM patients. Medical costs are reported in 2021 USD.
After matching, there were 339 AdvSM and 339 non-SM patients. Mean [SD] age was 68.2 [13.2] among AdvSM and 68.5 [13.9] among non-SM patients. More than 25% of patients were <65 years old at index and qualified for Medicare due to a preexisting disability. Majority of patients were female (59%) and White (91%). Compared to non-SM patients, AdvSM patients had more specialist and emergency department (ED) visits during the baseline period. Baseline prevalence of asthma (26% vs. 16%, p=0.0009) and any malignancy (60% vs. 23%, p<0.0001) was higher among AdvSM patients compared to controls, and lower for hypertension (70% vs. 81%, p=0.0006), and diabetes with and without complications (28% vs. 52%; 16% vs. 33%; both p<0.0001).
During the 12 months post-index, all cause total healthcare expenditures (Parts A/B/D) were significantly higher for AdvSM patients than for non-SM comparator patients (mean [SD]: $123,412 [$180,386] vs. $47,988 [$64,693]; p<0.0001). Pharmacy costs (Part D) were a key driver of the total, accounting for 41% ($50,494 [$140,561]) of the total costs for AdvSM patients and 19% ($9,221 [$22,270]) of the total for non-SM patients. Inpatient hospital stays made up 24% of AdvSM patient costs and 26% of non-SM patient costs. More AdvSM than non-SM patients had ≥1 inpatient hospitalization (58% vs. 42%; p=0.0001), and length of hospital stay was significantly longer for AdvSM patients (13.1 [26.95] days) than for comparator patients (5.22 [12.66]; p<0.0001). Mean [SD] number of ED visits per patient was over twice as high for AdvSM than for non-SM patients (3.7 [12.0] vs. 1.6 [3.6]; p=0.0026). AdvSM patients had more than 5 times as many oncology/hematology and allergy/immunology physician office visits per patient versus non-SM controls (10.9 [21.5] vs. 2.0 [7.2]; 2.3 [7.4] vs. 0.1 [0.7]; both p<0.0001). AdvSM patients were higher utilizers of epinephrine (29.2% vs. <3% non-SM patients; p<0.0001), oral and systemic corticosteroids (54.0% vs. 38.1%, p<0.0001; 51.9% vs. 41.6%, p=0.0071), chemotherapy (12.09% vs. 6.78%; p=0.0181), and omalizumab (4.7% vs. 0.0%, p<0.0001).
AdvSM Medicare FFS patients were more resource intensive and had 2.5 times higher per-patient healthcare costs in the 12 months following SM diagnosis compared to a matched cohort of non-SM patients. These costs were driven by significantly higher rates of inpatient stays, more frequent ED and physician outpatient visits, and higher utilization of multiple medications. Notably, AdvSM patients in this analysis included a larger proportion of patients <65 years old with preexisting disability compared to the broader Medicare population (~25% vs. 14%), suggesting that AdvSM patients may be more likely to qualify for Medicare due to disability rather than age compared to the overall Medicare population. Further research in this area is warranted.
Bibliografia. Gotlib J, George TI, Deininger MW, et al. ASH Meeting 2021; abstract #3636.
