JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit ...(Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). "Idiopathic erythrocytosis" loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer–associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and ...oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in DNMT3A or TET2 and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. TET2 mutations were more age-dependent, associated with a modest neutropenic effect (9%, P = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in DNMT3A had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.
•Somatic mutations driving clonal hematopoiesis occur mainly in DNMT3A and TET2 and have no significant impact on hematological phenotypes.•There is a familial predisposition to acquire TET2 mutation.
Disease overview
Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte ...hyperplasia, and frequent hepatosplenomegaly. The seminal discovery of oncogenic driver mutations in colony‐stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL in 2013 anchored a new scientific framework, deepening our understanding of its molecular pathogenesis, providing a diagnostic biomarker, and rationalizing the use of pharmacological targeting.
Diagnostic criteria
In 2016, the World Health Organization (WHO) included the presence of activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 109/L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.
Disease updates
Increasingly comprehensive genetic profiling of CNL has disclosed a complex genomic landscape and additional prognostically relevant mutational combinations. Though prognostic determination and therapeutic decision‐making remain challenging, emerging data on prognostic markers and the use of newer therapeutic agents, such as JAK inhibitors, are helping to define state‐of‐the‐art management in CNL.
Opinion statement
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by oncogenic driver mutations in colony-stimulating factor 3 receptor (
CSF3R
). Due in ...large part to the rarity of the disease and dearth of clinical trials, there is currently no standard of care for CNL. Available therapies range from conventional oral chemotherapy to targeted JAK inhibitors to hematopoietic stem cell transplant (HSCT), the latter representing the only potentially curative modality. For this reason, coupled with CNL’s typically aggressive clinical course, allogeneic HSCT remains the primary recommended therapy for eligible patients. For ineligible patients, a number of nontransplant therapies have been evaluated in limited trials. These agents may additionally be considered “bridging” therapies pre-transplant in order to control myeloproliferation and alleviate symptoms. Historically, the most commonly utilized first-line agent has been hydroxyurea, though most patients ultimately require second (or subsequent)-line therapy; still hydroxyurea remains the conventional frontline option. Dasatinib has demonstrated efficacy in vitro in cases of
CSF3R
terminal membrane truncation mutations and may cautiously be considered upfront in such instances, though no substantive studies have validated its efficacy in vivo. Numerous other chemotherapy agents, practically re-appropriated from the pharmaceutical arsenal of MPN, have been utilized in CNL and are typically reserved for second/subsequent-line settings; these include interferon-alpha (IFN-a), hypomethylating agents, thalidomide, cladribine, and imatinib, among others. Most recently, ruxolitinib, a JAK1/2 inhibitor targeting JAK-STAT signaling downstream from
CSF3R
, has emerged as a potentially promising new candidate for the treatment of CNL. Increasingly robust data support the clinical efficacy, with associated variable reductions in allele burden, and tolerability of ruxolitinib in patients with CNL, particularly those carrying the
CSF3R
T618I mutation. Similar to conventional nontransplant strategies, however, no disease-modifying or survival benefits have been demonstrated. While responses to JAK-STAT inhibition in CNL have not been uniform, data are sufficient to recommend consideration of ruxolitinib in the therapeutic repertory of CNL. There remains a major unmet need for prospective trials with investigational therapies in CNL.
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent ...splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes.
The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have ...suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple‐negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple‐negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9‐3.5), type 2/like CALR (HR 2.5, 95% CI 1.4‐4.5), MPL (HR 1.8, 95% CI 1.1‐2.9) and triple‐negative mutational status (HR 2.4, 95% CI 1.6‐3.6), but otherwise similar between the non‐type 1/like CALR mutational states (P = .41). In multivariable analysis, the absence of type 1/like CALR (P < .001; HR 2, 95% CI 1.4‐2.7), presence of ASXL1/SRSF2 mutations (P < .001; HR 1.9, 95% CI 1.5‐2.4) and DIPSS‐plus (P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple‐negative status did not disclose additional prognostic information for overall or leukemia‐free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.
Cytogenetic studies among 809 consecutive patients with essential thrombocythemia (ET; median age 59 years; 65% females) revealed normal karyotype in 754 (93%), loss of chromosome Y only (-Y) in 16 ...(2%), and abnormalities other than -Y in 39 (4.8%), the most frequent being sole 20q- (n = 8). At presentation, abnormal karyotype, excluding -Y, was associated with older age (p = 0.04), higher leukocyte count (p = 0.03) and arterial thrombosis history (p = 0.02); no associations were apparent for JAK2/CALR/MPL mutations whereas ASXL1 mutations clustered with normal karyotype/-Y and TP53 with abnormal karyotype. Survival was significantly shorter in patients with abnormal karyotype or -Y, compared to those with normal karyotype (median 12, 10, and 21 years, respectively; p < 0.0001). During multivariable analysis that included IPSET (international prognostic score for ET) variables, abnormal karyotype (p < 0.01, HR 2.0), age >60 years (p < 0.01, HR 4.5), leukocytosis >11 × 10
/L (p < 0.01, HR 1.5), and male gender (p < 0.01, HR 1.4) were independently associated with inferior survival; abnormal karyotype and age >60 years remained significant, along with SF3B1/SRSF2/U2AF1/TP53 mutations (p = 0.04; HR 2.9), when the latter was included in the multivariable model. The current study suggests prognostic relevance for karyotype in ET.
Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). ...MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm–relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval CI) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of RUNX1 mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of RUNX1 mutations.
•Mutation patterns in blast phase MPN, including paired sample analysis, point to specific mutations with potential pathogenetic relevance.•RUNX1 mutations predict inferior survival in blast phase MPN, independent of specific treatment strategies.
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