Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia.
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ABSTRACT:
SUBMITTER: Takahashi K
PROVIDER: S-EPMC3798995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPatients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients.Patients and methodsPatients with MM treated at our institution from 1993 to 2011 were reviewed. Forty-seven patients were diagnosed with t-MN. Our primary objective was to evaluate the interval to t-MN, response to treatment, and overall survival (OS).ResultsThe median patient age at the MM diagnosis was 65 years. Of the 47 patients, 32 (68.0%) initially received conventional chemotherapeutic agents, 7 (14.9%), novel agents (eg, lenalidomide, thalidomide, bortezomib), and 8 (17.0%), a combination. Twenty patients (42.6%) underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The median interval from the MM diagnosis to t-MN was 7 years (95% CI, 5.0-28.0). Of the 47 patients, 33 (70.2%) developed therapy-related myelodysplastic syndrome (t-MDS), 11 (23.4%) acute myeloid leukemia (t-AML), and 3 (6.4%) chronic myelomonocytic leukemia (t-CMML). The median age at the t-MN diagnosis was 65 years. Of the 47 patients, 26 (78.8%) with t-MDS, 9 (81.8%) with t-AML, and 1 (33.3%) with t-CMML had complex/high-risk cytogenetics. The median OS for all 47 patients after the t-MN diagnosis was 6.3 months (95% CI, 4.0-8.7).ConclusionThe development of t-MN in patients with MM is associated with poor outcomes. These patients, in general, have complex cytogenetic abnormalities and short complete remission and OS times. A better understanding of the disease biology and novel therapeutic approaches are warranted.
| S-EPMC4294996 | biostudies-literature
Project description:Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ?10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ?2 ARCH genes and 52% had ?7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.
| S-EPMC5096889 | biostudies-literature
Project description: Not available
| S-EPMC5093026 | biostudies-literature
Project description:Chronic myelomonocytic leukemia (CMML) can be complicated by autoimmune features associated with rheumatologic disorders, which have been commonly reported by more researches currently. The intrinsic correlation between CMML and autoimmune diseases can create significant pitfalls in differential diagnosis. CMML occasionally presents with clinical and histopathological manifestations that are similar to those of Immunoglobulin G4-related disease (IgG4-RD), a newly recognized systemic autoimmune disorder. Both CMML and IgG4-RD can have significant overlaps due to the common nature of these systemic disorders, especially when atypical clinical phenotypes are present. It is significant for physicians to accurately distinguish CMML and IgG4-RD because the therapy modalities could differ extremely between the two entities. Here we present a unique case of a 70-year-old female who had a condition that mimicked the onset of IgG4-RD not only in terms of clinical manifestations but also in serology and histopathology analyses. Following a series of rigorous examinations, this patient was ultimately diagnosed as having CMML. Herein, we discuss the aspects of IgG4-RD's differential diagnosis and the need for careful comparison of clinical and laboratory features as well as consideration of the pathogenesis of both IgG4-RD and CMML. We also stress a concept that the presence of autoimmune conditions cannot be the sole basis to exclude diagnosis of CMML, as these disorders can appear concomitantly.
| S-EPMC6684895 | biostudies-literature
Project description:Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
| S-EPMC7409251 | biostudies-literature
Project description:The biology, clinical phenotype and progression rate of chronic myelomonocytic leukemia (CMML) are highly variable due to diverse initiating and secondary clonal genetic events. To determine the effects of molecular features including clonal hierarchy in CMML, we studied whole-exome and targeted next-generation sequencing data from 150 patients with robust clinical and molecular annotation assessed cross-sectionally and at serial time points of disease evolution. To identify molecular lesions unique to CMML, we compared it to the related myeloid neoplasms (N=586), including juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and primary monocytic acute myeloid leukemia and discerned distinct molecular profiles despite similar pathomorphological features. Within CMML, mutations in certain pathways correlated with clinical classification, for example, proliferative vs dysplastic features. While most CMML patients (59%) had ancestral (dominant/co-dominant) mutations involving TET2, SRSF2 or ASXL1 genes, secondary subclonal hierarchy correlated with clinical phenotypes or outcomes. For example, progression was associated with acquisition of new expanding clones carrying biallelic TET2 mutations or RAS family, or spliceosomal gene mutations. In contrast, dysplastic features correlated with mutations usually encountered in MDS (for example, SF3B1 and U2AF1). Classification of CMML based on hierarchies of ancestral and subclonal mutational events may correlate strongly with clinical features and prognosis.
| S-EPMC8370480 | biostudies-literature
Project description:BACKGROUND:The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post clofarabine is unknown. METHODS:We reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53%) patients received salvage therapy after clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments. RESULTS:Eight patients achieved complete remission (CR) and three had stable disease for an overall response rate of 19%. With a median follow-up of 3 months from clofarabine failure, 12 patients (11%) remained alive, 5 remain in CR, 4 of them after ASCT. The median overall survival post clofarabine failure was 4 months with a 1-year survival rate of 23%. CONCLUSIONS:This outcome is predictable, with patients with high-risk disease at the time of clofarabine failure having the worse survival. To date, patients with MDS continue to have a short survival after failure of all available therapies. Ultimately, patients who are candidates for additional treatments should be offered novel approaches. In conclusion, the outcome of patients with MDS and CMML post clofarabine failure is poor. The pattern is similar to patients with MDS post hypomethylating agent failure and predictable using University of Texas M. D. Anderson Cancer Center global scoring system.
| S-EPMC3949300 | biostudies-literature
Project description:The impact of bone marrow fibrosis grade on the prognosis of patients with chronic myelomonocytic leukemia (CMML) remains controversial. Therefore, we examined the records of 82 patients diagnosed with CMML at our institution and summarized baseline characteristics and molecular profiles by subgroups of absent or mild (grades 0/1) and moderate (grade 2) fibrosis. Cox proportional hazards models were constructed to assess the prognostic significance of fibrosis grade. Grade 2 fibrosis was identified in 63 patients (76.8%), grade 1 in 16 patients (19.5%), and grade 0 in 3 patients (3.7%). Grade 2 fibrosis was associated with reduced hemoglobin levels (median 9.75 vs 11.0 g/dL in grade 0/1; p = 0.04) and increased percentages of ringed sideroblasts (7.5 vs 0%; p = 0.008). In multivariable analysis, grade 2 fibrosis was an independent predictor of poor overall survival (OS; 95% CI 1.32-6.35; HR 2.90; p = 0.008), but not event-free survival (EFS; 95% CI 0.62-2.67; HR 1.28; p = 0.50). Absolute neutrophil count (ANC) was found to impact OS (95% CI 1.01-1.09; HR 1.05; p = 0.009), while both ANC (95% CI 1.00-1.07; HR 1.04; p = 0.04) and peripheral blood blast percentage (95% CI 1.02-1.32; HR 1.16; p = 0.02) impacted EFS. These results implicate fibrosis grade is an important indicator of prognosis, with high-grade fibrosis predicting inferior survival. Given the prevalence of marrow fibrosis in CMML, fibrosis grading should be incorporated into prognostic assessment and therapeutic decision-making.
| S-EPMC6506234 | biostudies-literature
Project description:The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34+ cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS(G12D) mutation. CD34+ cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS(G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
| S-EPMC6939510 | biostudies-literature
Project description:PurposeChronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.Patients and methodsA total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.ResultsThe most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials.ConclusionsRuxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.See related commentary by Shastri and Adrianzen-Herrera, p. 6069.
| S-EPMC8595542 | biostudies-literature