The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share a common pathobiology of constitutive activation of the JAK and STAT pathway, despite having the 3 distinct phenotypes ...of essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Targeting the JAK-STAT pathway has led to remarkable clinical benefit, including reduction in splenomegaly, amelioration of cytokine-driven symptoms, improvement in quality of life, and even some improvement in survival. However, targeting this pathway has not resulted in consistent disease modification by current metrics, including a reduction in mutant allele burden or reversal of fibrosis. Moreover, targeting JAK-STAT can lead to limiting treatment-emergent side effects, such as anemia and thrombocytopenia. Continued discovery points to a complex system of pathogenesis beyond JAK-STAT driving the formation and evolution of MPNs. This article reviews the successes and limitations of JAK-STAT inhibition, surveys the strategies behind emerging therapies, and discusses the challenges that are present in moving beyond JAK-STAT.
Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia ...occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. The disease often manifests ...with burdensome symptoms and is associated with reduced survival. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first agent approved for MF. As a first-in-class targeted treatment, ruxolitinib approval transformed the MF treatment approach and remains standard of care. In addition, targeted inhibition of JAK1/JAK2 signaling, a key molecular pathway underlying MF pathogenesis, and the large volume of literature evaluating ruxolitinib, have led to a better understanding of the disease and improved management in general. Here we review ruxolitinib efficacy in patients with MF in the 10 years following approval, including demonstration of clinical benefit in the phase 3 COMFORT-I/II trials, real-world evidence, translational studies, and expanded access data. Lastly, future directions for MF treatment are discussed, including ruxolitinib-based combination therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Consensus guidelines have helped to standardize the care of patients with essential thrombocythemia and polycythemia vera, focusing on reducing the risk of thrombosis, mitigating symptoms, and ...avoiding therapies that may accelerate disease progression. However, many unmet needs still exist ranging from the roll of antiplatelet therapy in ET to medications that reduce disease progression. Retrospective studies suggest an improvement in myelofibrosis-free survival for treatment with interferons; new agents are looking to also enact disease modification.
A thoughtful conversation about sexual symptom burden should occur as part of a comprehensive assessment of the overall well‐being of patients with myeloproliferative neoplasms. In the article by ...Geyer et al in this issue of Cancer, the authors quantify the sexuality‐related symptoms, along with quality of life, in patients with myeloproliferative neoplasms, and evaluate how they correspond to disease features and treatment. See also pages 1888‐96.
Myelofibrosis is a rare bone marrow cancer. People with this disease do not live as long as the general population. They have difficult symptoms, can tire easily, and may have a large spleen that can ...be uncomfortable. Ruxolitinib is a treatment for myelofibrosis that can improve symptoms and help patients live longer.
This study asked how treating patients with ruxolitinib affected three things. (1) How often do they go to a healthcare provider? (2) How much do they spend on their healthcare? (3) How long do they live? The authors looked at Medicare records to answer these questions.
The study found that treated patients visited hospitals, doctors' offices, and other services less often. When they did require hospital care, they stayed in the hospital for a shorter amount of time. As a result, treated patients spent about half as much on these services. However, patients treated with ruxolitinib spent more at the pharmacy. Finally, treated patients lived about twice as long as those who were never treated with ruxolitinib. These findings suggest that ruxolitinib is worthwhile for patients with myelofibrosis.
This study evaluated real-world healthcare resource utilization (HCRU), direct costs, and overall survival (OS) of patients who were Medicare beneficiaries and were newly diagnosed with myelofibrosis (MF) who filled ≥1 prescription of ruxolitinib versus those who did not.
This was a study of the US Medicare fee-for-service database. Beneficiaries were aged ≥65 years with an MF diagnosis (index) between January 1, 2012 − December 31, 2017. Data were summarized descriptively. OS was estimated using Kaplan-Meier analysis.
Patients with ≥1 prescription fill of ruxolitinib (n = 2,787) had lower mean rates (per patient per month PPPM) versus patients who did not fill a prescription for ruxolitinib (n = 7,262) for hospitalizations (0.16 vs 0.32), length of inpatient stay (0.16 vs 2.44 days), emergency department visits (0.10 vs 0.14), physician office visits (4.68 vs 6.25), skilled nursing facility stays (0.02 vs 0.12), home health/durable medical equipment services (0.32 vs 0.47), and hospice visits (0.30 vs 1.70). Monthly medical costs were numerically lower in patients who had ≥1 fill of ruxolitinib versus those who did not fill a prescription for ruxolitinib ($6,553 vs $12,929), largely driven by inpatient costs ($3,428 vs $6,689). Pharmacy costs were $10,065 and $987 in patients who filled versus did not fill ≥1 prescription for ruxolitinib, respectively; total PPPM all-cause healthcare costs were $16,618 and $13,916, respectively. The median OS was 37.5 and 18.7 months for the cohorts of patients who filled versus did not fill ≥1 prescription for ruxolitinib, respectively (hazard ratio = 0.63, 95% CI = 0.59 − 0.67).
Ruxolitinib is associated with reduced HCRU and direct costs of medical care in addition to increased survival, suggesting it to be a cost-effective advance for patients with MF.
Decreasing efficacy over time and initial suboptimal response to Janus kinase (JAK) inhibitors such as ruxolitinib in a subset of patients are critical clinical challenges associated with ...myeloproliferative neoplasms (MPNs), primarily myelofibrosis.
The role of phosphatidylinositol-3 kinase (PI3K) in MPN disease progression and treatment resistance and as a potential therapeutic target in patients who experience loss of response to JAK inhibition is discussed. Understanding the complex signaling networks involved in the pathogenesis of MPNs has identified potentially novel therapeutic targets and treatment strategies, such as inhibiting other signaling pathways in addition to the JAK/signal transducer and activator of transcription (STAT) pathway. PI3K plays a crucial role downstream of JAK signaling in rescuing tumor cell proliferation, with PI3Kδ being particularly important in hematologic malignancies. Concurrent targeting of both PI3K and JAK/STAT pathways may offer an innovative therapeutic strategy to maximize efficacy.
Based on our understanding of the underlying mechanisms and the role of PI3K pathway signaling in the loss of response or resistance to JAK inhibitor treatment and initial results from clinical studies, the combination of parsaclisib (PI3Kδ inhibitor) and ruxolitinib holds great clinical potential. If confirmed in larger clinical trials, parsaclisib may provide more treatment options and improve clinical outcomes for patients with MPNs.
Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 ...(JAK2) inhibitor ruxolitinib.
To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.
For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly.
Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT.
Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data.
Overall, 311 patients (mean SD age, 63.70 9.08 years; 171 men 55% and 140 women 45%) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients 45%); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients 18% vs 2 patients 3%; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients 25% vs 10 patients 14%; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients 22% vs 2 patients 3%; P = .001; ≥50% reduction in TSS: 24 patients 32% vs 10 patients 14%; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients 31%, 34 patients 32%, 18 patients 18%), and anemia (28 patients 27%, 23 patients 22%, 14 patients 14%). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%).
In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.
clinicaltrials.gov Identifier: NCT02055781.
Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with ...radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.
Myelodysplastic and myeloproliferative neoplasms (MDS/MPN) is a rare and distinct group of myeloid neoplasms with overlapping MDS and MPN features. Next generation sequencing studies have led to an ...improved understanding of MDS/MPN disease biology by identifying recurrent somatic mutations. Combining the molecular findings to patho-morphologic features has improved the precision of diagnosis and prognostic models in MDS/MPN. We discuss and highlight these updates in MDS/MPN nomenclature and diagnostic criteria per revised 2016 WHO classification of myeloid neoplasms in this article. There is an ongoing effort for data integration allowing for comprehensive genomic characterization, development of improved prognostic tools, and investigation for novel therapies using an international front specific for MDS/MPN. In this article, we discuss updates in prognostic models and current state of treatment for MDS/MPN.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
