scholarly journals Primary Myelofibrosis-Related Renal Disorders Treated with a Janus Kinase Inhibitor

2021 ◽  
pp. 1-9
Author(s):  
Mea Asou ◽  
Tomohiko Asakawa ◽  
Makoto Araki ◽  
Takashi Ehara ◽  
Tsunekazu Hishima ◽  
...  
Keyword(s):  
Interstitial Nephritis ◽  
Kinase Inhibitor ◽  
White Blood Cells ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Detailed Examination ◽  
Extramedullary Hematopoiesis ◽  
Janus Kinase ◽  
Interstitial Tissue ◽  
Renal Disorders

Extramedullary hematopoiesis is widely known to occur in patients with primary myelofibrosis (PMF). Autopsy studies on individuals with PMF revealed that extramedullary hematopoiesis occurred in the kidneys in 35% of the cases, but there is little awareness regarding such lesions. A 63-year-old man was diagnosed with PMF based on a detailed examination of persistent high white blood cells. An examination of the patient’s medical records revealed an increased white blood cell count, deterioration of kidney function, and urinary protein excretion developed simultaneously. Thus, a kidney biopsy was performed. Advanced lymphocyte invasion was recognized in the interstitial tissue, and the tubular structure was highly disrupted. Based on these findings, he was diagnosed with interstitial nephritis. However, because of the large number of cells with nuclear atypia in the stroma, additional immunohistochemical staining was also performed, such as glycophorin A, naphthol AS-D, myeloperoxidase, and CD42b. As a result, invasion of three lineages of immature cells, erythroblasts, megakaryocytes, and granulocytes, was identified. Renal dysfunction resulting from interstitial cellular infiltration due to extramedullary hematopoiesis was therefore diagnosed. Treatment with ruxolitinib was initiated after a renal biopsy and the rate of decline in renal function was slightly reduced. Although, in myeloproliferative disorders, proliferative glomerular lesions are widely considered to be renal disorders, there is little awareness regarding interstitial lesions. Extramedullary hematopoiesis of the kidney in PMF is not uncommon, but 40% of cases are reportedly misdiagnosed as interstitial nephritis. Because extramedullary hematopoiesis can be controlled by ruxolitinib, early detection is important.

scholarly journals Evaluation of Ruxolitinib versus Best Available Therapy in Treating Primary Myelofibrosis

2021 ◽  
Author(s):  
Kawa M. Hasan ◽  
Ahmed Y. Elmeshhadany ◽  
Nazar P. Shabila
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitor ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
Risk Groups ◽  
Janus Kinase ◽  
Response To Treatment ◽  
International Prognostic Scoring System ◽  
Janus Kinase Inhibitor ◽  
Treatment Groups

Objectives: Ruxolitinib is a Janus kinase inhibitor (JAK) that is approved for the treatment of myelofibrosis. The therapeutic protocol has changed after the introduction of Ruxolitinib. The aim of this study was to evaluate the effectiveness of Ruxolitinib and to compare it with best available therapy in patients with primary myelofibrosis. Methods: In this retrospective study, 72 patients with primary myelofibrosis were scrutinized in the period from 2012 to 2018 at Nanakali hemato-oncology teaching center, Erbil, Iraqi Kurdistan. The patients were divided into 2 cohorts, 26 of them were treated with Ruxolitinib and 46 others received best available therapy. The patients’ characteristics, their response to treatment, and the outcomes were evaluated. The efficacy of treatment in both arms was compared. Results: The majority our studied patients (46, 63.8%) were in the high and intermediate-2 risk groups according to international prognostic scoring system. At time of diagnosis, there were no noticeable differences in the clinical characteristics and laboratory data among the Ruxolitinib and best available treatment groups of patients. Ruxolitinib was found to be effective in reducing the size of spleen and improving the overall survival when compared to best available treatment group (p<0.001, p= 0.008 respectively). The patients’ performance state had a significant effect on the overall survival in both treatment groups (p=0.003). Conclusion: Ruxolitinib has a significant role in reduction of spleen size, and potentially affect the survival outcomes in patients with myelofibrosis. Keywords: Ruxolitinib, Myelofibrosis, Splenomegaly, Outcomes.

scholarly journals Janus kinase inhibitors: jackpot or potluck?

2012 ◽  
pp. e13
Author(s):  
Pavithran Keechilat ◽  
Shripad Brahmanand Pande
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Current Evidence ◽  
Federal Drug Administration ◽  
Janus Kinase Inhibitors

The reports of a unique mutation in the Janus kinase-2 gene (JAK2) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

scholarly journals A patient with a germline GATA2 mutation and primary myelofibrosis

2021 ◽  
Vol 5 (3) ◽  
pp. 791-795
Author(s):  
Cyrill V. Rütsche ◽  
Eugenia Haralambieva ◽  
Veronika Lysenko ◽  
Stefan Balabanov ◽  
Alexandre P. A. Theocharides
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Bone Marrow Failure ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Janus Kinase Inhibitor ◽  
Key Points

Key Points First description of a patient with a germline GATA2 mutation and diagnosis of primary myelofibrosis. Development of bone marrow failure on a Janus kinase inhibitor.

Persistent foot ulcer due to ruxolitinib therapy for primary myelofibrosis

2017 ◽  
Vol 24 (3) ◽  
pp. 226-228 ◽  
Author(s):  
Michael Del Rosario ◽  
Henry Tsai ◽  
Constantin A Dasanu
Keyword(s):  
Scientific Literature ◽  
Kinase Inhibitor ◽  
Wound Care ◽  
Foot Ulcer ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Oral Agent ◽  
Bone Marrow Fibrosis ◽  
Janus Kinase Inhibitor ◽  
Marrow Fibrosis

Primary myelofibrosis is characterized by bone marrow fibrosis, splenomegaly and presence of JAK-2 V617F mutation in more than 90% of patients. Ruxolitinib is a Janus kinase inhibitor used for the treatment of primary myelofibrosis. We describe herein a persistent foot ulcer development attributed to ruxolitinib therapy. We are unaware of any previous reports of this phenomenon in the scientific literature. A thorough examination of the lower extremities is perhaps necessary before initiating this oral agent. If ruxolitinib therapy cannot be safely discontinued, diligent wound care and a course of antibiotics are warranted.

scholarly journals The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis

2020 ◽  
Vol 11 ◽  
pp. 204062072092520
Author(s):  
Jeanne Palmer ◽  
Ruben Mesa
Keyword(s):  
Kinase Inhibitor ◽  
Clinical Investigation ◽  
Symptom Burden ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
First Line ◽  
Myeloid Neoplasm ◽  
Duration Of Response ◽  
Line Setting ◽  
Secondary Myelofibrosis

Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by either primary myelofibrosis, or secondary MF following essential thrombocythemia or polycythemia vera. Historically, therapy has been symptom directed; however, in 2011, the first janus kinase inhibitor (JAK-i) – ruxolitinib – was approved for treatment. This medication was found to be effective in reduction of symptom burden and spleen size; however, the median duration of response is about 3 years. In addition, many patients are intolerant or develop toxicities to ruxolitinib, including patients with anemia, as well as thrombocytopenia. Therefore, there is a critical need for alternate therapeutic options for patients with MF. Additional JAK-i have been developed over the last 8 years, including fedratinib, momelotinib, and pacritinib. Fedratinib recently received approval for treatment of MF both in the first-line and second-line setting. It has shown efficacy in the first-line setting, as well as in 30% of patients who are refractory/intolerant of ruxolitinib. This review covers the trials that have led to the approval of ruxolitinib as well as fedratinib, as well as reviews of two JAK inhibitors that are still under clinical investigation: momelotinib and pacritinib.

scholarly journals Janus kinase inhibitors: jackpot or potluck?

2012 ◽  
Vol 6 (1) ◽  
pp. 13
Author(s):  
Pavithran Keechilat ◽  
Shripad Brahmanand Pande
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Current Evidence ◽  
Federal Drug Administration ◽  
Janus Kinase Inhibitors

The reports of a unique mutation in the Janus kinase-2 gene (<em>JAK2</em>) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

Jak2 Exon 12 Mutational Status in a Cohort of Idiopathic Erithrocytosis V617F Negative Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4648-4648
Author(s):  
Martina Bernardi ◽  
Marco Ruggeri ◽  
Elena Albiero ◽  
Domenico Madeo ◽  
Silvia Finotto ◽  
...  
Keyword(s):  
Clinical Features ◽  
Peripheral Blood ◽  
High Performance ◽  
White Blood Cells ◽  
Myeloproliferative Disorders ◽  
Janus Kinase ◽  
Who Criteria ◽  
Erythroid Hyperplasia ◽  
Mutational Status ◽  
Idiopathic Erythrocytosis

Abstract Background: V617F gain-of-function mutation in exon 14 of Janus Kinase 2 gene (JAK2) has been recognized as a major pathogenetic event of many cases of chronic myeloproliferative disorders, in particular in Polycythemia Vera (PV). The molecular basis of myeloproliferative disorders in patients without the V617F is still unclear but, recently, four new heterozygous allelic variants affecting JAK2 exon 12 have been described in V617F negative patients receiving a diagnosis of PV or Idiopathic Erythrocytosis (IE) (Scott et al, NEJM 2007). Revised WHO criteria for PV have been proposed considering these mutations as indicative for PV diagnosis (Tefferi et al, 2007). Aim: To determine the JAK2 exon 12 mutational status in patients with IE in a cohort of 40 consecutive IE V617F negative patients; 2 PV patients, V617F negative, were also included. 36 males and 6 females with a median age of 63 years (range: 25–85), median follow-up 109 months (range: 7–205) were studied. IE was diagnosed in presence of increased haemoglobin (>186 gr/L) and hematocrit levels (>51%) and normal white blood cells and platelet counts. In addition, no splenomegaly, and a normal or low serum erythropoietin (Epo) levels were present along with a bone marrow biopsy showing erythroid hyperplasia with normal megakaryopoiesis and granulopoiesis. They were treated only with phlebotomy therapy. PV was diagnosed according to the WHO criteria. Methods: Granulocytes were isolated from the lower interface of a density gradient separation of peripheral blood samples; the granulocytes were then submitted to erythrocytes lysis (mean purity of the granulocytes 97%) and DNA was extracted. Exon 12 was amplified using the couple of JAK2exon12F (5′-ctcctctttggagcaattca-3′) and JAK2exon12R (5′-caatgtcacatgaatgtaaatcaa-3′) primers. The amplicons were submitted to denaturing high performance liquid chromatography (dHPLC) analysis and runs were performed at 53° C. The amplicons showing a heteroduplex profile were sequenced directly in both strands. Results: 4 of the 40 (10%) IE patients were heterozygous positive for N542-E543del JAK2 exon 12 mutation; both PV patients were negative for JAK2 exon 12 mutations (figure 1). Conclusion: N542-E543del JAK2 was found only in 10% of patients with a diagnosis of IE, a frequency lower than that previously reported (Scott et al, NEJM 2007). This result could be due to the low levels of mutation prevalence in peripheral blood granulocytes. The sensitivity could be increase using erythroid colonies grown on colture media. In addition, different patients selection criteria could explain our results. Accordingly with the proposed revised WHO criteria for Polycythemia, a diagnosis of PV instead of IE should be made in these four patients. figure 1: Clinical features of patients with JAK2 exon 12 mutations and Idiopathic Erythrocytosis. figure 1:. Clinical features of patients with JAK2 exon 12 mutations and Idiopathic Erythrocytosis.

scholarly journals Cementless bipolar hemiarthroplasty in a patient with PMF: a case report

2019 ◽  
Vol 2019 (11) ◽  
Author(s):  
Abdullah A Alturki ◽  
Nayf A Alshammari ◽  
Firas M Alsebayel ◽  
Ali A Alhandi
Keyword(s):  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Bipolar Hemiarthroplasty ◽  
Myeloproliferative Disease ◽  
Neck Of Femur ◽  
Janus Kinase Inhibitor ◽  
History Of ◽  
Neck Of Femur Fracture

Abstract Myelofibrosis is a myeloproliferative disease that falls under a group of bone marrow malignancies known as myeloproliferative neoplasms. It manifests with splenomegaly, anemia, leukocytosis and, less commonly, bone pain. Ruxolitinib, Janus kinase inhibitor, has been shown to increase survival, to improve symptoms and has the potential to decrease osteosclerotic changes. Herein, we present a case of primary myelofibrosis (PMF) in a 60-year-old female who presented with 8-month history of progressive left hip pain and later was diagnosed with pathological neck of femur fracture that was treated with cementless hemiarthroplasty. In conclusion, the use of cementless implants in hip arthroplasty in the presence of PMF has shown to be an effective and safe choice.

scholarly journals Cryptococcal fungemia and Mycobacterium haemophilum cellulitis in a patient receiving ruxolitinib: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Naruemit Sayabovorn ◽  
Piriyaporn Chongtrakool ◽  
Methee Chayakulkeeree
Keyword(s):  
Amphotericin B ◽  
Kinase Inhibitor ◽  
Opportunistic Infections ◽  
Kidney Injury ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
First Case ◽  
Atypical Pathogens ◽  
The Right ◽  
Mycobacterium Haemophilum

Abstract Background Ruxolitinib is a novel oral Janus kinase inhibitor that is used for treatment of myeloproliferative diseases. It exhibits potent anti-inflammatory and immunosuppressive effects, and may increase the risk of opportunistic infections. Here, we report a rare case of Cryptococcus neoformans and Mycobacterium haemophilum coinfection in a myelofibrosis patient who was receiving ruxolitinib. Case presentation A 70-year-old Thai man who was diagnosed with JAK2V617F-mutation-positive primary myelofibrosis had been treated with ruxolitinib for 4 years. He presented with cellulitis at his left leg for 1 week. Physical examination revealed fever, dyspnea, desaturation, and sign of inflammation on the left leg and ulcers on the right foot. Blood cultures showed positive for C. neoformans. He was prescribed intravenous amphotericin B deoxycholate with a subsequent switch to liposomal amphotericin B due to the development of acute kidney injury. He developed new onset of fever after 1 month of antifungal treatment, and the lesion on his left leg had worsened. Biopsy of that skin lesion was sent for mycobacterial culture, and the result showed M. haemophilum. He was treated with levofloxacin, ethambutol, and rifampicin; however, the patient eventually developed septic shock and expired. Conclusions This is the first case of C. neoformans and M. haemophilum coinfection in a patient receiving ruxolitinib treatment. Although uncommon, clinicians should be aware of the potential for multiple opportunistic infections that may be caused by atypical pathogens in patients receiving ruxolitinib.

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