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Article ; Online: Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia.

Tawfiq, Reema K / Abeykoon, Jithma P / Kapoor, Prashant

2024

Abstract: Purpose of review: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our ... ...

Abstract	Purpose of review: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. Recent findings: Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4
Language	English
Publishing date	2024-03-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2229765-0
ISSN	1558-822X ; 1558-8211
ISSN (online)	1558-822X
ISSN	1558-8211
DOI	10.1007/s11899-024-00731-0
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Article: Treatment paradigm in Waldenström macroglobulinemia: frontline therapy and beyond.

Zanwar, Saurabh / Abeykoon, Jithma P

Therapeutic advances in hematology

2022 Volume 13, Page(s) 20406207221093962

Abstract: Waldenström macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma. Recent strides made in the genomic profiling of patients with WM have led to the identification of many novel therapeutic targets. Patients with WM can present with ... ...

Abstract	Waldenström macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma. Recent strides made in the genomic profiling of patients with WM have led to the identification of many novel therapeutic targets. Patients with WM can present with asymptomatic disease and not all patients require treatment. When criteria for initiating systemic therapy are met, the choice of therapy depends on the tumor genotype (
Language	English
Publishing date	2022-04-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2585183-4
ISSN	2040-6215 ; 2040-6207
ISSN (online)	2040-6215
ISSN	2040-6207
DOI	10.1177/20406207221093962
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Article ; Online: Frontline Management of Waldenström Macroglobulinemia with Chemoimmunotherapy.

Kapoor, Prashant / Paludo, Jonas / Abeykoon, Jithma P

Hematology/oncology clinics of North America

2023 Volume 37, Issue 4, Page(s) 671–687

Abstract: Despite the introduction of effective novel agents, chemoimmunotherapy (CIT), with its widespread use, retains relevance and is one of the 2 vastly disparate strategies to treat Waldenström macroglobulinemia (WM), the alternative being the Bruton ... ...

Abstract	Despite the introduction of effective novel agents, chemoimmunotherapy (CIT), with its widespread use, retains relevance and is one of the 2 vastly disparate strategies to treat Waldenström macroglobulinemia (WM), the alternative being the Bruton tyrosine kinase inhibitor (BTKi)-based approach. Considerable evidence over the past decades supports the integration of the monoclonal anti-CD20 antibody, rituximab, to the CIT backbone in WM, a CD20+ malignancy. Besides substantial efficacy, the finite duration of the treatment, coupled with lower rates of cumulative and long-term, clinically significant adverse effects and greater affordability, make CIT appealing, notwithstanding the lack of quality-of-life data with such an approach in WM. A phase 3 randomized controlled trial reported substantially higher efficacy and a more favorable safety profile of the bendamustine-rituximab (BR) doublet compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) among patients with WM. Subsequent studies reaffirmed its high efficacy and tolerability, making BR the mainstay of managing treatment-naïve patients with WM. High-quality evidence supporting the use of BR over Dexamethasone, Rituximab, and Cyclophosphamide (DRC), another commonly used regimen, is lacking, as is its comparison with the continuous BTKi-based approach. However, DRC appeared less potent than BR in cross-trial comparisons and retrospective series involving treatment-naïve patients with WM. Additionally, a recent retrospective, international study demonstrated comparable outcomes with fixed-duration BR and continuous ibrutinib monotherapy among previously untreated, age-matched patients exhibiting MYD88
MeSH term(s)	Humans ; Waldenstrom Macroglobulinemia/pathology ; Rituximab/therapeutic use ; Myeloid Differentiation Factor 88/genetics ; Retrospective Studies ; Cyclophosphamide ; Vincristine ; Bendamustine Hydrochloride/therapeutic use ; Prednisone ; Doxorubicin ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic
Chemical Substances	Rituximab (4F4X42SYQ6) ; Myeloid Differentiation Factor 88 ; Cyclophosphamide (8N3DW7272P) ; Vincristine (5J49Q6B70F) ; Bendamustine Hydrochloride (981Y8SX18M) ; Prednisone (VB0R961HZT) ; Doxorubicin (80168379AG)
Language	English
Publishing date	2023-05-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	93115-9
ISSN	1558-1977 ; 0889-8588
ISSN (online)	1558-1977
ISSN	0889-8588
DOI	10.1016/j.hoc.2023.04.003
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Article ; Online: Monoclonal gammopathy of undetermined significance: evaluation, risk assessment, management, and beyond.

Abeykoon, Jithma P / Tawfiq, Reema K / Kumar, Shaji / Ansell, Stephen M

Faculty reviews

2022 Volume 11, Page(s) 34

Abstract: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant state for a spectrum of lymphoplasmacytic malignancies. The risk of progression of MGUS to a symptomatic therapy requiring plasma cell dyscrasia is about 1% per year. Studies ... ...

Abstract	Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant state for a spectrum of lymphoplasmacytic malignancies. The risk of progression of MGUS to a symptomatic therapy requiring plasma cell dyscrasia is about 1% per year. Studies carried out over the previous 10 years have improved risk stratification of MGUS based on serologic and genomic evaluations, which has led to better management of patients. In this review, we address the epidemiology, diagnosis, and pathogenesis of MGUS and discuss risk-adapted best practice approaches to monitor patients.
Language	English
Publishing date	2022-11-29
Publishing country	England
Document type	Journal Article ; Review
ISSN	2732-432X
ISSN (online)	2732-432X
DOI	10.12703/r/11-34
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Article ; Online: BRAF testing modalities in histiocytic disorders: Comparative analysis and proposed testing algorithm.

Acosta-Medina, Aldo A / Abeykoon, Jithma P / Go, Ronald S / Goyal, Gaurav / Ravindran, Aishwarya / Schram, Susan M / Rech, Karen L

American journal of clinical pathology

2023 Volume 160, Issue 5, Page(s) 483–489

Abstract: Objectives: Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to ... ...

Abstract	Objectives: Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to compare performance of testing modalities, to propose a framework for evaluation of BRAFV600E mutation status in histiocytic disorders. Methods: We retrospectively reviewed patients with histiocytic disorders and BRAF mutation testing on a lesional tissue specimen. Results: In 120 patients, BRAF assessment included immunohistochemistry (IHC) in 97 (80.2%), polymerase chain reaction (PCR) in 35 (28.9%), and next-generation sequencing (NGS) in 62 (51.2%). Forty-five underwent both NGS and IHC. With NGS as the gold standard, the sensitivity and specificity of IHC were 82.4% and 96.4%. Three false negatives were observed in biopsy specimens with low BRAFV600E variant allele frequency or decalcified tissue. One false-positive IHC was observed in a lung biopsy specimen, likely due to antibody cross-reactivity with respiratory cilia. Among 14 with successful NGS and PCR, a single discordance was observed. Two PCR-to-IHC discrepancies were observed, including one other false-positive IHC. Conclusions: Immunohistochemistry was highly specific for detection of BRAFV600E. Main caveats were false negatives and lack of detection of non-BRAFV600E mutations. We propose the use of IHC as initial screening in general practice with reflex molecular testing if negative.
MeSH term(s)	Humans ; Proto-Oncogene Proteins B-raf/genetics ; Retrospective Studies ; Mutation ; Sensitivity and Specificity ; Algorithms
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; BRAF protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2944-0
ISSN	1943-7722 ; 0002-9173
ISSN (online)	1943-7722
ISSN	0002-9173
DOI	10.1093/ajcp/aqad076
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Article ; Online: Spectrum of second primary malignancies and cause-specific mortality in pediatric and adult langerhans cell histiocytosis.

Goyal, Gaurav / Parikh, Richa / Richman, Joshua / Abeykoon, Jithma P / Morlote, Diana / Go, Ronald S / Bhatia, Smita

Leukemia research

2023 Volume 126, Page(s) 107032

Abstract: With the advent of targeted therapeutics in Langerhans cell histiocytosis (LCH), there is a growing survivor population that might be at risk for late mortality from non-LCH causes, including second primary malignancies (SPMs). We undertook a large study ...

Abstract	With the advent of targeted therapeutics in Langerhans cell histiocytosis (LCH), there is a growing survivor population that might be at risk for late mortality from non-LCH causes, including second primary malignancies (SPMs). We undertook a large study using the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the patterns of SPMs and cause-specific mortality among individuals with LCH (2000-2016) from the US. We found an increased risk of SPMs in the cohort (standardized incidence ratio [SIR] 2.07). The pediatric group was at a high risk of developing Hodgkin lymphoma (SIR 60.93) and non-Hodgkin lymphoma (SIR 60.88). People with adult-onset LCH were found to have a high risk of developing miscellaneous malignant cancers (SIR 11.43), which primarily included myelodysplastic syndrome. Adults were also at a high risk of developing carcinoma in-situ of vulva at 2-11 months [SIR 62.72] and B-ALL at 60-119 months [SIR 66.29] after LCH diagnosis. Additionally, 5% and 1% of the patients developed prior or concomitant malignancies with LCH, respectively. The 5 yr overall survival (OS) was 96.6% for pediatric and 88.5% for adult LCH cohorts. Most common cause of death was infections in pediatric and SPMs in adult LCH. Our study highlights that despite advances in treatments, people with LCH have an increased mortality risk from non-LCH causes when compared with the general population, including a high risk of SPMs.
MeSH term(s)	Female ; Humans ; Adult ; Child ; Neoplasms, Second Primary/diagnosis ; Cause of Death ; SEER Program ; Histiocytosis, Langerhans-Cell ; Hodgkin Disease/complications
Language	English
Publishing date	2023-02-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/j.leukres.2023.107032
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Article ; Online: Monocyte response to SARS-CoV-2 protein ORF8 is associated with severe COVID-19 infection in patients with chronic lymphocytic leukemia.

Ruan, Gordon J / Wu, Xiaosheng / Gwin, Kimberly A / Manske, Michelle K / Abeykoon, Jithma P / Bhardwaj, Vaishali / Witter, Taylor L / Schellenberg, Matthew J / Rabe, Kari G / Kay, Neil E / Parikh, Sameer A / Witzig, Thomas E

Haematologica

2024

Abstract: The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would ...

Abstract	The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe COVID-19. We tested ORF8 ex vivo on peripheral blood mononuclear cells (PBMCs) from 26 anonymous healthy blood donors and measured intracellular cytokine/chemokine levels in monocytes by flow cytometry. The % monocytes staining positive in the sample and change in mean fluorescence intensity (ΔMFI) after ORF8 were used to calculate the adjusted MFI for each cytokine. We then tested pre-COVID-19 PBMC samples from 60 CLL patients who subsequently developed COVID-19 infection. Severe COVID-19 was defined as hospitalization due to COVID-19. In the 26 normal donor samples, the adjusted MFI for interleukin (IL)-1β, IL-6, IL-8, and CCL-2 were significantly different with ORF8 stimulation vs controls. We next analyzed monocytes from pre-COVID-19 PBMC samples from 60 CLL patients. The adjusted MFI to ORF8 stimulation of monocyte intracellular IL-1β was associated with severe COVID-19 and a reactive ORF8 monocyte response was defined as an IL- 1β adjusted MFI ≥ 0.18 (sensitivity 67%, specificity 75%). The median time to hospitalization after infection in CLL patients with a reactive ORF8 response was 12 days versus not reached for patients with a non-reactive ORF8 response with a hazard ratio of 7.7 (95% CI: 2.4-132, p=0.005). These results provide new insight on the monocyte inflammatory response to virus with implications in a broad range of disorders involving monocytes.
Language	English
Publishing date	2024-04-24
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284617
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Article ; Online: Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Ruan, Gordon J / Zanwar, Saurabh / Ravindran, Aishwarya / Schram, Susan / Abeykoon, Jithma P / Hazim, Antonious / Young, Jason R / Shah, Mithun V / Bennani, N Nora / Jiang, Liuyan / Morlote, Diana / Rech, Karen L / Goyal, Gaurav / Go, Ronald S

American journal of hematology

2024 Volume 99, Issue 5, Page(s) 871–879

Abstract: Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January ... ...

Abstract	Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.
MeSH term(s)	Humans ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Histiocytic Sarcoma/genetics ; Histiocytic Sarcoma/therapy ; Histiocytic Sarcoma/pathology ; Macrophages/pathology ; Bone Marrow/pathology ; Prognosis ; Liver/pathology
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.27263
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Article ; Online: The promise of the gut microbiome as part of individualized treatment strategies.

Schupack, Daniel A / Mars, Ruben A T / Voelker, Dayne H / Abeykoon, Jithma P / Kashyap, Purna C

Nature reviews. Gastroenterology & hepatology

2021 Volume 19, Issue 1, Page(s) 7–25

Abstract: Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and ... ...

Abstract	Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.
MeSH term(s)	Gastrointestinal Diseases/diagnosis ; Gastrointestinal Diseases/etiology ; Gastrointestinal Diseases/therapy ; Gastrointestinal Microbiome ; Humans ; Liver Diseases/diagnosis ; Liver Diseases/etiology ; Liver Diseases/therapy ; Precision Medicine
Language	English
Publishing date	2021-08-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/s41575-021-00499-1
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Article ; Online: Non-tender recurrent scrotal cellulitis.

Abeykoon, Jithma P / Paludo, Jonas / Enzler, Mark

Postgraduate medical journal

2018 Volume 94, Issue 1111, Page(s) 310

Language	English
Publishing date	2018-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	80325-x
ISSN	1469-0756 ; 0032-5473
ISSN (online)	1469-0756
ISSN	0032-5473
DOI	10.1136/postgradmedj-2017-135170
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