Chronic Lymphocytic Leukemia

Jain, Preetesh; O’Brien, Susan

doi:10.1002/9781118468678.ch13

Cited by 2 publications

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“…After several months of treatment, lymphocyte counts returned to, or dropped below, baseline level. This redistribution of CLL cells 34 , 35 followed by reduction in peripheral blood lymphocyte counts implies that ruxolitinib might exert a therapeutic effect, possibly by inducing apoptosis of mobilized CLL cells. 14 However, because our trial was designed to assess the effect of ruxolitinib on patients’ symptom and patients with a significant disease burden were not included, these preliminary observations should be taken with caution.…”

Section: Discussionmentioning

confidence: 97%

“…Like ibrutinib 34 and other BCR signaling inhibitors, 35 ruxolitinib decreased lymph node size and increased peripheral blood lymphocyte counts, likely by reducing chemokine levels and mobilizing CLL cells from bone marrow and lymph nodes into the peripheral blood. After several months of treatment, lymphocyte counts returned to, or dropped below, baseline level.…”

Section: Discussionmentioning

confidence: 99%

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Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Jain

Keating

Renner

et al. 2017

The Lancet Haematology

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Summary Background Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. Currently available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates Janus kinase (JAK)-2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms of patients with myelofibrosis, we hypothesized that ruxolitinib would improve disease-related symptoms in CLL patients. Methods Ruxolitinib (10 mg twice daily) was administered to symptomatic CLL patients who did not require systemic therapy for CLL. Scores on the brief fatigue inventory (BFI), CLL module of the MD Anderson symptom inventory (MDASI) and symptom-associated interference in daily activities (interference score; IS), were assessed prior to treatment and after 3 months of treatment. Plasma cytokine/chemokine levels were measured at baseline and at 3 months. Findings Forty-one CLL patients (25 untreated and 16 previously treated) were enrolled. Thirty-two (78%) of the participants experienced ≥20% reduction in the average BFI score or in the average MDASI score. 59% of the participants had ≥2 units reduction in worst fatigue score in 24 hours as assessed by the BFI. The mean percentage reductions in BFI, MDASI, and IS scores were >42% (p<0.0001). Improvements in the three symptom scores correlated with reductions in levels of IL-6, C-reactive protein, CXCL10, osteopontin, TNF-α, ICAM-1/CD54, VCAM-1/CD106, and beta-2 microglobulin. Furthermore, treatment with ruxolitinib increased and then decreased lymphocyte counts to baseline levels or lower. Grade 3/4 cytopenias were recorded in three patients. Interpretation In CLL patients, ruxolitinib significantly improved disease-related symptoms, reduced cytokine and chemokine levels, and increased and then decreased lymphocyte counts, likely through mobilization followed by apoptosis of CLL cells. Further studies aimed at testing the therapeutic efficacy of ruxolitinib in CLL are warranted. Funding Supported by the Incyte Corp., MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Jain

Keating

Renner

et al. 2017

The Lancet Haematology

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Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

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108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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Chronic Lymphocytic Leukemia

Cited by 2 publications

References 182 publications

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Chronic lymphocytic leukemia (CLL)—Then and now

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