Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy

Woyach, Jennifer A.; Smucker, Kelly A.; Smith, Lisa L.; Lozanski, Arletta; Zhong, Yun‐Shi; Ruppert, Amy S.; Lucas, David M.; Williams, Katie; Zhao, Weiqiang; Rassenti, Laura Z.; Ghia, Emanuela M.; Kipps, Thomas J.; Mantel, Rose; Jones, Jeffrey A.; Flynn, Joseph M.; Maddocks, Kami J.; O’Brien, Susan; Furman, Richard R.; James, Danelle F.; Clow, Fong; Lozanski, Gerard; Johnson, Amy J.; Byrd, John C.

doi:10.1182/blood-2013-09-527853

Cited by 251 publications

(232 citation statements)

References 24 publications

Supporting

Mentioning

205

Contrasting

Unclassified

Order By: Relevance

“…A recent analysis from the phase 2 trial of single-agent ibrutinib in patients with relapsed/refractory CLL showed that PR with prolonged lymphocytosis was not associated with inferior PFS outcomes compared with a traditional clinical response. 32 This finding with single-agent ibrutinib 32 along with data from the present study with the combination of ibrutinib and ofatumumab and reported attenuation of lymphocytosis with the combination of ibrutinib and rituximab 36 raises an important question on whether additional targeting of lymphocytosis with anti-CD20 monoclonal antibodies improves long-term PFS/overall survival outcomes over single-agent ibrutinib therapy.…”

Section: Discussionmentioning

confidence: 72%

“…[24][25][26] Ofatumumab is approved in the United States for treatment of CLL refractory to fludarabine and alemtuzumab 27 and in combination with chlorambucil for previously untreated CLL where fludarabine-based treatment is inappropriate. 28,29 Studies with single-agent ibrutinib showed early lymphocytosis in patients with CLL, [30][31][32] which is considered a pharmacodynamic effect of ibrutinib resulting in mobilization of lymphocytes into the peripheral blood from tissue compartments. 18,20 Combining ibrutinib with an anti-CD20 monoclonal antibody to clear blood lymphocytes was thought to reduce the duration and incidence of lymphocytosis, thereby potentially shortening the time to response.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Jaglowski¹,

Jones²,

Nagar³

et al. 2015

Blood

Self Cite

127

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Jaglowski¹,

Jones²,

Nagar³

et al. 2015

Blood

Self Cite

127

View full text Add to dashboard Cite

show abstract

“…Resistance mutations were detected when progressive disease was first observed, but not before treatment or during the initial response to treatment (including lymphocytosis) (14,15). In addition, the CLL cells found during lymphocytosis in nonprogressing patients have been found to be quiescent rather than carrying mutations that confer ibrutinib resistance (30,31).…”

Section: Resistant Mutants Can Have a Selective Advantage In The Absementioning

confidence: 99%

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Komarova

Burger

Wodarz

2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.evolutionary dynamics | drug resistance | personalized medicine | mathematical models | stochastic dynamics

show abstract

“…This phenomenon is due to rapid (<24 hr after drug intake) egress [110] and mobilization of lymphocytes residing in the protective tissue niches of lymph nodes into the peripheral blood [111,112]. These agents interfere with the adhesion molecules, chemokine receptor interactions and homing of CLL cells [113,114].…”

Section: Bcr Signaling Kinase Inhibitorsmentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

137

108

View full text Add to dashboard Cite

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...

show abstract

Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy

Abstract: Key Points Persistent CLL cells during ibrutinib therapy show evidence of biochemical activation, but inhibited BCR and no proliferation. Long lymphocytosis during ibrutinib therapy is not associated with adverse progression-free survival.

Cited by 251 publications

References 24 publications

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL)—Then and now

Contact Info

Product

Resources

About