Chronic lymphocytic leukemia (CLL)—Then and now

Abstract

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...

Systemic eosinophilia with skin and pulmonary infiltrates in a patient with chronic lymphocytic leukemia: A case report

“…In the mid to late 2000s, standard first line treatment of CLL changed from single agent chemotherapy to rituximab-based chemoimmunotherapy. [41] As our patient was treated prior to approval of rituximab for CLL in Switzerland, he was unable to benefit from this development. Currently, anti-CD20 monoclonal antibodies (rituximab, ofatumumab or obinutuzumab) in combination with chemotherapeutic agents are standard of care in treatment of CLL.…”

“…[44,45] Recently, another paradigm shift in treatment of relapsed or refractory CLL has been heralded by the introduction of promising new treatment concepts including inhibition of Bruton's tyrosine kinase (BTK), phospoinositide 3-kinase (PI3K) delta or B-cell lymphoma 2 (Bcl2) and many other novel agents. [41,42] Given the extended treatment armamentarium available nowadays and in the near future, this elderly patient would probably not be treated with fludarabine today.…”

“…Currently, anti-CD20 monoclonal antibodies (rituximab, ofatumumab or obinutuzumab) in combination with chemotherapeutic agents are standard of care in treatment of CLL. [41,42] Considering the current approach for elderly patients with CLL, this patient would most likely have received a chemoimmunotherapeutic treatment regimen such as obinutuzumab/chlorambucil [42,43] or rituximab/bendamustine. [44,45] Recently, another paradigm shift in treatment of relapsed or refractory CLL has been heralded by the introduction of promising new treatment concepts including inhibition of Bruton's tyrosine kinase (BTK), phospoinositide 3-kinase (PI3K) delta or B-cell lymphoma 2 (Bcl2) and many other novel agents.…”

Possibilities of therapy recurrent b-cell chronic lymphocytic leukemia associated with autoimmune complications: data from literature and personal observation

“…В основе патогенеза болезни лежит дефект апоптоза в циркулирующих клетках ХЛЛ, находя-щихся в фазах G 0 /G 1 , и активная пролиферация клеток ХЛЛ, происходящая в специализированных нишах микро-окружения, так называемых центрах пролиферации [1,2].…”

Long-term Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Standard Therapy

“…With the FISH analysis, at least five forecasting alterations have been identified: in 13q14, trisomy 12, in 11q22-23, in 13p13 and in 17p; these chromosome anomalies range from a good to a bad forecast With immunogenetics techniques, it is possible to identify mutated or unmutated LCL cells, with worse results in the latter kind [12,13]. Through sequencing, many mutations have been identified; there are four forecasting implications at least: NOTCH1, SF3B1, BIRC3 and TP5 (fludarabin refractories); these are all related to a bad forecast [14,15]. The CD38 and CD49 level increase and the ZAP70 incidence are equally related to a bad forecast [12,16].…”