Latest News on Lymphocytic Leukaemia : Aug – 2020

Latest News on Lymphocytic Leukaemia : Aug – 2020

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia

Ibrutinib (Imbruvica®) is an oral irreversible inhibitor of Bruton’s tyrosine kinase, a B-cell receptor (BCR) signalling kinase expressed by various haematopoietic cells, B-cell lymphomas and leukaemias. The drug is indicated for the treatment of certain haematological malignancies, including chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), which are the focus of this review. In phase III CLL/SLL trials, ibrutinib monotherapy was more effective than chlorambucil in the first-line treatment of elderly patients (RESONATE-2) and more effective than ofatumumab in previously-treated adults (RESONATE). Likewise, a combination of ibrutinib, bendamustine and rituximab was more effective in previously-treated adults than bendamustine plus rituximab in a phase III placebo-controlled study (HELIOS). These ibrutinib regimens were associated with significantly better progression-free survival, overall response rates, and overall survival than the comparators (in protocol-specified or planned analyses), with ibrutinib therapy providing benefit regardless of adverse prognostic factors, such as del(17p)/TP53 mutation and del(11q). Ibrutinib has an acceptable tolerability profile, although certain adverse events (e.g. bleeding and atrial fibrillation) require consideration. Redistribution lymphocytosis can occur, but is not indicative of disease progression. Although longer-term data would be beneficial, ibrutinib is a welcome treatment option for patients with CLL, including those who have higher-risk disease or are less physically fit. Indeed, current EU and US guidelines recommend/prefer the drug for the first- and/or subsequent-line treatment of certain patients, including those with del(17p)/TP53 mutation. [1]

Current and Emerging Treatments for Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Europe and North America. The disease is characterized by proliferation and accumulation of small CD5+ B cells in blood, lymph nodes, spleen, liver and bone marrow. The natural clinical course of CLL is highly variable, and chemotherapy is usually not indicated in early and stable disease. However, patients with progressive and more advanced CLL require treatment. For many years, chlorambucil with or without corticosteroids was used in previously untreated patients with CLL. More recently, purine nucleoside analogues (PNAs) [fludarabine, cladribine and pentostatin] have been included in treatment approaches for this disease, and chlorambucil is no longer the leading standard everywhere. Currently, this drug is rather recommended for the treatment of older, unfit patients with co-morbidities, especially in European countries. Significantly higher overall response (OR) and complete response (CR) rates in patients treated initially with PNAs than in those treated with chlorambucil or cyclophosphamide-based combination regimens have been confirmed in randomized, prospective, multicentre trials. Moreover, PNAs administered in combination with cyclophosphamide produce higher response rates, including CR and molecular CR, compared with PNA as monotherapy.

Recent reports suggest that the administration of monoclonal antibodies (mAbs) can significantly improve the course of CLL. At present, two mAbs have the most important clinical value in patients with CLL. The first is rituximab, a human mouse antibody that targets CD20 antigens, and the second is alemtuzumab, a humanized form of a rat antibody active against CD52. Several recent reports suggest that in patients with CLL, rituximab combined with a PNA can increase the OR and CR rates compared with PNA or rituximab alone, with acceptable toxicity. In randomized trials, the combination of rituximab with fludarabine and cyclophosphamide (FC-R regimen) demonstrated higher rates of OR, CR and progression-free survival in patients with previously untreated and relapsed or refractory CLL than fludarabine plus cyclophosphamide (FC regimen). Several reports have confirmed significant activity with alemtuzumab in relapsed or refractory CLL, as well as in previously untreated patients.

Recently, several new agents have been investigated and have shown promise in treating patients with CLL. These treatments include new mAbs, agents targeting the antiapoptotic bcl-2 family of proteins and receptors involved in mediating survival signals from the microenvironment, antisense oligonucleotides and other agents. The most promising are new mAbs directed against the CD20 molecule, lumiliximab and anti-CD40 mAbs. Oblimersen, alvocidib (flavopiridol) and lenalidomide are also being evaluated both in preclinical studies and in early clinical trials. In recent years, a significant improvement in haematopoietic stem cell transplantation (HSCT) procedures in patients with high-risk CLL has been observed. However, the exact role of HSCT, autologous or allogeneic, in the standard management of CLL patients is still undefined. [2]

From pathogenesis to treatment of chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice. [3]

Clinical and Haematological Pattern of Chronic Lymphocytic Leukaemia in Sudanese Patients

Aims: Chronic lymphocytic leukemia is the most frequent adult leukemia in Western countries accounting for 25 to 30% of all leukemic patients. The clinical and haematological features vary from patient to patient. The aim of this study is to describe the clinical presentation of chronic lymphocytic leukemia, to evaluate haematological patterns of the disease in the peripheral blood and bone marrow and to correlate them with the clinical stage of the disease.

Study Design: This is a retrospective descriptive study.

Place and Duration: Radio Isotope Centre Khartoum (RICK), haematology laboratory during the period of January 2010 to December 2011.

Methodology: The data were collected at the haematology laboratory from patients’ records as well as from a special questionnaire designed for this study. Clinical data, complete blood count, bone marrow examination and immunophenotyping results were used.

Results: Out of 98 cases studied 69 (70.4%) were males and 29 (29.6%) were females. Sixteen patients (16.3%) were less than 50 years old (young patients) and 82 (83.7%) were more than 50 years of age (elderly patients). 49.1% of the patients were from western Sudan. Eight patients (8.2%) were asymptomatic. Absolute lymphocyte count above 5× 109/L had significant association with diffuse pattern of infiltration (P value=0.035) and was not significantly associated with advanced Rai stage (stage III 32.6%, Rai stage IV 22.8%) (P value=0.710).

Conclusion: Clinical and haematological pattern of chronic lymphocytic leukaemia in Sudanese patients has comparable results with previous studies in other parts of the world. Most of the patients were elderly male, from western Sudan presented with nonspecific symptoms, generalized lymphadenopathy and leukocytosis. The majority of patients presented in advanced stage at the diagnosis. [4]

Reference

[1] Deeks, E.D., 2017. Ibrutinib: a review in chronic lymphocytic leukaemia. Drugs, 77(2), pp.225-236.

[2] Robak, T., Jamroziak, K. and Robak, P., 2009. Current and emerging treatments for chronic lymphocytic leukaemia. Drugs, 69(17), pp.2415-2449.

[3] Zenz, T., Mertens, D., Küppers, R., Döhner, H. and Stilgenbauer, S., 2010. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nature Reviews Cancer, 10(1), pp.37-50.

[4] Abd Elgleel Mohammed Ahmed, R. and Mohammed Osman, I. (2017) “Clinical and Haematological Pattern of Chronic Lymphocytic Leukaemia in Sudanese Patients”, International Blood Research & Reviews, 7(1), pp. 1-10. doi: 10.9734/IBRR/2017/31359.

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