Talk:Immune System - Abnormalities

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Chronic Lymphocytic Leukaemia

 ICD-11 Mature B-cell neoplasms

2A82.0 Chronic lymphocytic leukaemia or small lymphocytic lymphoma

An indolent, mature B-cell neoplasm composed of small, round B-lymphocytes. When the bone marrow and peripheral blood are involved, the term chronic lymphocytic leukemia is used. The term small lymphocytic lymphoma is restricted to cases which do not show leukemic involvement of the bone marrow and peripheral blood.

• Dohner’s Hierarchical CLL Classification (2000) identified p53 poor prognosis

Therapies

See British Society for Haematology 2019 Guideline

Ibrutinib

Ibrutinib (trade name, Imbruvica) is a small molecule drug that binds permanently to B cells Bruton's tyrosine kinase (BTK).

• 2016 - ibrutinib cost US$116,600 to $155,400 a year wholesale in the United States.
• 2018 - Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme.

Australian Pharmaceutical Benefits Scheme

ibrutinib 140 mg capsule, 120

ibrutinib 140 mg capsule, 120 (PI, CMI) 1 120 5 $11662.09 $40.30

General Patient Charge $40.30 Available brands - Imbruvica

ibrutinib 140 mg capsule, 90

ibrutinib 140 mg capsule, 90 (PI, CMI) 1 90 5 $8784.33 $40.30

General Patient Charge $40.30

Links: Pharmaceutical Benefits Scheme (PBS)

Recent Papers/Reviews

Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia

Edelmann J & Gribben JG. (2017). Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia. J Oncol Pract , 13, 371-377. PMID: 28605616 DOI.

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

• B-cell receptor inhibitors - ibrutinib and idelalisib
• BH3 mimetic - venetoclax

Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options

Bond DA & Woyach JA. (2019). Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep , , . PMID: 31028669 DOI.

Within a period of just over a decade, managing chronic lymphocytic leukemia (CLL) has become more effective and yet more challenging than ever before. The important improvement in the treatment of CLL can be ascribed to the availability of many new options, mainly with the development of novel targeted therapies, such as ibrutinib, idelalisib, duvelisib and venetoclax. There are now newer tests that reliably define high-risk patients, and treatment plans can be tailored accordingly. Overall, this indeed is a new era in the treatment of patients with CLL. However, despite this progress, CLL remains an incurable disease and continues to remain challenging. In this brief review, the authors highlight the many great choices available to clinicians who manage patients with CLL and focus on the sequencing of these choices based on the available data.

Guideline for the treatment of chronic lymphocytic leukaemia

A British Society for Haematology Guideline

Schuh AH, Parry-Jones N, Appleby N, Bloor A, Dearden CE, Fegan C, Follows G, Fox CP, Iyengar S, Kennedy B, McCarthy H, Parry HM, Patten P, Pettitt AR, Ringshausen I, Walewska R & Hillmen P. (2018). Guideline for the treatment of chronic lymphocytic leukaemia: A British Society for Haematology Guideline. Br. J. Haematol. , 182, 344-359. PMID: 30009455 DOI.

• Chemoimmunotherapy is ineffective in patients with TP53 disruption, defined by either deletion of chromosome 17p or mutation in the TP53 gene. As alternative agents are available, it is therefore essential that all patients are tested for the presence of both deletions AND mutations of TP53 before each line of therapy.

• The results of TP53 testing should be interpreted in light of the sensitivity of the diagnostic methodologies used. The definition of test sensitivity should always be established as part of the clinical laboratory accreditation process and sensitivity thresholds should be included in the diagnostic report.

• Tests forTP53 disruption should be performed on all patients prior to each line of therapy, should include both mutation and deletion detection (GRADE IB) and ideally should also reveal subclonalTP53 mutations (GRADE IIA).

Treatment of patients with TP53 disruption (deletions and/or mutations)

Compelling data has been published on the treatment of patients with TP53 disruption with BCRi, namely idelalisib with rituximab or ibrutinib monotherapy, or the BCL2 inhibitor venetoclax (Furman et al, 2014; Farooqui et al, 2015; O'Brien et al, 2016; Stilgenbauer et al, 2016). Although the majority of TP53‐disrupted patients in these studies were treated at relapse, similarly high ORR and superior PFS were observed in the few patients with TP53‐disrupted CLL treated in front‐line. These favourable outcomes led to the current licensing of these drugs for front‐line treatment of TP53‐disrupted CLL, and to subsequent National Institute for Health and Care Excellence (NICE) approval of ibrutinib monotherapy and idelalisib with rituximab for this indication. However, ongoing pharmacovigilance revealed a higher risk of infection and death with idelalisib therapy than previously noted (Lampson et al, 2016), leading the European Medicine Agency (EMA) to review its license for idelalisib, and to recommend idelalisib for “first‐line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies”. The same guidance also recommended that all patients should undergo regular cytomegalovirus (CMV) monitoring and pneumocystis jiroveci pneumonia (PJP) prophylaxis.

Recommendation

• Ibrutinib is the treatment of choice in front‐line therapy for patients with TP53 disruption and is now NICE approved (GRADE IB).

• Idelalisib and rituximab combination therapy is a suitable alternative for patients for whom ibrutinib is deemed inappropriate, such as patients with significant cardiac disease or patients receiving vitamin K antagonists, and is also NICE approved (GRADE IB).

Relevance of TP53 for CLL diagnostics

Catherwood MA, Gonzalez D, Donaldson D, Clifford R, Mills K & Thornton P. (2019). Relevance of TP53 for CLL diagnostics. J. Clin. Pathol. , 72, 343-346. PMID: 30712002 DOI.

TP53 disruption in chronic lymphocytic leukaemia (CLL) is a well-established prognostic marker and informs on the appropriate course of treatment for patients. TP53 status is commonly assessed by fluorescence in situ hybridisation for del(17 p) and Sanger sequencing for TP53 mutations. At present, current screening methods for TP53 mutations fail to detect diagnostically relevant mutations potentially leading to inappropriate treatment decisions. In addition, low levels of mutations that are proving to be clinically relevant may not be discovered with current less sensitive techniques. This review describes the structure, function and regulation of the TP53 protein, the mutations found in cancer and CLL, the relevance of TP53 disruption in CLL and the current screening methods for TP53 mutations including next-generation sequencing.

Genomic aberrations and survival in chronic lymphocytic leukemia

Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M & Lichter P. (2000). Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. , 343, 1910-6. PMID: 11136261 DOI.

BACKGROUND: Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications. METHODS: Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22-23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings. RESULTS: Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (7 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality; the median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients in the 17p- and 11q-deletion groups had more advanced disease than those in the other three groups. Patients with 17p deletions had the shortest median treatment-free interval (9 months), and those with 13q deletions had the longest (92 months). In multivariate analysis, the presence or absence of a 17p deletion, the presence or absence of an 11q deletion, age, Binet stage, the serum lactate dehydrogenase level, and the white-cell count gave significant prognostic information. CONCLUSIONS: Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression and survival. These findings have implications for the design of risk-adapted treatment strategies.

References

Reviews

Sharma S & Rai KR. (2019). Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer , 125, 1432-1440. PMID: 30807655 DOI.

Bond DA & Woyach JA. (2019). Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep , , . PMID: 31028669 DOI.

Articles

Edelmann J & Gribben JG. (2017). Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia. J Oncol Pract , 13, 371-377. PMID: 28605616 DOI.