Therapeutic Options for Patients with TP53 Deficient Chronic Lymphocytic Leukemia: Narrative Review

Figures & data

Table 1 Genetic and Molecular Prognostic Factors in CLL

Markers of Very Low Risk	Markers of Low Risk	Markers of Intermediate Risk	Markers of Poor Prognosis
13q14 deletion only	Trisomy 12* Normal genetics	11q22-q23 deletion Mutations in SF3B1 Mutations in NOTCH1	TP53 aberrations Complex karyotype Unmutated IGHV genes High expression of ZAP-70, CD-38, CD49d mutations in BIRC3

Notes: Data from references,^{12,13,16,19,21,25,27–29,43} *Döhner et al¹⁶ considered trisomy 12 as a marker of intermediate risk.

Abbreviation: IGHV, immunoglobulin heavy-chain.

Figure 1 p53 structure and functions. The tp53 protein has two N-terminal transactivation domains, a central DNA binding domain, C-terminus involved in down regulation of DNA binding of the central domain and an oligomerization domain, which is essential for transcriptional activity.^48,49 In response to cellular stress p53 is activated which leads to promotion of the elimination or repair of damaged cells.^47,48 Interestingly, other “non–canonical” functions of p53, contributing to its effects, are still being discovered.^48,52,53

Table 2 Current Treatment Options for Patients with CLL with TP53 Disrupted (Outside the Context of Clinical Trials)

Drug/Procedure	Indications in CLL and SLL	Date of FDA Approval
Ibrutinib	Frontline therapy in adult patients	First approval in February, 2014 (for patients who have received at least one previous therapy), then the indications have been expanded
Ibrutinib+rituximab	Initial treatment of adult patients	April, 2020
Ibrutinib+obinotuzumab	Treatment-naïveadultpatient	January, 2019
Ibrutinib+bendamustine+rituximab	Patientsa after at least one prior therapy	May, 2016
Idelalisib+rituximab	R/R CLL, in adultpatients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities	July,2014
Acalabrutinib	Adult patients	November, 2019
Duvelisib	Adult patients with R/R CLL after at least two prior therapies	September, 2018
Venetoclax	Adult patients who have relapsed or are not suitable for treatment with BCR inhibitors	First approval in April, 2016 (for patients with CLL who have 17p deletion and who have been treated with at least one prior therapy), then the indications have been expanded
Venetoclax+obinotuzumab	Adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitors	EMA approval:January, 2020
allo-HSCT	High risked disease and lower transplant risk (young, fit patients with well-matched donors)

Note: Data from references.^{18,69,72,91,93,94}

Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; FDA, Food and Drug Administation; R/R CLL, relapsed/refractory chronic lymphocytic leukemia; EMA, European Medicines Agency; allo-HSCT, allogenic hematopoietic stem cell transplantation.

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