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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[1]
  • β2-Microglobulin levels >3.5 mg/L are associated with a worse prognosis and poor survival.
  • Over-expression of ZAP-70, CD38, and CD49d, are associated with an unfavourable prognosis (Flow cytometry predictor)
Rai and Binet Staging System for CLL
Risk Stratification Rai Stage Binet Stage
Low risk 0: Lymphocytosis only A: <3 Lymphadenopathies
Intermediate risk I: Lymphadenopathy II: Organomegaly (splenomegaly/hepatomegaly) B: >3 Lymphadenopathies
High risk III: Anemia (hemoglobin <11 g/dL)

IV: Thrombocytopenia (platelets <100 x 109/L)

C: Hemoglobin <10 g/dL and/or platelets <100 x 109/L
Table Data [2]

Therapies

See British Society for Haematology 2019 Guideline [3]

Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib (on PBS)

Second-generation BTKi include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. (not on PBS)[4]

Ibrutinib

Ibrutinib

Ibrutinib (trade name, Imbruvica) is a small molecule drug that binds permanently to B cells Bruton's tyrosine kinase (BTK), but also inhibits multiple related TEC family kinases (contribute to specific ibrutinib toxicities).

  • rash and diarrhea - related to EGFR inhibition
  • increased incidence of atrial fibrillation (AF) and rare ventricular arrhythmia (VA)
  • increased risk for bleeding - serious bleeding episodes observed in patients on warfarin or aspirin


  • 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

  • Available brands - Imbruvica - Janssen-Cilag Pty Ltd (Manufacturer code: JC) 1-5 Khartoum Road, Macquarie Park NSW 2113, Tel:+61 (0)1800 226 334


Links: Pharmaceutical Benefits Scheme (PBS)

Idelalisib

Idelalisib

Idelalisib is a second-line drug for patients whose chronic lymphocytic leukemia (CLL) has relapsed. Used in combination with rituximab, idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions.

Acts as a phosphoinositide 3-kinase inhibitor, blocks delta isoform of the enzyme phosphoinositide 3-kinase (P110δ).

Australian Pharmaceutical Benefits Scheme

  • Available brands - Zydelig

Venetoclax

Venetoclax

Venetoclax (trade name, Venclexta and Venclyxto) is a medication used to treat chronic lymphocytic leukemia (CLL) in those who have failed first line treatment

In January 2017, the drug (marketed as VENCLAXTA) was approved for use by the Australian Therapeutic Goods Administration and made available to Australian patients.


Links: WEHI

Australian Pharmaceutical Benefits Scheme

  • Available brands - Venclexta


Anti-CD20 Monoclonal Antibodies

The CD20 antigen is expressed on the surface of pre–B-lymphocytes and mature B-lymphocytes. After binding to CD20, these monoclonal antibodies activate complement-dependent cytotoxicity and antibody-dependent cell-mediated toxicity directed toward cells that express CD20. Used either in combination with chemotherapy (chemoimmunotherapy) or as single agents.

  • Obinutuzumab
  • Ofatumumab
  • Rituximab


Duvelisib

Duvelisib results in the dual inhibition PI3Kδ and PI3Kγ. Inhibition of the δ isoform results in apoptosis of malignant tumor cells, whereas inhibition of the γ isoform reduces differentiation and migration of support cells in the tumor microenvironment. It also inhibits B-cell receptor signaling pathways and CXCR12-mediated chemotaxis of malignant B-cells. Duvelisib is approved by the FDA and is used in patients with relapsed/refractory CLL who have received at least 2 prior therapies.

Second-generation BTKi


Second-generation Bruton’s Tyrosine Kinase Inhibitors (BTKi) for CCL Treatment
BTK inhibitor BTK binding mechanism Selectivity for BTK Relevant non-BTK targets Clinical Phase
Acalabrutinib Covalent, irreversible High N/A II/III
Zanubrutinib Covalent, irreversible Moderate N/A II/III
Tirabrutinib Covalent, irreversible High N/A I/II
Vecabrutinib Non-covalent, reversible Moderate interleukin-2-inducible (ITK) I/II
LOXO-305 Non-covalent, reversible High N/A I
ARQ-531 Non-covalent, reversible Low Lck/Yes novel tyrosine kinase (LYN),
mitogen-activated protein kinase kinase 1 (MEK1)
I
Table data [4]

Acalabrutinib

Acalabrutinib received an accelerated US FDA approval for patients with relapsed/refractory mantle cell lymphoma in 2017 and is currently being evaluated in chronic lymphocytic leukemia (CLL). To date, ibrutinib is the only Bruton tyrosine kinase (BTK) inhibitor that's approved for treatment of CLL.[5]


Acalabrutinib potently and irreversibly inhibits BTK in vitro and in vivo, while displaying significantly less off-target inhibition of other TEC family.

Acalabrutinib is a second generation BTK inhibitor that binds covalently to the Cys481 residue on BTK and has half maximal inhibitory concentration (IC50) of 3 nM. In preclinical mouse models, acalabrutinib significantly reduced proliferation of CLL cells. Results of Phase I/II trials revealed overall response rates (ORR) of 96% in treatment-naive, 93% in relapsed/refractory and 76% in ibrutinib intolerant patients with CLL. The most common adverse effects (>20%) were grade 1-2 comprising constitutional symptoms, GI toxicity, rash and myelosuppression. There were limited grade 3 or 4 toxicities, involving syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.

Observed adverse events (AE) of any grade

  • headache in 43% of patients
  • diarrhea in 39%
  • weight gain in 26%
  • hypertension in 20%
  • nausea in 20%.
  • Grade 3/4 toxicities were uncommon and included hypertension (7%), pyrexia (3%), fatigue (3%), diarrhea (2%), and arthralgia (2%) with no major bleeding, although petechiae occurred in 16% and contusion in 18% of patients
  • Acalabrutinib in two Mouse Models of Chronic Lymphocytic Leukemia.[6]
  • USA Clinical Trial - NCT02717611 A Phase 2 Study of the Efficacy and Safety of ACP-196 (Acalabrutinib) in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy (60 participants; Study Start Date - Jan 2016; Estimated Study Completion Date - Feb 2020)


Zanubrutinib

Zanubrutinib (BGB-3111, BeiGene, Beijing, CN) is a second-generation irreversible BTKi.

Tirabrutinib

Tirabrutinib (ONO/GS-4059, Ono Pharmaceutical, Osaka, Japan) is a potent and selective second-generation covalent irreversible BTKi, which similar to acalabrutinib demonstrates a high degree of selectivity for BTK.

GDC-0853

GDC-0853 (Genentech, South San Francisco, CA, USA) is a highly selective reversible BTKi with a distinct BTK binding configuration relative to ibrutinib.

Vecabrutinib

Vecabrutinib (SNS-062, Sunesis Pharmaceuticals, South San Francisco, CA, USA) is a potent reversible inhibitor of BTK and ITK currently in clinical development.

LOXO-305

LOXO-305 (Loxo Oncology, Stamford, CT, USA) is a selective, reversible, non-covalent BTKi.


ARQ-531

ARQ-531 (ArQule, Inc., Woburn, MA, USA) is a reversible BTKi, occupies the ATP binding region within the kinase domain of BTK without interaction with C481.


Clinical Trials

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world.

Search: CLL

Recent Papers/Reviews

More recent papers  
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Search term: Chronic lymphocytic leukemia

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).

Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia - A Systematic Review and Meta-analysis

Molica S, Giannarelli D & Montserrat E. (2019). Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis. Clin Lymphoma Myeloma Leuk , , . PMID: 31027992 DOI.

Patients with chronic lymphocytic leukemia (CLL) who achieve undetectable minimal residual disease (U-MRD) (ie, < 10-4 detectable leukemic cells in peripheral blood or bone marrow) have better outcomes than those with detectable MRD. To assess the magnitude of improvement of progression-free survival (PFS) or overall survival (OS) in patients who achieved U-MRD after upfront chemotherapy (CT) or chemo-immunotherapy (CIT), we conducted a systematic review and meta-analysis. MATERIALS AND METHODS: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. RESULTS: Eleven studies comprising 2457 patients with CLL treated in upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Nine studies (n = 2088) provided data on the impact of MRD on PFS and 6 (n = 1234) on OS. MRD was the main endpoint in only 2 of these studies (n = 213). Tests of heterogeneity revealed significant differences among studies for PFS and OS, which highlights differences across studies. U-MRD status was associated with significantly better PFS overall (P < .001) and in patients who achieved conventional complete remission (P = .01). Regarding OS, U-MRD predicted longer OS globally (P < .001) but not in patients having achieved complete remission (P = .82). CONCLUSIONS: U-MRD status after treatment with CT or CIT in newly diagnosed CLL is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of CLL.


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).


Targeting BTK in CLL - Beyond Ibrutinib

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

Purpose of Review While the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL), current limitations include off-target toxicities and the development of resistance. In this review, we summarize the emerging data for alternative BTKi. Second-generation BTKi include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. While these agents may limit off-target toxicity, they do not overcome common mechanisms of ibrutinib resistance. Reversible BTKi including vecabrutinib and LOXO-305 inhibit BTK in the presence of C481S mutation, and non-selective reversible BTKi, including ARQ-531, may retain activity despite mutations within PLCG2. Early-phase studies are underway to establish the clinical efficacy and toxicity of these agents. Summary A randomized trial of ibrutinib versus acalabrutinib is ongoing, and acalabrutinib may be an option for ibrutinib- intolerant patients. Results from ongoing trials of alternate BTKi will help to define their role in CLL therapy as single agents or in combination therapy.


Acalabrutinib and its use in treatment of chronic lymphocytic leukemia

Khan Y & O'Brien S. (2019). Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol , 15, 579-589. PMID: 30381956 DOI.

Acalabrutinib received an accelerated US FDA approval for patients with relapsed/refractory mantle cell lymphoma in 2017 and is currently being evaluated in chronic lymphocytic leukemia (CLL). To date, ibrutinib is the only Bruton tyrosine kinase (BTK) inhibitor that's approved for treatment of CLL. Acalabrutinib is a second generation BTK inhibitor that binds covalently to the Cys481 residue on BTK and has half maximal inhibitory concentration (IC50) of 3 nM. In preclinical mouse models, acalabrutinib significantly reduced proliferation of CLL cells. Results of Phase I/II trials revealed overall response rates (ORR) of 96% in treatment-naive, 93% in relapsed/refractory and 76% in ibrutinib intolerant patients with CLL. The most common adverse effects (>20%) were grade 1-2 comprising constitutional symptoms, GI toxicity, rash and myelosuppression. There were limited grade 3 or 4 toxicities, involving syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.

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

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


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


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

  1. 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.
  2. Sharma S & Rai KR. (2019). Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer , 125, 1432-1440. PMID: 30807655 DOI.
  3. 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.
  4. 4.0 4.1 Bond DA & Woyach JA. (2019). Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep , , . PMID: 31028669 DOI.
  5. Khan Y & O'Brien S. (2019). Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol , 15, 579-589. PMID: 30381956 DOI.
  6. Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, McClanahan F, Harrington BK, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Ulrich R, Johnson AJ, Lannutti BJ, Wiestner A & Woyach JA. (2017). The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clin. Cancer Res. , 23, 2831-2841. PMID: 27903679 DOI.

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.

External Links

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