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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.


Diagnosis

  • presence of equal or greater than 5 x 109/L B lymphocytes in the peripheral blood, sustained for at least 3 months
  • CLL cells co-express the surface antigen CD5 together with the B-cell antigens CD19, CD20, and CD23.
  • Each clone of leukemia cells is restricted to expression of either κ or γ immunoglobulin light chains


  • 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)
  • Unfavourable chromosomal abnormalities - deletion of the short arm of chromosome 17 (del17p) and of the long arm of chromosome 11 (del11q). (FISH)
  • TP53 mutation (determined by DNA sequencing with cutoff of 10%)
  • leukemia cells with a complex karyotype (equal or greater than 3 chromosomal abnormalities) may have adverse prognostic significance.
  • Palpable spleen - greater 6 cm below the left costal margin or progressive or symptomatic splenomegaly.
  • Palpable liver (clinically enlarged).
  • Studies have demonstrated that treating early stage, asymptomatic disease has no survival benefit.



Overall Survival Prognostic Markers

  1. Age
  2. Clinical stage
  3. TP53 mutation status
  4. IGHV mutation status
  5. Serum β2-microglobulin level


In general practice, patients with asymptomatic early-stage disease (Rai 0, Binet A), should be monitored without therapy unless they have evidence of disease progression or disease-related symptoms.


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]

Rai staging system[3] The modified Rai classification defines low-risk disease as occurring in patients who have lymphocytosis with leukemia cells in the blood and/or marrow (formerly considered Rai stage 0). Patients with peripheral blood lymphocytosis, enlarged lymph nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not) are defined as having intermediate-risk disease (formerly considered Rai stage I or II). High-risk disease includes patients with disease-related anemia (as defined by a haemoglobin [Hb] level less than 1 g/dL) (formerly stage III) or thrombocytopenia (as defined by a platelet count of less than 100 x 109/L; formerly stage IV).


Binet staging system[4] The Binet staging system is based on the number of involved lymphoid areas, as defined by the presence of enlarged lymph nodes equal or greater than 1 cm in diameter or organomegaly, and on whether there is anemia or thrombocytopenia.


Everything You Need to Know About Genetic Testing and CLL

FISH test

  • trisomy 12, which is an extra copy of chromosome 12.
  • loss of the long arm of chromosome 11, which is 11q deletion.
  • loss of the short arm of chromosome 17, 17p deletion, which affects the TP 53 gene, which people know, that is the only one of these that really affects our treatment decisions once a person needs treatment. Because, that has historically been associated with not as good responses to chemo-immunotherapy, for example. So, we moved to novel agents immediately.
  • usually include a test for—a translocation between chromosomes 11 and 14, which is important to make sure that there is not overlap with another kind of lymphoma called mantle cell lymphoma. And that test also gives us information on whether there are any abnormalities of chromosome 14, which is also a recurrent abnormality in about 7 percent of CLLs in our patient cohort.


Jennifer R. Brown, MD, PhD Director, Chronic Lymphocytic Leukemia Center Dana-Farber Cancer Institute.

Therapies

See British Society for Haematology 2019 Guideline [5]

Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib (on PBS)[6]

Second-generation BTKi include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. (not on PBS)[7]

TP53 mutation respond poorly to chemo(immuno)therapy but fare significantly better when treated with non-chemotherapeutic agents, such as small molecule inhibitors of BTK, phosphatidylinositol 3-kinase, or BCL2.[8]

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

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; ABT-199, GDC-0199, VEN) is a medication used to treat chronic lymphocytic leukemia (CLL) in those who have failed first line treatment. Small molecules binding to BCL-2 family anti-apoptotic factors (BCL-2 family inhibitors) able to mimic the function of pro-apoptotic BH3-only proteins (BH3s) directly induces apoptosis independently of TP53. Venetoclax displays the activity in patients with del17p/TP53 mutation and in patients failing on ibrutinib or other BCR pathway inhibitors. Combination of venetoclax with other targeted drugs, in particular with anti-CD20 monoclonal antibodies or BCR pathway inhibitors, seems to be very promising in CLL treatment.[9]


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

Venetoclax in the treatment of chronic lymphocytic leukemia.[9]

Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.


Links: WEHI

Australian Pharmaceutical Benefits Scheme

  • Available brands - Venclexta

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 [7]

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.[10]


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
  • Severe arthritic syndrome [11]
  • Acalabrutinib in two Mouse Models of Chronic Lymphocytic Leukemia.[12]


  • 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.[13] Lower off-target inhibitory activity on other kinases, including ITK JAK3 and EGFR.[14]


Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia.[15]

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.

Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or refractory B-cell malignancies in Japan[16]

Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B-cell NHL/CLL.

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.

Spebrutinib

Spebrutinib (CC-292) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL.[17]

Bendamustine - chemotherapy is in the alkylating agents family of medication. It works by interfering with the function of DNA and RNA. Structural similarities to both alkylating agents (nitrogen mustard derivative) and purine analogues (benzimidazole ring). Its structure and configuration is aimed at reducing the toxicity of the nitrogen mustard moiety.

Not Suitable for p53 Loss

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.

Clinical Trials

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

Search: CLL

Recent Papers/Reviews

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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 for TP53 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 subclonal TP53 mutations (GRADE IIA).

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O'Brien S, Robak T, Seymour JF & Kipps TJ. (2018). iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood , 131, 2745-2760. PMID: 29540348 DOI.

The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.


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.


Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF & Kipps TJ. (2015). Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N. Engl. J. Med. , 373, 2425-37. PMID: 26639149 DOI.

First published phase 3 study establishing ibrutinib as a frontline therapy for patients with CLL.

BACKGROUND: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS: Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

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.


Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

Boudny M, Zemanova J, Khirsariya P, Borsky M, Verner J, Cerna J, Oltova A, Seda V, Mraz M, Jaros J, Jaskova Z, Spunarova M, Brychtova Y, Soucek K, Drapela S, Kasparkova M, Mayer J, Paruch K & Trbusek M. (2019). Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. Haematologica , , . PMID: 30975914 DOI.

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is therefore of critical importance. Herein, we detail anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G2/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγnull) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.

Older Papers

A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis

Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S & Gremy F. (1981). A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer , 48, 198-206. PMID: 7237385


Survivals of two series of CLL patients (99 from a retrospective series and 196 from a prospective series) were studied separately. The three main staging systems (Rai, Binet, Rundles) agreed well, but as far as survival is concerned, too many stages are defined. The authors performed a Cox multivariate analysis of survival in order to isolate important prognostic factors at diagnosis and to use them to build a simple three-stage classification. Thrombopenia and anemia appeared as the most important risk factors. Among the nonanemic and nonthrombopenic patients, the number of involved areas was clearly related to prognosis in the authors' two series. This study allowed the authors to propose a new classification in three prognostic groups. Group C: anemia (Hb less than 10 g) and/or thrombopenia (platelets less than 100,000/mm3); about 15% of the patients; median of 2 years. Group B: no anemia, no thrombopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver); about 30% of patients; median of 7 years. Group A: no anemia, no thrombopenia, less than three involved areas; about 55% of patients; the survival of this group does not seem different from that of the French population of the same age and sex distribution. This three-stage classification only requires clinical examination and routine hemogram, has a good prognostic value which was confirmed on the series of Montserrat and Rozman (146 patients), and should therefore be helpful in planning new clinical trials.

Clinical staging of chronic lymphocytic leukemia

Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN & Pasternack BS. (1975). Clinical staging of chronic lymphocytic leukemia. Blood , 46, 219-34. PMID: 1139039

A method of clinical staging of chronic lymphocytic leukemia (CLL) has been proposed which is based on the concept that CLL is a disease of progressive accumulation of nonfunctioning lymphocytes: stage O, bone marrow and blood lymphocytosis only; stage 1, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia. Analysis of 125 patients. in the present series showed the following median survival times (in months) from diagnosis: stage 0, is greater than 150; stage I 101; stage II, 71; stage III, 19; stage IV, 19, The median survival for the entire series was 71 mo. The prognostic significance of the stage remained even after adjustment was made for age and sex. However, both sex and age were shown to be poor predictors of survival after adjustment for stage. The method of staging proved to be a reliable predictor of survival whether used at diagnosis or during the course of the disease. The proposed staging system was an equally accurate indicator for survival when applied to two other previously published studies of large series of patients.


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. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN & Pasternack BS. (1975). Clinical staging of chronic lymphocytic leukemia. Blood , 46, 219-34. PMID: 1139039
  4. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S & Gremy F. (1981). A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer , 48, 198-206. PMID: 7237385
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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.

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