Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia

Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the occidental countries. Until now, it is considered a chronic disease without a cure. The development of new molecular therapies have showed that the cure may be an option. This protocol propose a triple sequential therapy with three direct therapies for the leukemic cell: an inhibitor of Bruton´s tyrosine kinase (ibrutinib), a second generation monoclonal antibody versus CD20 (obinutuzumab) and a BCL-2 inhibitor (venetoclax) as treatment of first or second line in CLL. Objective: Negativize the minimal residual disease and by this way obtain longer survivals (overall survival and relapse free survival). Design: This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study coordinated by the "Grupo Cooperativo de Hemopatías Malignas" situated on Hospital Angeles Lomas in Huixquilucan, México. The study, is a phase II clinical study that will employ three target therapy drugs in sequencing phases. It will start with a BTK inhibitor as induction, later an anti-CD20 will be used for consolidation and it will end with a BH3 analog as maintenance for one year. The primary outcome is the negativization of minimal residual disease.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Patients diagnosed with B cell chronic lymphocytic leukemia according to 2017 WHO criteria by immunophenotype/immunohistochemistry with active disease according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and do not present TP53 mutation and/or del(17)p. (Cohort 1).
* Patients diagnosed with relapsed/refractory chronic lymphocytic leukemia that have previously received at least one line of treatment that does not include the drugs in the study scheme. (Cohort 2).
* Functional stage of 0 - 2 measured by the Eastern Cooperative Oncology Group (ECOG) scale.
* Creatinine depuration ≥ 30 ml/min measured in a 24-hour urine recollection or utilizing the CKD-EPI formula.
* Proper liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in patients with Gilbert syndrome, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.
* Capacity and willingness to provide a written informed consent.

Exclusion Criteria:

* T cell lymphocytic leukemia diagnosis.
* TP53 mutation and/or del(17)p presence.
* Non-controlled systematic active infection (viral, bacterial and/or fungic).
* Patients with known infection by human immunodeficiency virus (HIV).
* Active infection by hepatitis B (defined as the presence of detectable HBV's DNA, HBe antigen or HBs antigen). Patients with serological evidence of previous vaccination (HBsAg negative, anti-HBs positive antibodies, anti-HBc negative antibodies) are eligible. The patients that are HBsAg negative/ anti-Hbs positive antibodies but anti-HBc positive antibodies are eligible, if the HBV DNA is negative, and the HBV-DNA PCR is realized every 12 months after the last cycle of treatment.
* Active infection by hepatitis C, defined by the ribonucleic acid (RNA) of hepatitis C is detectable in plasma by polymerase chain reaction (PCR).
* Significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure or acute myocardial infarction within 2 months prior to screening, or any class 3 or 4 heart disease according to the functional classification of the NYHA.
* Diagnosis of previous malignancies for 2 years, with exception of patients with basal or squamous cell carcinoma or "in situ" carcinoma of cervix or breast.
* Requiring therapy with inhibitors or potent inducers of CYP3A4 and CYP3A5 inhibitors.
* Anticoagulant therapy with acenocoumarol or warfarin.
* History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to screening.
* History of allergic reaction or severe anaphylaxis to humanized or murine monoclonal antibodies.
* Pregnant or lactating women.

• BACKGROUNDHallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner 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. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018 Jun 21;131(25):2745-2760. doi: 10.1182/blood-2017-09-806398. Epub 2018 Mar 14. PMID 29540348
• BACKGROUNDRai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016 Mar;91(3):330-40. doi: 10.1002/ajh.24282. PMID 26690614
• BACKGROUNDGarcia Marco JA, Giraldo Castellano P, Lopez Jimenez J, Rios Herranz E, Sastre Moral JL, Terol Castera MJ, Bosch Albareda F; en representacion del Grupo Espanol de Leucemia Linfatica Cronica (GELLC); Sociedad Espan ola de Hematologi a y Hemoterapia. [National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan ola de Hematologi a y Hemoterapia and Grupo Espan ol de Leucemia Linfoci tica Cro nica]. Med Clin (Barc). 2013 Aug 17;141(4):175.e1-8. doi: 10.1016/j.medcli.2013.04.041. Epub 2013 Jul 3. Spanish. PMID 23830547
• BACKGROUNDCartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. doi: 10.1182/blood-2014-07-586610. Epub 2014 Aug 20. PMID 25143487
• BACKGROUNDFarooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. doi: 10.1016/S1470-2045(14)71182-9. Epub 2014 Dec 31. PMID 25555420