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1. CLL: clinical casesCelso Arrais
2. Conflict of InterestsI declare NO relevant conflict of interests in:Honoraria: noConsulting: noResearch funding: noAdvisory boards: noPatents e Royalties: noDiscussing Off-label drugs: no
3. Case 1: Venetoclax + obinutuzumab first-line
4. Case 1: Venetoclax + obinutuzumab first-line69 year-old, femaleHypertension, insulin-dependent diabetes, COPD2005: Asymptomatic lymphocytosisCLL Binet A – no risk stratification performed2014: Symptomatic axillary lymph nodes (+/- 2 cm)Observation2016: Treatment indication – enlarged cervical lymph nodes and right axillary conglomerate (11 cm)Risk stratification performed (FISH, TP53, IGHV)
5. Questions to be discussedRole of stratification at diagnosis or only before treatmentMinimal essential exams at diagnosisTreatment indications
6. Questions to be discussedRole of cytogenetics at diagnosis or only before treatmentMinimal essential laboratory tests at diagnosisTreatment indications
7. Questions to be discussedRole of cytogenetics at diagnosis or only before treatmentMinimal essential laboratory tests at diagnosisTreatment indications (IWCLL)
8. TREATMENT INDICATIONS - IWCLLHallek M et al. Blood. 2018 Jun 21;131(25):2745-2760. 1Linfonodos > 10cm ou sintomáticos2Citopenias3Esplenomegalia sintomática4Duplicação de Linfócitos (LDT) <6m ou um aumento ≥ 50% em 2m5Anemia autoimune refratária e/ou trombocitopenia6Sintomas B:Sintomas constitucionais7AcometimentoExtranodalHallek M et al. Blood. 2018 Jun 21;131(25):2745-2760.
9. “CONSERVATIVE” TREATMENT INDICATIONS - GBCLL1Linfonodos > 10cm ou sintomáticos2Citopenias3Esplenomegalia sintomática4Duplicação de Linfócitos (LDT) <6m ou um aumento ≥ 50% em 2m5Anemia autoimune refratária e/ou trombocitopenia6Sintomas B:Sintomas constitucionais7AcometimentoExtranodalHallek M et al. Blood. 2018 Jun 21;131(25):2745-2760. Morais F. et al. IWCLL 2021.
10. Morais F. et al. IWCLL 2021.ICESP | UNIFESP | Santa Casa | Sirio Libanes | Hemomed“CONSERVATIVE” TREATMENT INDICATIONS - GBCLLN = 590 patients: Mar/2013 – Mar/2020Median follow-up: 40 months4 centers from the Brazilian Registry of CLL
11. Morais F. et al. IWCLL 2021.N = 590 patients: Mar/2013 – Mar/2020Median follow-up: 40 months4 centers from the Brazilian Registry of CLLOS in patients with treatment indication according to the IWCLL“CONSERVATIVE” TREATMENT INDICATIONS - GBCLL
12. IGHV: unmutatedFISH: 17p deletion in 158/200 interphasesTP53 not availableNo metaphases (PB karyotyping)No health insurancePatient from a public university hospitalAlemtuzumab or HD steroids+R: only available optionsEnrolled in the CLL14 trialVen-G armCase 1: Venetoclax + obinutuzumab first-line
13. Nov/16Feb/17Hemoglobin10.711.8WBC139,3802,580ANC7,560940ALC130,8301120Platelets 113,000127,000Right axillary lymph nodes: 11cm >>> 1 cm in 30 daysCase 1: Venetoclax + obinutuzumab first-line
14. Nov/16Feb/17May/17Aug/17Hemoglobin10.711.813.513.6WBC139,3802,5805,7207,520ANC7,5609402,8505,020ALC130,830112019802,180Platelets 113,000127,000206,000172,000Right axillary lymph nodes: 11cm >>> 1 cm in 30 daysG-CSF for severe neutropenia used 2 times in the first 2 months onlyCase 1: Venetoclax + obinutuzumab first-line
15. Nov/16Feb/17May/17Aug/18Hemoglobin10.711.813.513.6WBC139,3802,5805,7207,520ANC7,5609402,8505,020ALC130,830112019802,180Platelets 113,000127,000206,000172,000Right axillary lymph nodes: 11cm >>> 1 cm in 30 daysBy May 2023, remains in complete remission, MRD negativeCase 1: Venetoclax + obinutuzumab first-line
16. Questions to be discussedTreatment for 1st line del17p and/or TP53 : iBTK or iBCL2?Role of associations in first lineBest treatment option for relapsed CLL after 1st line Ven-GEarly relapses (<24 months)Late relapses
17. Second-line therapiesBRCLLClinical outcomes of second-line treatment in patients with CLL included in the Brazilian Registry of CLL (BRCLL)Second-line treatments for 444 CLL patients were analyzedMedian age: 66 years (range: 23-93), 264 were male (59%)Unmutated IGHV in 61% of patientsFISH performed in 166 patients (37%): 33 patients del(17p) - 20%Treatment regimensFC (+/-R) -36%Chlorambucil (+/- R) – 25%Ibrutinib – 14%CVP/CHOP (+/- R) – 14%Monoclonal antibodies (+/- steroides) – 7%Allogeneic stem cell transplantation – 2%Venetoclax – 2%Lacerda MP et al. Blood (2022) 140 (Supplement 1): 7041–7042.
18. Second-line therapiesBRCLLClinical outcomes of second-line treatment in patients with CLL included in the Brazilian Registry of CLL (BRCLL)Second-line treatments for 444 CLL patients were analyzedMedian age: 66 years (range: 23-93), 264 were male (59%)Unmutated IGHV in 61% of patientsFISH performed in 166 patients (37%): 33 patients del(17p) - 20%Treatment regimensFC (+/-R) -36%Chlorambucil (+/- R) – 25%Ibrutinib – 14%CVP/CHOP (+/- R) – 14%Monoclonal antibodies (+/- steroides) – 7%Allogeneic stem cell transplantation – 2%Venetoclax – 2%83%inadequateLacerda MP et al. Blood (2022) 140 (Supplement 1): 7041–7042.
19. Second-line therapiesBRCLLPatients in clinical trials: 3-year TFS 70% vs. 38%OS at 3 years: 80% targeted therapies vs. 53% for CHOP-like vs.69% for FC/chlb-basedMedian follow-up after second-line treatment: 34 months (range: 3-176)Time to next treatmentLacerda MP et al. Blood (2022) 140 (Supplement 1): 7041–7042.
20. Case 2: Ibrutinib second-line
21. NRP, 58 years old, maleHypertension and dyslipidemia2012 - asymptomatic lymphocytosis CLL - Binet A Watch and WaitNo risk stratification performedMay/17: Symptomatic lymphadenopathy 6 FCR PR (↓ 50% lymphadenopathy)No risk stratification performedCase 2: Ibrutinib second-line
22. December /2017 (one month after the end of FCR)Intensive fatigue, progressive lymphadenopathyPhysical Examination:Left cervical 3 cm (largest axis)Right axillary 6 cm (largest axis) Case 2: Ibrutinib second-line
23. BRAZILIAN REGISTRY OF CLL
24. BRAZILIAN REGISTRY OF CLL2573 (80.5%) from public hospitals 622 (19.5%) from private hospitalsAmong public hospitals, 1792 (70%) at university hospitals 871 (30%) at non-university hospitalsThe majority were male (56%), Binet A (53%) Median age was 65 years (23 - 106)FISH for del(17p): 532 patients (17%)IGVH mutational status: 272 patients (9%)Karyotype:253 patients (8%)Pfister et al. eJHaem.2022;3:698–706.
25. December/2017 (one month after the end of FCR)FISH: normal TP53: not availableIGHV: unmutatedSPEP: 3 M-spikes in the gammaglobulin zone (0,27; 0,15 e 0,06g/dL)Serum immunoglobulins: normalCase 2: Ibrutinib second-line
26. January/2018: Ibrutinib was startedWell tolerated in the first 6 monthsIron deficiency anemia in September/2018Odynophagia EGDEsophageal candidiasisSevere lymphopenia - CD4 57/mm3Case 2: Ibrutinib second-line
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28. Colonoscopy: diverticulosis and angiodysplasiaUnresponsive to intravenous ferric carboxymaltoseCase 2: Ibrutinib second-line
29. Questions to be discussedOff-target side effects of BTKiManagement of anemia as sign of platelet dysfunction due to ibrutinibT-cell lymphodepletion
30. Colonoscopy: diverticulosis and angiodysplasiaUnresponsive to intravenous ferric carboxymaltoseJanuary/2019: Ibrutinib was withdrawnVenetoclax started after ramp upMarch/2019: Rapidly progressive lymphadenopathyBiopsy: Diffuse large B-cell lymphoma (Richter’s syndrome)(external pathologist)Case 2: Ibrutinib second-line
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33. Pathology review by specialized hematopathologist:Expanded proliferation centers with increased mitotic activity, Ki-67 labeling 50%“Accelerated” CLLNo criteria for Richter’s transformationCase 2: Ibrutinib second-line
34. Questions to be discussedManagement of Richter’s in 2023Management of “accelerated” CLLStart ibrutinib again? Change to acalabrutinib / zanubrutinib?Still a role for cellular therapy (allo HSCT / CAR-T) if R/R to both classes in young and fit patients?At best response or at first progression?
35. Brazilian Registry of CLLThanks to all participating centers, patients and families!Celso Arraiscelsoarrais@gmail.com Carlos Sérgio Chiattonecarlos.chiattone@terra.com.brMatheus Vescovi Gonçalvesmatheus.vescovi@gmail.comVerena Pfisterverena.registro@abhh.org.br (data manager)Flávia Parraflavia.registro@abhh.org.br (data manager)Fernanda Marquescelsoarrais@gmail.com
36. Hospital Nove de JulhoHospital São PauloRoberta SzorVinicius MollaPedro Henrique MoraesRoberta AzevedoCainã DabbousPedro MaranhãoAna Carolina MaiaVerena PfisterFernanda MoraisMihoko YamamotoMatheus VescoviVinicius MollaAna Marcela RojasPedro Henrique MoraesRayana BomfimRoberta AzevedoThank you!