The ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

• MeSH
• adenin * analogy a deriváty   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   mortalita   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• piperidiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrazoly * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• MeSH
• adenin * analogy a deriváty   terapeutické užití   MeSH
• chemorezistence * MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• inhibitory proteinkinas * terapeutické užití   škodlivé účinky   MeSH
• lidé MeSH
• piperidiny * terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyraziny terapeutické užití   MeSH
• pyrazoly * terapeutické užití   MeSH
• pyrimidiny * terapeutické užití   MeSH
• thiazoly terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Nejnovější poznatky v biologii chronické lymfocytární leukemie (CLL) mají významný dopad na léčbu tohoto onemocnění. Buňky CLL vykazují závislost na zvýšené expresi BCL-2, autonomní BCR signalizaci a vyznačují se nadměrnou expresí delta izoformy p110 PI3K kinázy a BTK kinázy, která podporuje přežívání nádorových buněk. Cílená léčba monoklonálními protilátkami rituximabem a obinutuzumabem spolu s malými molekulami, jako je ibrutinib, idelalisib a venetoklax, výrazně rozšířila terapeutické možnosti, což vedlo ke zlepšení celkového přežití pacientů. V této souvislosti je pozoruhodné, že pacienti, kteří zahájili léčbu ibrutinibem, vykazují míru přežití srovnatelnou s celkovou populací. Ne všechny problémy spojené s CLL však byly vyřešeny, neboť stále přetrvávají otázky týkající se dysfunkce imunitního systému a sekundárních malignit, jednotnosti léčebných přístupů pro pacienty s vysokým a nízkým rizikem, dlouhodobých strategií pro mladé pacienty a terapie pro pacienty s Richterovou transformací. Přestože inhibitory BTK a BCL-2 mohou pozitivně ovlivnit imunitní systém, problémy spojené s infekcemi a sekundárními nádory přetrvávají. Pokud jde o Richterovu transformaci, identifikace specifických genetických abnormalit může v budoucnu umožnit cílenější a účinnější léčbu, včetně terapie CAR-T a bispecifických protilátek.

New findings in the biology of chronic lymphocytic leukemia (CLL) have major implications for the treatment of this disease. CLL cells exhibit a dependence on increased expression of BCL-2, an autonomous BCR signaling pathway, and are charac­terized by overexpression of the p110 PI3K delta kinase isoform and BTK kinase, which promotes tumor cell survival. Targeted therapies such as the monoclonal antibodies rituximab and obinutuzumab, along with small molecules such as ibrutinib, idelalisib, and venetoclax, have dramatically expanded therapeutic options, resulting in improved overall patient survival. In this context, it is note­worthy that patients starting treatment with ibrutinib have survival rates comparable to the general population. However, not all issues have been resolved, as there are questions regarding the immune system, consistency in treatment approaches and long-term strategies for young patients, especially those with Richter transformation. Although BTK and BCL-2 inhibitors can positively influence the immune system, we still face challenges related to infections and secondary tumors. Regarding Richter transformation, identification of specific genetic abnormalities may allow more targeted and effective therapies in the future, including CAR-T therapy and bispecific antibodies.

• Klíčová slova
• Richterova transformace,
• MeSH
• chronická lymfatická leukemie farmakoterapie   genetika   patologie   MeSH
• imunitní systém imunologie   patologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 genetika   MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protinádorové látky aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové léčby MeSH
• protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH

Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).

• MeSH
• adenin * analogy a deriváty   farmakologie   MeSH
• chronická lymfatická leukemie * farmakoterapie   metabolismus   genetika   patologie   MeSH
• forkhead box protein O1 * metabolismus   genetika   MeSH
• fosforylace MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny metabolismus   genetika   MeSH
• piperidiny * farmakologie   MeSH
• protein RICTOR * genetika   metabolismus   MeSH
• proteinkinasa BTK metabolismus   genetika   antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-akt * metabolismus   genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyrimidiny * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The impact of chemoimmunotherapy (CIT) on immunoglobulin (Ig) quantities in patients with chronic lymphocytic leukemia (CLL) has not been extensively studied. METHODS: We analyzed Ig levels in 45 stable patients with indolent CLL (without indication for treatment) and 87 patients with progressive disease before first-line treatment. Fifty-five patients were evaluated again after the treatment with CIT. RESULTS: We observed significantly lower levels of all Ig classes and subclasses in patients with progressive disease compared to patients with indolent disease. After treatment, median IgA increased from 0.59 g/L to 0.74 g/L (p = 0.0031). In stable patients, lower IgA2 was associated with shorter time to first treatment, although it did not reach statistical significance (p = 0.056). Shorter overall survival was observed in patients with progressive disease and lower IgG2 (p = 0.043). Surprisingly, among the patients with progressive CLL, unmutated IGHV genes were associated with higher levels of IgG, IgG1 and IgM, while TP53 mutation and/or 17p deletion were associated with higher levels of IgA and IgA1. CONCLUSIONS: CIT may lead to increase in IgA levels. Hypogammaglobulinemia is more common in patients with progressive CLL and unmutated IGHV or TP53 dysfunction.

• MeSH
• chronická lymfatická leukemie * farmakoterapie   krev   imunologie   mortalita   MeSH
• dospělí MeSH
• imunoglobulin A * krev   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• časopisecké články MeSH

BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS: At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).

• MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• lidé MeSH
• nemoci srdce * chemicky indukované   MeSH
• progrese nemoci MeSH
• protinádorové látky * škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: In chronic lymphocytic leukemia (CLL), changes in the peripheral blood lymphocyte subsets play an important role in disease progression and infectious complications. The impact of chemoimmunotherapy (CIT) on these changes has not been extensively studied METHODS: We used multi-color flow cytometry, to prospectively measure absolute and relative numbers of CD4+ and CD8+ T-cells and their subsets in 45 patients with indolent untreated CLL, 86 patients indicated for first-line treatment, and 34 healthy controls. In 55 patients, we analyzed the impact of CIT RESULTS: CLL patients had a significant increase in most cell populations in comparison to controls. Progression of CLL was characterized by significantly elevated counts with the exception of a lower percentage of naïve T-cells. After treatment, the percentage of naïve T-cells further decreased at the expense of effector memory T-cells (TEM). In patients with indolent CLL, higher percentages of naïve CD4+ (p = 0.0026) and naïve CD8+ (p = 0.023) T-cells were associated with a longer time to first treatment (TTFT). The elevation of CD4+ central memory T-cells (TCM) (p = 0.27) and TEM (p = 0.003) counts and a higher percentage of CD4+ TEM (p = 0.0047), were linked with shorter TTFT. In treated patients, increased regulatory T-cells count was associated with shorter time to next treatment (TTNT) (p = 0.042), while higher CD4+ TCM count with shorter TTNT (p = 0.035) and shorter overall survival (p = 0.041). CONCLUSION: Our results indicate that naïve cell depletion and CD4+ TCM and TEM increases are detrimental to CLL patients' prognosis.

• MeSH
• CD4-pozitivní T-lymfocyty MeSH
• CD8-pozitivní T-lymfocyty MeSH
• chronická lymfatická leukemie * MeSH
• lidé MeSH
• podskupiny lymfocytů MeSH
• prognóza MeSH
• regulační T-lymfocyty MeSH
• T-lymfocyty - podskupiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

• MeSH
• adenin terapeutické užití   MeSH
• B-buněčný lymfom * farmakoterapie   MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• fibrilace síní * MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH