Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

• MeSH
• Bendamustine Hydrochloride * administration & dosage   therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Piperidines therapeutic use   administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Pyrazoles * therapeutic use   administration & dosage   adverse effects   MeSH
• Pyrimidines * therapeutic use   administration & dosage   adverse effects   MeSH
• Rituximab * administration & dosage   therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

Východiska: Castlemanova choroba (Castleman disease – CD) nese název po autorovi prvního popisu. Používá se pro ložisko či ložiska charakteru nemaligní lymfoproliferace. Dle rozsahu postižení organizmu se dělí na dvě základní formy, unicentrickou formu (unicentric Castleman disease – UCD) a multicentrickou formu, přičemž UCD je tvořena hyalinně vaskulárním typem CD. Pozorování: Prvním symptomem v popsaném případě UCD byly bolesti vyzařující do levé horní končetiny, obzvláště při pohybu. Vyšetření krční páteře pomocí MR odhalilo jako příčinu patologickou expanzi na pomezí krku a horního mediastina, více vlevo. Cílená biopsie prokázala CD, hyalinně vaskulární typ. Dle PET/CT zobrazení s využitím fluorodeoxyglukózy (FDG-PET/CT) se jednalo o jediné patologické ložisko v těle. Velikost tumorózní rezistence neumožnovala bezpečnou resekci, a tak jediným řešením bylo podávání adjuvantní léčby. Pacientka zahájila léčbu ve složení rituximab 850 mg v den 1 28denního cyklu, cyklofosfamid 600 mg v dny 1 a 15 a dexametazon 20 mg také v dny 1 a 15 28denního cyklu. Pro individuální intoleranci cyklofosfamidu v prvním cyklu bylo podávání tohoto léku přerušeno a od třetího cyklu dostávala místo cyklofosfamidu bendamustin v celkové dávce 100 mg v dny 1 a 15. Výsledky: Zobrazení pomocí FDG-PET/CT po devíti cyklech léčby prokázalo výrazné zmenšení velikosti infiltrátu a zmenšení míry akumulace FDG. To umožnilo týmu hrudního chirurga a kardiochirurga kompletní odstranění až do zdravé tkáně. Závěr: Léčbou volby pro UCD je operační odstranění. V případě, že uložení či velikost ložiska neumožnuje radikální operaci, je možné dosáhnout zmenšení uvedenou medikamentózní léčbou. V popsaném případě kombinace rituximabu, bendamustinu a dexametazonu zmenšila velikost ložiska, což umožnilo jeho kompletní resekci.

Background: Castleman disease (CD) is a historical name derived from the name of the surgeon who first described it. It is used for lesions or foci of the character of non-malignant lymphoproliferative activity. According to the extent of the affliction, it is divided into two basic forms, the unicentric form (UCD) and the multicentric form of Castleman disease, where UCD is formed by the hyaline vascular type of CD. Observation: The first symptom in the described case of UCD was pain radiating to the left upper limb, especially when moving. MRI of the cervical spine revealed pathological expansion on the border between the neck and the upper mediastinum, more on the left. Targeted biopsy showed Castleman disease, hyaline vascular type. According to PET/CT imaging with fluorodeoxyglucose (FDG-PET/CT), it was the only pathological lesion in the body. The size of the tumour resistance did not allow safe resection, so the only solution was to administer adjuvant treatment. The patient started treatment with rituximab 850 mg on day 1 of a 28-day cycle, cyclophosphamide 600 mg on days 1 and 15 and dexamethasone 20 mg, also on days 1 and 15 of a 28-day cycle. Due to individual intolerance of cyclophosphamide in the first cycle, the administration of this drug was discontinued, and from the third cycle onwards, instead of cyclophosphamide, she received bendamustine at a total dose of 100 mg on days 1 and 15. Results: FDG-PET/CT imaging after 9 cycles of treatment showed a marked reduction in the infiltrate size and a decrease in the rate of FDG accumulation. This allowed the team of thoracic and cardiac surgeons to completely remove it down to healthy tissue. Conclusion: The treatment of choice for UCD is surgical removal. If the location or size of the lesion does not allow radical surgery, it is possible to achieve reduction by the mentioned drug treatment. In the case described, the combination of rituximab, bendamustine and dexamethasone reduced the size of the lesion, which allowed its complete resection.

• MeSH
• Bendamustine Hydrochloride pharmacology   therapeutic use   MeSH
• Dexamethasone pharmacology   therapeutic use   MeSH
• Diagnosis, Differential MeSH
• Castleman Disease * diagnosis   drug therapy   classification   MeSH
• Drug Therapy, Combination * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoproliferative Disorders diagnosis   drug therapy   classification   MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.

• MeSH
• Bendamustine Hydrochloride MeSH
• Cyclophosphamide MeSH
• Doxorubicin MeSH
• Lymphoma, Follicular * MeSH
• Gallium * therapeutic use   MeSH
• Humans MeSH
• Prednisone MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Neoplasm, Residual drug therapy   MeSH
• Rituximab MeSH
• Vincristine MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

• MeSH
• Bendamustine Hydrochloride adverse effects   MeSH
• Lymphoma, Large B-Cell, Diffuse * etiology   MeSH
• Lymphoma, Follicular * drug therapy   etiology   MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• Immunoconjugates * adverse effects   MeSH
• Humans MeSH
• Antibodies, Monoclonal * MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Rituximab adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Randomized Controlled Trial MeSH

Východiska: Rituximab je již standardní součástí léčby pacientů s Waldenströmovou makroglobulinemií (WM). U malé části pacientů se vůči němu však v průběhu podávání rozvine intolerance nebo je léčba málo účinná. U těchto pacientů stojíme před otázkou, zda a s jakým výsledkem lze použít jinou anti-CD20 monoklonální protilátku. Soubor pacientů a metody: V letech 2020–2022 jsme podali u pěti pacientů s WM novou anti-CD20 monoklonální protilátku obinutuzumab v kombinaci s bendamustinem a dexametazonem. Všichni pacienti dokončili osm cyklů uvedené léčby. U dvou z nich se jednalo o léčbu 2. linie, u dalších dvou o léčbu 3. linie a u jednoho pacienta byla tato léčba podána v rámci 4. linie. U žádného pacienta jsme nepozorovali signifikantní toxicitu (grade III a IV). Výsledky: U všech pěti pacientů bylo dosaženo hlubší léčebné odpovědi (1× kompletní odpověď, 4× velmi dobrá částečná odpověď) než v přechozích liniích léčby. Při mediánu sledování po ukončené léčbě 30 měsíců (rozmezí 28–48) relabovala nemoc pouze u jednoho pacienta, u ostatních trvá remise. Závěr: Obinutuzumab v kombinaci s bendamustinem je velmi účinnou alternativou léčby WM. U popsaných pěti pacientů dosáhl obinutuzumab s bendamustinem a dexametazonem hlubší léčebné odpovědi než předchozí léčebné linie. Obinutuzumab přestavuje lék, který pro vybrané pacienty s WM bude velkým přínosem.

Background: Rituximab is already a standard part of the treatment of patients with Waldenström‘s macroglobulinemia. However, a small proportion of patients develop intolerance to rituximab during administration or the treatment is not very effective. In these patients, we are faced with the question of whether another anti-CD20 monoclonal antibody can be used and what result will be achieved. Patient population and methods: Between 2020 and 2022, we administered the new anti-CD20 monoclonal antibody obinutuzumab in combination with bendamustine and dexamethasone in five patients with Waldenström‘s macroglobulinemia (WM). All patients completed eight cycles of the indicated treatment. Two of them received second-line treatment, another two received third-line treatment, and one patient received this treatment as part of fourth-line treatment. We did not observe significant toxicity (grade III and IV) in any patient. Results: All five patients achieved a deeper treatment response (once complete response, 4-times very good partial response) than in previous lines of treatment. At a median follow-up after treatment of 29 months (range 28–48), the disease relapsed in one patient only, the others are in remission. Conclusion: Obinutuzumab in combination with bendamustine is a very effective treatment alternative for WM. In the described five patients, obinutuzumab with bendamustine and dexamethasone achieved a deeper therapeutic response than the previous treatment lines. Obinutuzumab represents a drug that will be of great benefit to selected patients with WM.

• Keywords
• Obinutuzumab - Gazyvaro,
• MeSH
• Antigens, CD20 drug effects   MeSH
• Bendamustine Hydrochloride pharmacology   therapeutic use   MeSH
• Dexamethasone pharmacology   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized * pharmacology   therapeutic use   MeSH
• Clinical Studies as Topic methods   MeSH
• Humans MeSH
• Waldenstrom Macroglobulinemia * drug therapy   MeSH
• Check Tag
• Humans MeSH

• Keywords
• venetoklax, obinutuzumab, studie CLL 14, studie Murano,
• MeSH
• Antigens, CD20 * pharmacology   therapeutic use   MeSH
• Bendamustine Hydrochloride administration & dosage   therapeutic use   MeSH
• Chlorambucil administration & dosage   therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * diagnosis   drug therapy   MeSH
• Humans MeSH
• Meta-Analysis as Topic MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Randomized Controlled Trials as Topic MeSH
• Rituximab administration & dosage   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit with monotherapy in a phase 2 study in relapsed or refractory (R/R) follicular lymphoma (FL). CITADEL-102 (NCT03039114), a phase 1, multicenter study, assessed the efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with R/R FL. Patients were ≥18 years of age with histologically confirmed and documented CD20-positive FL, and R/R to previous rituximab-containing treatment regimens. Part one (safety run-in) determined the maximum tolerated dose of parsaclisib in combination with standard dosage regimens of obinutuzumab and bendamustine. Part two (dose expansion) was an open-label, single-group design evaluating safety, tolerability (primary endpoint), and efficacy (secondary endpoint) of parsaclisib combination therapy. Twenty-six patients were enrolled in CITADEL-102 and all patients received parsaclisib 20 mg once daily for 8 weeks, followed by 20 mg once weekly thereafter, in combination with obinutuzumab and bendamustine. One patient in safety run-in experienced a dose-limiting toxicity of grade 4 QT interval prolongation that was considered related to parsaclisib. Eight patients (30.8%) discontinued treatment due to treatment-emergent adverse events (TEAEs) of colitis (2 [7.7%]), alanine aminotransferase and aspartate aminotransferase increase (both in one patient [3.8%]), neutropenia, thrombocytopenia, QT prolongation, tonsil cancer, and maculopapular rash (each 1 [3.8%]). The most common reported TEAEs were pyrexia (53.8%), neutropenia (50.0%), and diarrhea (46.2%). Twenty-three patients (88.5%) experienced grade 3 or 4 TEAEs; the most common were neutropenia (34.6%), febrile neutropenia (23.1%), and thrombocytopenia (19.2%). Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens.

• MeSH
• Bendamustine Hydrochloride MeSH
• Lymphoma, Follicular * pathology   MeSH
• Humans MeSH
• Neutropenia * chemically induced   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Rituximab MeSH
• Thrombocytopenia * etiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Multicenter Study MeSH

Východiska: Waldenströmova makroglobulinemie (WM) je lymfoplazmocytární lymfom produkující monoklonální imunoglobulin typu IgM. Incidence této nemoci je nízká (0,4/100 000), takže tuto chorobu lze považovat za tzv. nemoc-sirotka. To znamená, že nové léky jsou testovány a registrovány většinou pro častější diagnózy, než je WM. Cíl: V tomto textu shrnujeme informace o účinnosti nových léků pro WM. Výsledky: Z klasických chemoterapeutik se nyní za nejúčinnější lék v kombinaci s rituximabem považuje bendamustin, který dosahuje dlouhodobější léčebné odpovědi než cyklofosfamid s rituximabem a dexametazonem. Mnoho léků používaných pro léčbu mnohočetného myelomu (MM), má dobrou účinnost také u WM. Bortezomib je vysoce účinný, ale neurotoxicita tohoto léku u WM je vyšší než u MM. Novější léky ze skupiny inhibitorů proteazomu, ixazomib a karfilzomib, s nižší neurotoxicitou jsou lépe tolerovány u WM, jak bylo prokázáno v několika studiích. Nové typy antiCD20 monoklonálních protilátek jsou přínosem obzvláště v případech intolerance rituximabu. Pět našich pacientů netolerujících rituximab ukončilo léčbu kombinací bendamustinu a obinutuzumabu. Všichni pacienti léčení touto kombinací dosáhli hlubší léčebné odpovědi po obinutuzumabu a bendamustinu, než bylo dosaženo v přechozích léčebných liniích. Registrace prvního perorálního inhibitoru Brutonovy tyrozinkinázy (BTK) ibrutinibu pro monoterapii či kombinaci s rituximabem rozšířilo léčebné možnosti u pacientů refrakterních k iniciální léčbě. Nové léky ze skupiny inhibitorů BTK (akalabrutinib, zanubrutinib, vekabrutinib) byly již u této nemoci testovány a ukázalo se, že mají nižší toxicitu při srovnatelném léčebném účinku. Kardiální komplikace typu fibrilace síní byly méně časté. A nově je testován také BCL2 inhibitor venetoklax. Závěr: Nová antiCD20 protilátka (obinutuzumab) je přínosem pro pacienty s WM s intolerancí rituximabu stejně jako bendamustin a nové inhibitory proteazomu (ixazomib a karfilzomib) nebo nové inhibitory BTK s nižší toxicitou. Mnoho z výše zmíněných léků nemá oficiální registraci pro WM a lze je podat pouze se souhlasem plátce zdravotní péče, proto tento text přináší důkazy o jejich účinnosti.

Background: Waldenström macroglobulinemia (WM) is a lymphoplasmocytic lymphoma with immunoglobulin M monoclonal protein. The incidence of this disease is very low (0.4/100,000), so that this disease can be regarded as an orphan’s disease. It means that new drugs are often tested and registered for more frequent diseases. Purpose: In this review we will focus on the efficacy of the new drugs for WM. Results: The current treatment options for symptomatic WM patients include alkylating agent cyclophosphamide and anti-CD20 monoclonal antibodies. Therapy with rituximab and bendamustin resulted in longer therapeutic response then therapy with rituximab, cyclophosphamide and dexamethasone. Many drugs, used in multiple myeloma (MM), shoved promising results in WM patients. Bortezomib is effective in WM, but its neurotoxicity is higher in WM than in MM patients. Therefore, new proteasome inhibitors, carfilzomib and ixazomib, are better tolerated as documented in several studies. New types of antiCD20 antibody (obinutuzumab) can be used in patients with rituximab intolerance. in five of our patients with WM, obinutuzumab and bendamustin reached deeper responses than therapies administered in previous lines of therapy. Oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab have extended the treatment options for WM patients. New BTK inhibitors (e. g. acalabrutinib, zanubrutinib, and vecabrutinib) were tested and their lower toxicity (atrial fibrillation) was documented. Moreover, the BCL2 inhibitor venetoclax is newly tested. Conclusion: New antiCD20 antibody (obinutuzumab) is of advantage in patients with WM with rituximab intolerance as well as bendamustin and new proteasome inhibitors (ixazomib and carfilzomib) or new BTK inhibitors with lower cardiotoxicity. Many of the abovementioned drugs do not have official registration for WM and can be administrated with the consent of the health care provider only. Thus, this work brings evidence of their efficacy.

• Keywords
• karfilzomib, ibrutinib, bendamustine, obinutuzumab, ixazomib,
• MeSH
• Bendamustine Hydrochloride pharmacology   therapeutic use   MeSH
• Humans MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Antineoplastic Protocols MeSH
• Waldenstrom Macroglobulinemia * diagnosis   epidemiology   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

CONTEXT: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. DESIGN: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. MAIN OUTCOME MEASURES: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading to death=11 patients (4.6%) versus 11 patients (4.8%). No sudden deaths occurred. CONCLUSIONS: In summary, zanubrutinib significantly improved PFS-IRC versus BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naïve CLL/SLL.

• MeSH
• Lymphoma, B-Cell * drug therapy   MeSH
• Bendamustine Hydrochloride therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   pathology   MeSH
• Cyclophosphamide therapeutic use   MeSH
• Protein Kinase Inhibitors * adverse effects   MeSH
• Humans MeSH
• Piperidines adverse effects   MeSH
• Agammaglobulinaemia Tyrosine Kinase MeSH
• Antineoplastic Combined Chemotherapy Protocols * adverse effects   MeSH
• Pyrazoles adverse effects   MeSH
• Pyrimidines adverse effects   MeSH
• Rituximab therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B). INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL. FUNDING: BeiGene.

• MeSH
• Bendamustine Hydrochloride MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   pathology   MeSH
• COVID-19 * MeSH
• Humans MeSH
• Piperidines MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH
• Rituximab MeSH
• Sequoia * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH