PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.

• MeSH
• bicyklické sloučeniny heterocyklické škodlivé účinky   MeSH
• chlorambucil škodlivé účinky   MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• doba přežití bez progrese choroby MeSH
• lidé MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• reziduální nádor farmakoterapie   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

CONTEXT: Minimal residual disease (MRD) is a predictive marker for progression-free survival (PFS) in chronic leukocytic leukemia (CLL) following chemoimmunotherapy and fixed-duration treatment with venetoclax and anti-CD20 antibodies. This has not been explored for ibrutinib+venetoclax (Ibr+Ven), a fixed-duration treatment with mechanisms of action that synergistically eliminate CLL subpopulations in distinct tumor compartments. OBJECTIVE: Investigate MRD outcomes at primary analysis of phase 3 GLOW study (NCT03462719). DESIGN: Randomized, open-label, active-control study. PATIENTS: Patients aged ≥65 years or 18-64 years with a CIRS score >6 or creatinine clearance <70 mL/min were randomized 1:1, stratified by IGHV mutational and del11q status, to Ibr+Ven (n=106) or chlorambucil+obinutuzumab (Clb+O) (n=105). Excluded: patients with del17p or known TP53 mutations. INTERVENTIONS: Ibr+Ven (3 cycles of ibrutinib lead-in, then 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. MAIN OUTCOME MEASURES: Primary endpoint: independent review committee-assessed PFS; secondary endpoint: rate of undetectable MRD (uMRD; <10-4); exploratory endpoints: MRD analyses. MRD results are by next-generation sequencing, reported 3 months after end of treatment (EOT+3) unless otherwise noted. RESULTS: Rates of uMRD<10-4 were higher for Ibr+Ven versus Clb+O in bone marrow (BM) (51.9% vs. 17.1%; P<0.0001) and peripheral blood (PB) (54.7% vs. 39.0%; P=0.0259). For Ibr+Ven, BM uMRD was higher for uIGHV (58.2%) versus mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of patients maintained PB uMRD from EOT+3 to EOT+12 versus 29.3% (12/41) with Clb+O. Rates of uMRD<10-5 were higher for Ibr+Ven versus Clb+O in BM (40.6% vs. 7.6%), including patients with uIGHV (45.5% vs. 5.6%). uMRD<10-5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46]) but not Clb+O (26.3% [5/19]). PFS rates for Ibr+Ven during the 12 months after EOT were >90% for patients with uMRD<10-4 and patients with detectable MRD; however, Clb+O arm patients with detectable PB MRD relapsed more quickly than those with uMRD<10-4. CONCLUSIONS: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfit patients with previously untreated CLL.

• MeSH
• adenin analogy a deriváty   MeSH
• bicyklické sloučeniny heterocyklické MeSH
• chlorambucil MeSH
• chronická lymfatická leukemie * patologie   MeSH
• humanizované monoklonální protilátky MeSH
• kreatinin MeSH
• lidé MeSH
• piperidiny MeSH
• prospektivní studie MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• reziduální nádor etiologie   MeSH
• senioři MeSH
• sulfonamidy MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

• MeSH
• analýza přežití MeSH
• bendamustin hydrochlorid aplikace a dávkování   MeSH
• chronická lymfatická leukemie diagnóza   farmakoterapie   mortalita   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• opakovaná terapie MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• pyrazoly aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• rituximab aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Itálie MeSH
• Spojené království MeSH

PURPOSE: This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. PATIENTS AND METHODS: In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. RESULTS: Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. CONCLUSION: The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

• MeSH
• antitumorózní látky aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• dospělí MeSH
• folikulární lymfom farmakoterapie   metabolismus   MeSH
• injekce subkutánní MeSH
• intravenózní podání MeSH
• lidé středního věku MeSH
• lidé MeSH
• myší monoklonální protilátky aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• progrese nemoci 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
• klinické zkoušky, fáze I MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH