Publications by authors named "Paul M Barr"

110 Publications

Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib.

Blood 2021 Aug 18. Epub 2021 Aug 18.

Mayo Clinic, Rochester, Minnesota, United States.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (< 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.
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http://dx.doi.org/10.1182/blood.2020010146DOI Listing
August 2021

Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma.

J Clin Oncol 2021 Jul 28;39(20):2257-2265. Epub 2021 Apr 28.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma.

Methods: In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4.

Results: Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible.

Conclusion: BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients.
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http://dx.doi.org/10.1200/JCO.21.00108DOI Listing
July 2021

Highlights in leukemia and lymphoma from the 62nd American Society of Hematology Annual Meeting and Exposition: commentary.

Authors:
Paul M Barr

Clin Adv Hematol Oncol 2021 Mar;19 Suppl 11(3):17-19

Clinical Trial Office, University of Rochester Medical Center, Rochester, New York.

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March 2021

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.

Blood 2021 May;137(20):2817-2826

Duke University Medical Center, Durham, NC.

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.
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http://dx.doi.org/10.1182/blood.2020007376DOI Listing
May 2021

Toxicity patterns of novel PI3K combinations in patients with non-Hodgkin lymphoma.

Leuk Lymphoma 2021 03 25;62(3):598-605. Epub 2020 Oct 25.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Phosphoinositide-3-kinase (PI3K) inhibitors have efficacy in lymphoid malignancies; however, inflammatory and infectious toxicities can compromise the treatment course. An improved understanding of these toxicities will guide clinical use and further development. We evaluated the occurrence of treatment-related adverse events (AEs) in a retrospective review of 79 patients treated in standard fashion with PI3K inhibitor monotherapy or with anti-CD20 monoclonal antibodies or as part of a novel combination regimen. Patients treated with a novel combination were at a higher risk of developing a severe AE compared to those treated with standard therapy (HR 1.89, 95% CI 1.02, 3.49;  = .04). Additionally, previously untreated patients were at higher risk of developing a severe AE compared to previously treated patients (HR 3.19, 95% CI 1.48, 6.84;  = .003). These results caution against the use of untested PI3K inhibitor combinations in routine practice and suggest that early phase clinical trials should utilize conservative treatment schemas.
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http://dx.doi.org/10.1080/10428194.2020.1837796DOI Listing
March 2021

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Cancer Med 2020 11 24;9(22):8468-8479. Epub 2020 Sep 24.

Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.
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http://dx.doi.org/10.1002/cam4.3470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666748PMC
November 2020

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

Early Progression of Follicular Lymphoma: Biology and Treatment.

Hematol Oncol Clin North Am 2020 08 5;34(4):757-769. Epub 2020 May 5.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.

Follicular lymphoma is the most common subtype of indolent non-Hodgkin lymphoma. Although a majority of patients have a favorable prognosis, a subset of patients experiences early treatment failure. Progression of disease within 24 months of initial chemoimmunotherapy is associated with inferior survival. The biology of early progression is the subject of ongoing study and depends on the unique genetic composition of neoplastic cells and their interaction with a complex tumor microenvironment. Clinicogenetic prognostic indices have been developed to identify high-risk patients. Several have been validated but are limited in identifying those at risk for early treatment failure.
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http://dx.doi.org/10.1016/j.hoc.2020.02.009DOI Listing
August 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 07 20;26(14):3589-3596. Epub 2020 Mar 20.

Division of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Additional B-cell malignancies in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL).

Leuk Lymphoma 2020 07 16;61(7):1636-1644. Epub 2020 Mar 16.

Wilmot Cancer Institute, Rochester, NY, USA.

Family and migration studies suggest a genetic risk of developing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). We hypothesized that CLL patients have an increased risk of additional clonally unrelated B-cell malignancies. To test this, we studied 467 CLL patients (2743 person-years (PYs)) at a single institution over 17 years. The incidence rate (IR) of any additional B-cell lymphoid malignancy was 10.9 per 1000 PYs ( = 30, 6.4%). Eighteen (4%) patients had a clonally unrelated B-cell malignancy (IR = 6.6 per 1000 PYs). Standardized incidence ratios (SIRs) were used to compare the incidence of additional clonally unrelated B-cell malignancies in CLL patients to the age- and sex-matched expected rates in the USA generated from the Surveillance, Epidemiology, and End Results (SEER) database. For the subset of 13 patients having data for comparison in the SEER database, the SIR was 5.41 (95% CI = 2.9, 9.3) which is supportive of our hypothesis.
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http://dx.doi.org/10.1080/10428194.2020.1737690DOI Listing
July 2020

Cognitive function in patients with chronic lymphocytic leukemia: a cross-sectional study examining effects of disease and treatment.

Leuk Lymphoma 2020 07 9;61(7):1627-1635. Epub 2020 Mar 9.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Cancer-related cognitive impairment (CRCI) has not been objectively assessed in chronic lymphocytic leukemia (CLL). It is currently unclear how much of CRCI is attributable to disease, treatment, or both. We used CLL as a novel model to study the differential roles of disease and treatment in CRCI. One hundred and fifty CLL patients (100 treatment-naïve and 50 chemotherapy-treated) including 84 patients with higher-risk of CLL progression completed objective neuropsychological tests. Sociodemographic-adjusted linear regression models examined cognitive outcomes in relation to risk and treatment. Higher-risk patients recalled two fewer words on a memory task ( = -1.8, 95%CI -3.3,-0.3) and took 15 s longer on an executive function task ( = 15.4, 95%CI 3.1, 27.6) than lower-risk patients, independent of treatment. Treated patients reported greater cognitive difficulties than treatment-naive patients ( = -6.1, 95%CI -10.1, -2.2) but did not perform worse on objective measures. Higher-risk patients experienced impairments in executive function and memory suggesting that disease biology contributes to CRCI independent of treatment.
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http://dx.doi.org/10.1080/10428194.2020.1728748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384931PMC
July 2020

Complete recovery of late onset progressive multifocal leukoencephalopathy related to treatment with chemoimmunotherapy: A case report.

Leuk Res 2020 03 21;90:106309. Epub 2020 Jan 21.

Department of Hematology-Oncology, Wilmot Cancer Center/Strong Memorial Hospital, Rochester, NY, United States.

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http://dx.doi.org/10.1016/j.leukres.2020.106309DOI Listing
March 2020

Initial treatment of B-cell prolymphocytic leukemia with ibrutinib.

Am J Hematol 2020 05 31;95(5):E108-E110. Epub 2020 Jan 31.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.

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http://dx.doi.org/10.1002/ajh.25733DOI Listing
May 2020

Efficacy of lenalidomide in high-risk diffuse large B-cell lymphoma.

Br J Haematol 2020 02 17;188(4):e33-e36. Epub 2019 Dec 17.

Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA.

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http://dx.doi.org/10.1111/bjh.16302DOI Listing
February 2020

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Br J Haematol 2020 03 4;188(6):918-923. Epub 2019 Nov 4.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
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http://dx.doi.org/10.1111/bjh.16271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528953PMC
March 2020

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study.

Leukemia 2020 03 18;34(3):787-798. Epub 2019 Oct 18.

UCSD Moores Cancer Center, San Diego, CA, USA.

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
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http://dx.doi.org/10.1038/s41375-019-0602-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214263PMC
March 2020

Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Am J Hematol 2019 12 13;94(12):1353-1363. Epub 2019 Oct 13.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).
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http://dx.doi.org/10.1002/ajh.25638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899718PMC
December 2019

Long-Term Studies Assessing Outcomes of Ibrutinib Therapy in Patients With Del(11q) Chronic Lymphocytic Leukemia.

Clin Lymphoma Myeloma Leuk 2019 11 15;19(11):715-722.e6. Epub 2019 Jul 15.

Department of Internal Medicine and German CLL Study Group, University of Cologne, Cologne, Germany.

Background: Certain genomic features, such as del(11q), expression of unmutated immunoglobulin heavy-chain variable region (IGHV) gene, or complex karyotype, predict poorer outcomes to chemotherapy in patients with chronic lymphocytic leukemia (CLL).

Patients And Methods: We examined the pooled long-term follow-up data from PCYC-1115 (RESONATE-2), PCYC-1112 (RESONATE), and CLL3001 (HELIOS), comprising a total of 1238 subjects, to determine the prognostic significance of these markers in patients treated with ibrutinib.

Results: With a median follow-up of 47 months, ibrutinib-treated patients had longer progression-free survival (PFS) than patients treated in the comparator arm, regardless of genomic risk factors. Among patients treated with ibrutinib, we found that high-risk genomic features were not associated with shorter PFS (63-75% across all subgroups at 42 months) or overall survival (79-83% across all subgroups at 42 months). Surprisingly, we observed that ibrutinib-treated patients with del(11q) actually had a significantly longer PFS than ibrutinib-treated patients without del(11q) (42-month PFS rate 70% vs. 65%, P = .02).

Conclusion: These analyses not only demonstrate that genomic risk factors previously associated with poor outcomes lose their adverse prognostic significance but also that del(11q) can be associated with a superior PFS with ibrutinib therapy.
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http://dx.doi.org/10.1016/j.clml.2019.07.004DOI Listing
November 2019

Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study.

J Clin Oncol 2019 11 9;37(33):3081-3089. Epub 2019 Aug 9.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL.

Methods: The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety.

Results: Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths.

Conclusion: In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.
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http://dx.doi.org/10.1200/JCO.19.01492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864847PMC
November 2019

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.

N Engl J Med 2019 08;381(5):432-443

From Stanford University, Stanford (T.D.S., S.E.C.), the University of California, Irvine, Medical Center, Orange (S.O.), and Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP)-Permanente Medical Group, Oakland (C.C.Z.) - all in California; Dana-Farber Cancer Institute, Boston (X.V.W., R.M.S.); Mayo Clinic, Rochester (N.E.K., C.A.H., J.F.L., M.L.), and Minnesota Oncology, Burnsville (A.K.S.) - both in Minnesota; Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Lake Success (J.B.), and University of Rochester, Rochester (P.M.B.) - both in New York; Mayo Clinic, Phoenix, AZ (D.F.J., E.B.); Washington University School of Medicine, St. Louis (A.F.C.); Memorial Sloan Kettering Cancer Center, New York (A.R.M., M.T.); Aurora Cancer Care, West Allis, WI (M.P.M.); National Cancer Institute, Bethesda, MD (R.F.L.); and the University of Alabama, Tuscaloosa (H.E.).

Background: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.

Methods: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.

Results: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region () mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).

Conclusions: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).
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http://dx.doi.org/10.1056/NEJMoa1817073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908306PMC
August 2019

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs.

Oncologist 2019 11 25;24(11):e1236-e1250. Epub 2019 Jul 25.

Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. IMPLICATIONS FOR PRACTICE: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.
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http://dx.doi.org/10.1634/theoncologist.2019-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853118PMC
November 2019

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Blood 2019 10;134(15):1238-1246

Division of Hematology/Oncology, University of Rochester, Rochester NY.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.
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http://dx.doi.org/10.1182/blood.2019000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788007PMC
October 2019
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