Introduction: The phosphatidylinositol 3-kinase inhibitor copanlisib was approved for use in the US in 2017 as monotherapy in patients with relapsed follicular lymphoma (FL) who have progressed after ≥2 therapies based on results from the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) (Dreyling et al. J Clin Oncol 2017). Here, we describe efficacy and safety data at the 6-year follow-up. Methods: CHRONOS-1 enrolled patients with FL, marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenström macroglobulinemia/lymphoplasmacytoid lymphoma (WM/LPL) who had received ≥2 therapies. Copanlisib 60 mg was administered intravenously on days 1, 8, and 15 of a 28-day cycle. The primary efficacy endpoint was objective response rate (ORR) per independent radiologic review (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). CTCAE v4.03 was used to grade adverse events (AEs). Results: 142 patients with iNHL (104 FL, 23 MZL, 8 SLL, 6 WM/LPL, 1 other) received treatment. 99.3% of patients had discontinued treatment by the data cut-off (June 30, 2022). During follow-up, 74% of patients (n = 105) received ≥1 line of subsequent systemic anti-cancer therapy, including 46% of patients treated with rituximab-based regimens. ORR was 59.9% (n = 85) with complete responses in 23 patients (16.2%). Median DoR was 14.9 months (mos) (range 0–80.6). With a median follow-up of 14 mos (95% confidence interval [CI] 10.3, 20.7), median PFS was 11.3 mos (range 0–82.1) with a 2-year PFS rate of 33%. With a median follow-up of 82.3 mos (95% CI: 79.3, 84.2), median OS was 59.1 mos (73 events, range 0.2–100.6) with a 6-year OS rate of 45% (Figure). Median duration of treatment was 6.0 mos (range 0.23–81.0). Transformation to aggressive lymphoma (diffuse large B-cell lymphoma) was not observed. Treatment was discontinued primarily due to radiologic disease progression (35.2%; n = 50) and AEs not associated with clinical disease progression (28.2%; n = 40). Copanlisib safety data were consistent with the 2-year follow-up (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent AEs (all grades/grades 3–4) were infusion-related hyperglycemia (50.7%/39.4%), diarrhea (35.9%/8.5%), hypertension (29.6%/23.9%), neutropenia (29.6%/24.7%), and pyrexia (26.8%/4.2%). The research was funded by Bayer AG with medical writing and editorial assistance from Complete HealthVizion Keyword: Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. M. Dreyling Consultant or advisory role: AstraZeneca, BeiGene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche Honoraria: AstraZeneca, BeiGene, Gilead/Kite, Janssen, Roche, Lilly, Novartis Research funding: AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche A. Santoro Consultant or advisory role: BMS (BRISTOL MYERS SQUIBB)/SERVIER/GILEAD/PFIZER/EISAI/BAYER/MSD (MERCK SHARP & DOHME), SANOFI/ INCYTE Other remuneration: Speaker's Bureau: TAKEDA/BMS/ROCHE/ABB-VIE/AMGEN/CELGENE/SERVIER/GILEAD/ASTRAZENECA/PFIZER/LILLY/SANDOZ/EISAI/NOVARTIS/BAYER/MSD S. Leppä Consultant or advisory role: Gilead Sciences, Novartis, Roche, BeiGene, Orion Clinical, Incyte, Pfizer, SOBI Honoraria: Gilead Sciences, Novartis, Incyte Research funding: Roche, Bayer, Celgene, Novartis, Genmab, Hutchison MediPharma G. A. Follows Consultant or advisory role: AbbVie, Roche, Janssen, AstraZeneca, Lilly, Centessa Honoraria: AbbVie, Roche, Janssen, AstraZeneca, Lilly Educational grants: Takeda G. Lenz Employment or leadership position: President elect German Lymphoma Alliance, Board of director German Lymphoma Alliance Consultant or advisory role: Roche, Janssen, Celgene, AstraZeneca, BMS, AbbVie, MorphoSys, Karyopharm, ADC, PentixaPharm, Hexal/Sandoz, Genase, Gilead, Bayer, Novartis, Takeda, NanoString, Incyte, Genmab, Constellation, Miltenyi, Sobi, Immagene, Lilly Honoraria: Roche, Bayer, Takeda, AbbVie, MorphoSys, Hexal/Sandoz, Janssen, Celgene, BMS, Incyte, Sobi Research funding: Roche, Gilead, Janssen, AstraZeneca, Bayer, Celgene, Novartis, MorphoSys Educational grants: Janssen, BMS, AbbVie P. Panayiotidis Other remuneration: Bayer AG, clinical trial support M. Özcan Research funding: AbbVie, Bayer, Janssen, Roche, Takeda, MSD, Pfizer, Acerta Educational grants: AbbVie M. Kosinova Other remuneration: Bayer AG, clinical trial support M. Provencio Consultant or advisory role: AstraZeneca, Bristol Myers Squibb Company, Eli Lilly, F. Hoffmann-La Roche, Janssen Global Services, LLC, Laboratorios Pfizer Ltda., Merck, Takeda Oncology. Research funding: Boehringer Ingelheim, Bristol Myers Squibb Company, F. Hoffmann-La Roche, Pierre Fabre Pharmaceuticals, Inc., Takeda Oncology. Educational grants: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb Company, Eli Lilly, F. Hoffmann-La Roche, Pierre Fabre Pharmaceuticals, Inc., Other remuneration: PATENTS, ROYALTIES, OTHER INTELLECTUAL PROPERTY: P201731067. Prognosis methods for patients with folicular lymphoma. España. 16/05/2017. FIBHUPH; PCT/ES2018/070463. Method for designing J. Munoz Consultant or advisory role: Pharmacyclics/AbbVie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosun Kite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, BeiGene, Servier, Novartis, MorphoSys/Incyte, MEI, Zodiac, TG Therapeutics, Lilly/Loxo Honoraria: Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics Research funding: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium Other remuneration: Speaker's Bureau: Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, BeiGene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche A. Cao Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. F. Hiemeyer Employment or leadership position: Bayer AG F. Odongo Employment or leadership position: Bayer SA J. Garcia-Vargas Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. B. H. Childs Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. P. L. Zinzani Consultant or advisory role: SECURA BIO, CELLTRION, GILEAD, JANSSEN- CILAG, BMS, SERVIER, SANDOZ, MSD, ASTRAZENECA, TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, ADC Therap., Incyte, BeiGene Other remuneration: Speaker's Bureau: CELLTRION, GILEAD, JANSSEN- CILAG, BMS, SERVIER, SANDOZ, MSD, ASTRAZENECA, TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, ADC Therap., Incyte, BeiGene
With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcomes of patients with chemosensitive r/R lymphomas undergoing ASCT.
Abstract The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non-driver candidates. These mutations are present at low frequency in the majority of individuals after middle-age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%–40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality. Blood cell parameters appear unmodified in these individuals, but a minority of them will develop a hematologic malignancy. At this time, the factors put forward as potentially influencing the risk of cancer development are clone size, specific gene, specific mutation, and the number of mutations. Specific stress on hematopoiesis also gives rise to clonal expansion. Genotoxic exposure (such as chemotherapy), or immune attack (as in aplastic anemia) selects/provides a fitness advantage to clones with a context-specific signature. Clonal hematopoiesis offers a new opportunity to understand the biology and adaptation mechanisms of aging hematopoiesis and provides insight into the mechanisms underlying malignant transformation. Furthermore, it might shed light on common denominators of age-associated medical conditions and help devise global strategies that will impact the prevention of hematologic cancers and promote healthy aging.
7535 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (iNHL) subtype, yet treatment options in the relapsed/refractory (r/r) setting are limited. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity. We report results from the FL subset of a large phase II study (n=141) in iNHL patients (pts) (NCT01660451, part B). Methods: A total of 104 pts with indolent FL (grade 1-3a) relapsed/refractory to ≥2 prior lines of treatment were treated with copanlisib (60 mg IV infusion) administered on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: Of the 104 pts treated, 62% were refractory; median prior lines 3 (range 2-8), median time from progression 8 wks (range 1-73 wks). 52% were male, 83% white, median age 62 yrs, and 62% ECOG 0. At the time of primary analysis the ORR was 58.7%, comprising 15 pts (14.4%) with complete response (CR) and 46 (44.2%) with partial response. Stable disease was observed in 35 (33.7%) pts and progression of disease as best response in 2 pts. The median duration of response was 370 days (range 0-687), with 43 responders censored at data cut-off. Median duration of treatment was 22 wks (range 1-105); 33 (32%) pts remained on treatment. For all pts, the most common treatment-emergent AEs occurring in >25% of pts included (all grade/grade 3+): diarrhea (34%/5%), reduced neutrophil count (30%/24%), fatigue (30%/2%), and fever (25%/4%). Hyperglycemia (50%/41%) and hypertension (30%/24%) were transient. The incidence of pneumonitis (8%/1.4%), hepatic enzymopathy (AST 28%/1.4%; ALT 23%/1.4%), opportunistic infection (1.4%) and colitis (0.7%) were low. Six deaths were observed, 3 of which were attributed to copanlisib: one lung infection, one respiratory failure, and one thromboembolic event. Conclusions: Copanlisib was highly active as a single agent in heavily pretreated r/r FL pts and resulted in durable responses in the majority of pts. Toxicities were manageable, with a low incidence of severe AEs associated with other PI3K inhibitors, especially hepatic enzymopathy, opportunistic infections, and colitis. Clinical trial information: NCT01660451.
Introduction: Marginal zone lymphoma (MZL) is an indolent B-cell malignancy, comprising >10% of non-Hodgkin lymphomas. In 2017, the FDA approved the BTK inhibitor ibrutinib for treatment of patients with relapsed/refractory MZL based on outcomes from a study of 60 patients, wherein an objective response rate (ORR) of 48% (3% complete responses [CR]) and a median progression-free survival (PFS) of 14.2 months were reported (Noy et al. Blood 2017). We report here on the results from 23 heavily pretreated patients with relapsed or refractory MZL from the Phase II CHRONOS-1 study (NCT01660451; Part B) with the pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib. Methods: Patients enrolled in the CHRONOS-1 trial with histologically confirmed MZL relapsed after or refractory to ≥2 prior lines of treatment, including rituximab and an alkylating agent, were included in the subset analysis. Copanlisib 60 mg was administered via a 1-hour infusion on days 1, 8 and 15 of a 28-day cycle. Treatment continued until progression or unacceptable toxicity. The primary efficacy endpoint was ORR after ≥4 cycles, per independent assessment (Cheson et al. J Clin Oncol 2007). Secondary efficacy endpoints included duration of response (DoR), PFS and overall survival (OS). AEs were reported using MedDRA (v.19.1). The last patient was enrolled in February 2016. The initial data cut-off was June 2016; the long-term follow-up is based on a data cut-off of February 2018. Results: The 23 MZL patients enrolled included 15 (65%) nodal MZL and 4 each (17%) with mucosa-associated lymphoid tissue (MALT) lymphoma and splenic MZL. Median age was 69 years (range 39-81). Patients had a median of 3 (range 2-9) prior lines of therapy; 48% were refractory to the last regimen and 44% were refractory to the last rituximab regimen. As of February 2018, patients received a median of 5.8 cycles of treatment, with a median treatment duration of 23 weeks (range 1-191). Objective responses by independent assessment were observed in 18 patients (ORR 78%) and CRs in 3 patients (13%); ORRs were 50% (2/4 patients) in MALT MZL, 87% (13/15 patients) in nodal MZL and 75% (3/4 patients) in splenic MZL. Overall median DoR was 17.4 months (range 0-37.6). Median PFS was 24.2 months (range 0-41.1) and median OS was not reached, with an estimated 83% alive at 2 years. The most common treatment-emergent AEs (TEAEs; all grade/grade 3+) for the total MZL population were fatigue (52.2%/13.0%), hyperglycaemia (52.2%/43.5%) and diarrhoea (47.8%/13.0% grade 3). Laboratory toxicities of interest were principally grade 1, including increased AST (31.8% all grade/22.7% grade 1) and increased ALT (27.3%/13.6%). No grade 5 TEAEs were reported. Conclusions: MZL patients with 2 or more lines of prior therapy treated with copanlisib had durable responses and PFS exceeding previous benchmarks. Keywords: marginal zone lymphoma (MZL); PI3K/AKT/mTOR. Disclosures: Panayiotidis, P: Research Funding: Bayer. Santoro, A: Consultant Advisory Role: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD, Arqule; Other Remuneration: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD. Hiemeyer, F: Employment Leadership Position: Bayer AG. Liu, L: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Garcia-Vargas, J: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Childs, B: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Zinzani, P: Consultant Advisory Role: Eusapharma, MSD, Sanofi, BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, Portola, Roche, Sandoz, Servier, Verastem; Other Remuneration: BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, MSD, Portola, Roche, Servier, Verastem. Dreyling, M: Consultant Advisory Role: Bayer, Celgene, Gilead, Janssen, Novartis, Sandoz and Roche; Research Funding: Celgene, Janssen, Mundipharma, Roche; Other Remuneration: Bayer, Celgene, Gilead, Janssen and Roche.
