Abstract
STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with DLBCL. Patients received R-CHOP at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n=55) or placebo (n=47) for 12 months. The complete response rate was numerically higher in the atorvastatin arm (95% [52/55] vs 85% [40/47], p=0.18), but this was not statistically significance. Adverse event rateswere similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the complete response rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies. This trial was registered at www.clinicaltrials.gov as #NCT02943590.
Keywords: atorvastatin, R-CHOP, anthracycline, diffuse large B-cell lymphoma
Introduction:
Patients with diffuse large B-cell lymphoma (DLBCL) are treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or more recently polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-RCHP).1–3Only approximately two-thirds of patients are cured with frontline chemoimmunotherapy, and there is an ongoing need to improve outcomes.
In STOP-CA, a multicenter, double-blind, randomized, placebo-controlled trial of atorvastatin versus placebo in lymphoma patients on anthracycline-based chemotherapies, the primary cardiac outcome(≥10% decline in left ventricular ejection fraction [LVEF]to <55%) was lower in the atorvastatin group.4These data support consideration of atorvastatin to prevent cardiac dysfunction, in particular for patients with increased cardiac risk (e.g., older or with borderline pretreatment LVEFor previous anthracycline exposure).
In a retrospective study, concurrent use of a medium/high-intensity statin with R-CHOP in patients with DLBCL was associated with more frequent complete responses (CR) and longer progression-free survival (PFS).5 Therefore, in this pre-planned subgroup analysis of the STOP-CA trial, we prospectively analyzed the impact of atorvastatinon lymphoma efficacy endpoints in patients with DLBCL receiving R-CHOP.
Methods:
This multicenter, double-blind, randomized, placebo-controlled clinical trial was approved by the Institutional Review Boardsat 9 centers in the US and Canada, registered at clinicaltrials.gov (NCT02943590), and complied with Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided informed consent.
Eligible patients were ≥18 years with treatment-naïve non-Hodgkin lymphoma or Hodgkin lymphoma diagnoses andplannedfor anthracycline-based chemotherapy. Exclusion criteria included statin use or indication based on guidelines, pregnancy/breastfeeding, ALT/ASTelevation >3x ULN, eGFR<45 ml/min/1.73 m2, LVEF<50%, or contraindication to cardiac MRI.
For the analysis described herein, eligible patients had DLBCL NOS or high-grade B-cell lymphoma (HGBCL) NOS, startingR-CHOPat standard dosing for six 21-day cycles,2,3,6 underwent response assessment or exhibited progressive disease.Exclusion criteria included presence of rearrangements in MYC and BCL2 and/or BCL6, and patients who did not receive R-CHOP at standard dosing with plan for six 21-day cycles (e.g., those planned for attenuated dosing, fewer than 6 cycles, or treated with an alternative regimen).
Planned chemoimmunotherapy was R-CHOP administered for six 21-day cycles with standard doses: rituximab administered intravenously at 375 or 500 mg/m2, cyclophosphamide administered intravenously at 750 mg/m2, doxorubicin administered intravenously at 50 mg/m2 and vincristine 1.4 mg/m2 (2 mg cap) on day 1, and prednisone 100 mg PO on days 1–5.Patients were randomized 1:1 to atorvastatin 40 mg by mouth (PO) daily or placebo for 12 months, with dose interruption/modification per standard guidelines.7
Patients were evaluated at baseline for cell of origin (Hans classification8), bulk (≥7.5 cm), Eastern Cooperative Oncology Group (ECOG) performance status, Ann Arbor stage, number of extra nodal sites, lactose dehydrogenase (LDH), and International Prognostic Index (IPI) score. Patients were evaluated for investigator-assessed response (Lugano criteria) with FDG-PET imaging at end-of-treatment.9 Toxicity assessments included history, vitals, physical exam, and laboratories at all visits. AEs Adverse events (AEs) were assessed per CTCAE v4.0 and AEs of special interest (AESI) were prespecified pooled categories of AEs.
In this prespecified secondary analysis, the primary objective was to determine the proportion of patients in each group achieving CR (assessed pre-unblinding).We expected that 128 STOP-CA patients would be eligible for this analysis. The base case assumptions were that 55% of placebo groupand 79% of atorvastatin group would achieve CR. These assumptions are based on the proportions of patients with DLBCL treated with R-CHOP with (79%) or without a statin (55%) reported previously in a retrospective analysis.5 With a Fisher’s exact test, this would provide 78% power at a two-sided significance level of 0.05.
Patient/disease characteristics are summarized using descriptive statistics (numbers/percentages for categorical variables; median/range for continuous variables). CRs were tabulated and summarized descriptively, and frequencies were calculated. PFS was calculated using the Kaplan-Meier method (start of treatment until progression or death from any cause). AEs were reported irrespective of the relationship to protocol therapy.
All statistical tests were two-sided, and P values of <0.05 were considered to indicate statistical significance. Statistical analyses were performed using R v4.2 (R Core Team, 2022).10
Results:
Between January 13, 2017, and September 16, 2022, 300 patientswere accrued and randomized to the atorvastatin (n=150) or placebo arms (n=150), and 102 met eligibility for the DLBCL R-CHOP subgroup analysis (Figure 1).
Figure 1:
CONSORT diagram.
Patient characteristics were balanced between the two arms (Table 1). The median age was 57 years, 57% were male, 56% had IPI ≥2,32% had ECOG performance status of ≥1, 64% had stage III-IV disease, 76% had multiple extranodal sites, 34% had LDH above the upper limit of normal, 28% (29/102) had bulky disease, the median time from diagnosis to R-CHOP was 26 days (range, 6–152), and 49%, 46% and 5% were germinal center B-cell (GCB), non-GCB, or unconfirmed, respectively.
Table 1:
Baseline characteristics.
| Treatment arm | ||||
|---|---|---|---|---|
|
|
||||
| Total | Statin | Placebo | p-value | |
| n = 102 (%) | n = 55 (54) | n = 47 (46) | ||
| Age at randomization, years | ||||
| Median (range) | 57 (20 – 78) | 60 (21 – 78) | 54 (20 – 78) | 0.20 † |
| Sex | ||||
| Female | 44 (43) | 21 (38) | 23 (49) | 0.32 ‡ |
| Male | 58 (57) | 34 (62) | 24 (51) | |
| Ethnicity | ||||
| Hispanic/Latino | 7 (7) | 6 (11) | 1 (2) | 0.17 ‡ |
| Non-Hispanic/Latino | 92 (90) | 48 (87) | 44 (94) | |
| Unknown | 3 (3) | 1 (2) | 2 (4) | |
| Race | ||||
| White | 91 (89) | 48 (87) | 43 (91) | 0.74 ‡ |
| Black | 2 (2) | 2 (4) | - | |
| Asian | 3 (3) | 2 (4) | 1 (2) | |
| Unknown | 6 (6) | 3 (5) | 3 (6) | |
| Ann Arbor stage | ||||
| 1 | 17 (17) | 10 (18) | 7 (15) | 0.56 ‡ |
| 2 | 20 (20) | 11 (20) | 9 (19) | |
| 3 | 20 (20) | 13 (24) | 7 (15) | |
| 4 | 45 (44) | 21 (38) | 24 (51) | |
| LDH | ||||
| Normal | 65 (64) | 36 (65) | 29 (62) | > 0.99 ‡ |
| Elevated | 35 (34) | 19 (35) | 16 (34) | |
| Missing | 2 (2) | - | 2 (4) | |
| Extranodal sites | ||||
| Median (range) | 1 (0 – 5) | 1 (0 – 4) | 1 (0 – 5) | 0.83 ‡ |
| 0–1 | 74 (73) | 41 (75) | 33 (70) | 0.66 ‡ |
| 2+ | 28 (27) | 14 (25) | 14 (30) | |
| ECOG Performance Status Scale | ||||
| Grade 0 | 70 (69) | 39 (71) | 31 (66) | 0.59 ‡ |
| Grade 1 | 23 (23) | 10 (18) | 13 (28) | |
| Grade 2 | 8 (8) | 5 (9) | 3 (6) | |
| Grade 3 | 1 (1) | 1 (2) | - | |
| Bulk (7.5cm) | ||||
| No | 73 (72) | 40 (73) | 33 (70) | 0.83 ‡ |
| Yes | 29 (28) | 15 (27) | 14 (30) | |
| Cell of origin | ||||
| GCB | 50 (49) | 29 (53) | 21 (45) | 0.31 ‡ |
| non-GCB | 47 (46) | 22 (40) | 25 (53) | |
| Missing | 5 (5) | 4 (7) | 1 (2) | |
| IPI | ||||
| 0 | 13 (13) | 5 (9) | 8 (17) | 0.66 ^ |
| 1 | 32 (31) | 18 (33) | 14 (30) | |
| 2 | 31 (30) | 18 (33) | 13 (28) | |
| 3 | 19 (19) | 11 (20) | 8 (17) | |
| 4 | 7 (7) | 3 (5) | 4 (9) | |
| Time from diagnosis to treatment (days) | ||||
| Median (range) | 26 (6 – 152) | 28 (6 – 77) | 25 (9 – 152) | 0.39 † |
| Cycles received | ||||
| <6 | 7 (7) | 3 (5) | 4 (9) | 0.70 ‡ |
| 6 | 95 (93) | 52 (95) | 43 (91) | |
| Radiation treatment | ||||
| No | 87 (85) | 50 (91) | 37 (79) | 0.099 ‡ |
| Yes | 15 (15) | 5 (9) | 10 (21) | |
Although the proportion of patients with non-GCB disease was numerically higher in the placebo arm, the proportion of patients achieving CR was numerically higher among patients with non-GCB subtype (96% [45/47] vs 88% [44/50]). GCB, germinal center B-cell subtype; non-GCB, non-germinal center B-cell subtype; IPI, international prognostic index
Wilcoxon rank-sum test
Fisher’s exact test
Cochran-Armitage test
Most (81%)completed all six full-dose cycles of R-CHOP or stopped early due to progressive disease, 3.9% (4/102) received <6 cycles of R-CHOP (n=4), and 14.7% (15/102) required dose modifications due to AE. Fifteen patients (15%) received planned radiotherapy after completing R-CHOP.
The proportion of patients who achieved a CRappeared numerically higher in the atorvastatin arm (95% [52/55]) compared with the placebo arm(85% [40/47], although this did not reach statistical significance (p=0.18; Figure 2A).
Figure 2: Efficacy endpoints.
(A) The proportion of patients who achieved a CR appeared numerically higher in the atorvastatin arm (95% [52/55]) compared with the placebo arm (85% [40/47], but this was not statistically significant (p=0.18).(B)With a median follow-up of 45.4 months (range, 7–70), PFS at 12 and 24 months were numerically higher in the atorvastatin group (12 months: 93% [95% CI 86–100%]; 24 months: 86% [95% CI 77–96]) than in the placebo arm (12 months: 83% [95% CI 73–94]; 24 months: 81% [95% CI 70–93]), although this was not statistically significant. CR, complete response; PFS, progression-free survival.
After a median follow-up of 45.4 months (range, 7–70), the median PFS was not reached(range, 1.3–69.6) with 12-month PFS of 88% and 24-month PFS of 84%. PFS at 12 and 24 months were numerically higher in the atorvastatin group (12 months: 93% [95% CI 86–100%]; 24 months: 86% [95% CI 77–96]) thanin the placebo arm (12 months: 83% [95% CI 73–94]; 24 months: 81% [95% CI 70–93]), although this was not statistically significant (Figure 2B).
Rates of AESIs were consistent with the complete STOP-CA dataset (Figure 3).4 Muscle pain and increased ALT or AST were numerically higher in the atorvastatin group compared with the placebo group, although neither reached statistical significance. Specifically, muscle pain occurred in 12 (22%) in the atorvastatin arm and 7 (15%) in the placebo arm (p=0.45), with no cases of myositis or elevated creatinine kinase level.Increased ALT or AST occurred in 14 (25%) in the atorvastatin arm and 8 (17%) in the placebo arm. One patient in the atorvastatin arm had doxorubicin reduced by 25% in cycle 6 for grade 1 ALT/AST elevation in the setting of preexisting liver disease.
Figure 3: Safety endpoints.
Rates of muscle pain, increased ALT or AST are shown.
Discussion:
In this prespecified subgroup analysis of the STOP-CA multicenter, double-blind, randomized, placebo-controlled trial, we analyzed the impact of atorvastatin vs placebo on R-CHOP efficacy in patients with diffuse large B-cell lymphoma. Atorvastatin did not result in a statistically significant improvement in the CR rate or PFS, but both CR and PFS were numerically improved in the atorvastatin arm and supports further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.
This study was not adequately powered to demonstrate statistically significant improvements in efficacy endpoints, thus these data should be considered hypothesis-generating. However, randomized, placebo-controlled trial of atorvastatin versus placebo in patients with advanced stage DLBCL receiving frontline chemoimmunotherapy is warranted. We propose that this be nested within an upcoming randomized trial in DLBCL, e.g., of R-CHOP or Pola-RCHP plus investigational agent versus placebo, by incorporating a second randomization to atorvastatin 40 mg daily or placebo (i.e., 2 × 2 design). Although it is unlikely that an industry sponsor would support such a design, this may be feasible within a cooperative group study. In addition to answering whether atorvastatin improves the efficacy of anthracycline-based chemotherapy in patients with DLBCL, this would provide greater clarity on the impact of atorvastatin on the incidence of cardiac dysfunction in a population with uniform anthracycline exposure.
Multiple antineoplastic mechanisms of statins have been proposed. The mevalonate and cholesterol-synthesis pathways provide downstream products that are essential to proliferating cancer cells, contributing to plasma membrane integrity, and playing key roles in cell signaling, protein synthesis, and cell cycle progression.11,12 Cholesterol synthesis is dysregulated in cancer cells, which might be partially driven by augmented HMG-CoA reductase activity, and statins have been shown to have proapoptotic and antiproliferative effects.11–16 Moreover, modification of cholesterol synthesis has been shown to sensitize DLBCL cells to doxorubicin, with in vivo experiments in a murine model demonstrating that addition of a statin to doxorubicin increases antitumor activity.5
Our study has several limitations. Fewer than expected patients were eligible for this subgroup analysis and importantly the CR rate was higher than expected, both of which contributed to this study being underpowered to determine if atorvastatin increases the proportion of patients achieving CR. As STOP-CA evaluated the impact of atorvastatin on safety and cardiacoutcomes across a range of anthracycline-based regimens, only selected AESI were collected.4 However, AESI and rates of treatment modification or discontinuation were similar between arms. Additionally, statins are commonly used in patients receiving R-CHOP, can be administered concomitantly with associated supportive care medications (e.g., antimicrobial prophylaxis and antiemetics), and to our knowledge, significant safety concerns have not been reported in the literature.
Acknowledgements:
The authors are grateful to the patients who participated in the STOP-CA trial.
Footnotes
Declaration of interests statement
Ronald Nemec, Robert Redd, Hannah K. Gilman, Terry Ho, Jessica Wu, Julius Heemelar, Marielle Scherrer-Crosbie, Ephraim P. Hochberg, Jeffrey A. Barnes, Eric D. Jacobsen, and Austin I. Kimreport no relevant conflicts of interest. Donna Neuberg Reports stock ownership in Madrigal Pharmaceuticals. Philippe Armand reports receiving consulting fees from Merck, BMS, ADC Therapeutics, GenMab, Enterome, Genentech/Roche, ATB Therapeutics, Foresight, and Regeneron, and research funding from Kite, and research funding paid to institution from Merck, BMS, Adaptive, Genentech, IGM, Astra Zeneca. Caron Jaconson reports receiving consulting fees from Kite/Gilead, Novartis, BMS/Celgene, ImmPACT Bio, Instil Bio, Caribou Bio, Abintus Bio, Ipsen, Miltenyi, Morphosys, ADC Therapeutics, Abbvie, AstraZeneca, Sana, and Synthekine, and research funding paid to institution from Kite/Gilead and Pfizer. Robb S. Friedman reports receiving consulting fees from AbbVie and Beigene. Ann S. Lacasce reports receiving consulting or personal fees from Research to Practice, Kite Pharma, and Seagen. Tomas G. Neilan reports consulting or personal feesfrom Bristol Myers Squibb, Genentech, Roche, Sanofi, C4 Therapeutics, CardiolRx, RACE, and CRC Oncology, and receiving grant support from Bristol Myers Squibb, Abbott, and AstraZeneca.Jeremy S. Abramson reports consulting fees from AbbVie, Astra-Zeneca, BeiGene, BMS, Caribou Biosciences, Cellectar, Century Therapeutics, Epizyme, Genentech, Genmab, Incyte, Interius, Janssen, Kite Pharma, Lilly, and Takeda, and research support paid to institution from BMS, Cellectis, Merck, Mustang Bio, Seagen. Jacob D. Soumerai reports consulting fees from Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, Roche, Seattle Genetics, and TG Therapeutics, and research funding paid to institution from Adaptive Biotechnologies, Beigene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics.
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