Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL

J. A. Woyach, A. S. Ruppert, N. A. Heerema, W. Zhao, A. M. Booth, Wei D Ding, N. L. Bartlett, D. M. Brander, P. M. Barr, K. A. Rogers, Sameer A Parikh, S. Coutre, A. Hurria, J. R. Brown, G. Lozanski, J. S. Blachly, H. G. Ozer, B. Major-Elechi, B. Fruth, S. NattamR. A. Larson, H. Erba, Mark R Litzow, C. Owen, C. Kuzma, J. S. Abramson, R. F. Little, S. E. Smith, R. M. Stone, Sumithra J Mandrekar, J. C. Byrd

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Abstract

BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progressionfree survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P>0.001). There was no significant difference between the ibrutinib-plusrituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P = 0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872.).

Original languageEnglish (US)
Pages (from-to)2517-2528
Number of pages12
JournalNew England Journal of Medicine
Volume379
Issue number26
DOIs
StatePublished - Dec 27 2018

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B-Cell Chronic Lymphocytic Leukemia
Disease-Free Survival
PCI 32765
Rituximab
Clinical Trials Data Monitoring Committees
Confidence Intervals
Survival
National Cancer Institute (U.S.)
United States Food and Drug Administration
Therapeutics
Bendamustine Hydrochloride
Disease Progression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W. D., ... Byrd, J. C. (2018). Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. New England Journal of Medicine, 379(26), 2517-2528. https://doi.org/10.1056/NEJMoa1812836

Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. / Woyach, J. A.; Ruppert, A. S.; Heerema, N. A.; Zhao, W.; Booth, A. M.; Ding, Wei D; Bartlett, N. L.; Brander, D. M.; Barr, P. M.; Rogers, K. A.; Parikh, Sameer A; Coutre, S.; Hurria, A.; Brown, J. R.; Lozanski, G.; Blachly, J. S.; Ozer, H. G.; Major-Elechi, B.; Fruth, B.; Nattam, S.; Larson, R. A.; Erba, H.; Litzow, Mark R; Owen, C.; Kuzma, C.; Abramson, J. S.; Little, R. F.; Smith, S. E.; Stone, R. M.; Mandrekar, Sumithra J; Byrd, J. C.

In: New England Journal of Medicine, Vol. 379, No. 26, 27.12.2018, p. 2517-2528.

Research output: Contribution to journalArticle

Woyach, JA, Ruppert, AS, Heerema, NA, Zhao, W, Booth, AM, Ding, WD, Bartlett, NL, Brander, DM, Barr, PM, Rogers, KA, Parikh, SA, Coutre, S, Hurria, A, Brown, JR, Lozanski, G, Blachly, JS, Ozer, HG, Major-Elechi, B, Fruth, B, Nattam, S, Larson, RA, Erba, H, Litzow, MR, Owen, C, Kuzma, C, Abramson, JS, Little, RF, Smith, SE, Stone, RM, Mandrekar, SJ & Byrd, JC 2018, 'Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL', New England Journal of Medicine, vol. 379, no. 26, pp. 2517-2528. https://doi.org/10.1056/NEJMoa1812836
Woyach, J. A. ; Ruppert, A. S. ; Heerema, N. A. ; Zhao, W. ; Booth, A. M. ; Ding, Wei D ; Bartlett, N. L. ; Brander, D. M. ; Barr, P. M. ; Rogers, K. A. ; Parikh, Sameer A ; Coutre, S. ; Hurria, A. ; Brown, J. R. ; Lozanski, G. ; Blachly, J. S. ; Ozer, H. G. ; Major-Elechi, B. ; Fruth, B. ; Nattam, S. ; Larson, R. A. ; Erba, H. ; Litzow, Mark R ; Owen, C. ; Kuzma, C. ; Abramson, J. S. ; Little, R. F. ; Smith, S. E. ; Stone, R. M. ; Mandrekar, Sumithra J ; Byrd, J. C. / Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 26. pp. 2517-2528.
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abstract = "BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progressionfree survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74{\%} with bendamustine plus rituximab and was higher with ibrutinib alone (87{\%}; hazard ratio for disease progression or death, 0.39; 95{\%} confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88{\%}; hazard ratio, 0.38; 95{\%} CI, 0.25 to 0.59; P>0.001). There was no significant difference between the ibrutinib-plusrituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95{\%} CI, 0.62 to 1.62; P = 0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61{\%}) than with ibrutinib or ibrutinib plus rituximab (41{\%} and 39{\%}, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63{\%}) than with the ibrutinib-containing regimens (74{\%} with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872.).",
author = "Woyach, {J. A.} and Ruppert, {A. S.} and Heerema, {N. A.} and W. Zhao and Booth, {A. M.} and Ding, {Wei D} and Bartlett, {N. L.} and Brander, {D. M.} and Barr, {P. M.} and Rogers, {K. A.} and Parikh, {Sameer A} and S. Coutre and A. Hurria and Brown, {J. R.} and G. Lozanski and Blachly, {J. S.} and Ozer, {H. G.} and B. Major-Elechi and B. Fruth and S. Nattam and Larson, {R. A.} and H. Erba and Litzow, {Mark R} and C. Owen and C. Kuzma and Abramson, {J. S.} and Little, {R. F.} and Smith, {S. E.} and Stone, {R. M.} and Mandrekar, {Sumithra J} and Byrd, {J. C.}",
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TY - JOUR

T1 - Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL

AU - Woyach, J. A.

AU - Ruppert, A. S.

AU - Heerema, N. A.

AU - Zhao, W.

AU - Booth, A. M.

AU - Ding, Wei D

AU - Bartlett, N. L.

AU - Brander, D. M.

AU - Barr, P. M.

AU - Rogers, K. A.

AU - Parikh, Sameer A

AU - Coutre, S.

AU - Hurria, A.

AU - Brown, J. R.

AU - Lozanski, G.

AU - Blachly, J. S.

AU - Ozer, H. G.

AU - Major-Elechi, B.

AU - Fruth, B.

AU - Nattam, S.

AU - Larson, R. A.

AU - Erba, H.

AU - Litzow, Mark R

AU - Owen, C.

AU - Kuzma, C.

AU - Abramson, J. S.

AU - Little, R. F.

AU - Smith, S. E.

AU - Stone, R. M.

AU - Mandrekar, Sumithra J

AU - Byrd, J. C.

PY - 2018/12/27

Y1 - 2018/12/27

N2 - BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progressionfree survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P>0.001). There was no significant difference between the ibrutinib-plusrituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P = 0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872.).

AB - BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progressionfree survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P>0.001). There was no significant difference between the ibrutinib-plusrituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P = 0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872.).

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