Comment
Chronic lymphocytic leukaemia is the most common leukaemia in western countries and mainly affects elderly people: the median age at diagnosis is 72 years. Nonetheless, elderly people have been underrepresented in most landmark trials.1–4 Findings from such studies therefore had little validity for elderly patients with chronic lymphocytic leukaemia. In The Lancet, Peter Hillmen and colleagues5 report results from a trial that enrolled mainly older individuals (median age 69 years, range 35–92). 447 patients with previously untreated chronic lymphocytic leukaemia were enrolled, and were treated with chlorambucil alone (226 patients) or with chlorambucil plus ofatumumab, a type 1 anti-CD20 monoclonal antibody (221 patients). Patients assigned to chlorambucil plus ofatumumab had more complete remissions and significantly improved median progression-free survival, the trial’s primary endpoint, than did those assigned to chlorambucil (22·4 months vs 13·1 months; hazard ratio 0·57 [95% CI 0·45–0·72]). Side-effects such as neutropenia were more common with the combination treatment and infusion-related reactions occurred, but side-effects were manageable and did not greatly affect treatment feasibility. More clinical trials are now being done in elderly patients with chronic lymphocytic leukaemia and various candidate regimens for such patients have emerged.6–11 Several aspects of Hillmen and colleagues’ study5 deserve emphasis and could be key to further improvements in treatment of chronic lymphocytic leukaemia in this population. Systematic assessment and reporting of comorbidities is one of these aspects. Elderly patients with chronic lymphocytic leukaemia are heterogeneous in individual burden of comorbidity—a known determinant of patient survival and perhaps treatment toxicity or feasibility.12,13 Hillmen and colleagues applied a comorbidity score, the cumulative illness rating scale, to quantify and report overall burden of comorbidity in their trial population. This approach allowed assessment of whether elderly patients were more likely to be fit or unfit. We believe that such an approach is worthy of consideration for continuing and future trials in chronic lymphocytic leukaemia. Assessment based on age alone will not be sufficiently informative about patient fitness and vulnerability in
a trial population. However, since many comorbidity scores, and even several versions of single scores such as the cumulative illness rating scale, exist, comorbidity assessment in chronic lymphocytic leukaemia trials will need harmonisation. Comparisons will undoubtedly be drawn between the results of Hillmen and colleagues’ study5 and another large phase 3 trial6 that also included patients with previously untreated chronic lymphocytic leukaemia and comorbidities. This second study compared chlorambucil alone, chlorambucil plus rituximab, and chlorambucil plus obinutuzumab, a glycoengineered type 2 anti-CD20 monoclonal antibody. Median progression-free survival values for the three study groups were 11·1, 15·4, and 29·2 months, respectively.14 It must be emphasised that direct comparisons between the two trials are limited by differences in patient characteristics, study drug dosing, treatment schedules, and methods of data processing. Evidence from these trials does not allow for definitive conclusions on the optimum dose of chlorambucil when combined with anti-CD20 antibodies. Indeed, except for the comparison of obinutuzumab with rituximab (for which head-to-head data exist), conclusions about superiority of one or another antibody with regard to efficacy or tolerability are uncertain. While these debates are relevant to treatment of elderly people with chronic lymphocytic leukaemia, the key achievement of Hillmen and colleagues5 is the firm establishment of chemoimmunotherapy as a standard of care in older and less fit patients with previously untreated chronic lymphocytic leukaemia. Evidence is increasing that anti-CD20 antibodies (when combined with chemotherapy) might even prolong life for such patients.14 Therefore, randomised trials investigating novel front-line regimens in this patient population will now have to use chemoimmunotherapy rather than chemotherapy as a comparator. Backed by phase 3 studies such as the one by Hillmen and colleagues,5 chemoimmunotherapy with chlorambucil and an anti-CD20 antibody can be considered as a good starting point for further treatment advances. The next step forward is combination of anti-CD20 antibodies with backbone therapies other than chlorambucil, including other chemotherapeutics (eg, bendamustine)
www.thelancet.com Published online April 14, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60293-8
Pr J Bernard/CNRI/Science Photo Library
Towards improved frontline treatment of CLL in the elderly
Chronic lymphocytic leukaemia Published Online April 14, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60293-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)60027-7
1
Comment
or targeted drugs (eg, ibrutinib, idelalisib, venetoclax, or lenalidomide). Combinations of such drugs with antiCD20 antibodies have shown promise in elderly patients with chronic lymphocytic leukaemia, and therefore are being investigated in randomised trials. The work by Hillmen and colleagues5 has reinforced the basis for these efforts towards a better front-line treatment of chronic lymphocytic leukaemia in elderly individuals. *Valentin Goede, Michael Hallek German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University of Cologne, Cologne 50924, Germany [email protected] VG has received personal fees from GlaxoSmithKline, Roche, and Mundipharma, and research funding from Roche and Mundiphama. MH has received personal fees from GlaxoSmithKline, Roche, Mundipharma, Janssen, Gilead, AbbVie, and Celgene. 1
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Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–74. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4378–84. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007; 25: 793–98. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107: 885–91.
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Hillmen P, Robak T, Janssens A, et al, for the COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPEMENT1): a randomised, multicentre, open-label phase 3 trial. Lancet 2015; published online April 14. http://dx.doi.org/10.1016/ S0140-6736(15)60027-7. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014; 370: 1101–10. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007. O’Brien S, Lamanna N, Kipps TJ, et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014; 124: abstract 1994. Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014; 124: abstract 1986. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48–58. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011; 118: 3489–98. Baumann T, Delgado J, Santacruz R, et al. Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model. Haematologica 2014; 99: 1599–604. Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014; 99: 1095–100. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015; published online Jan 30. DOI:10.1038/leu.2015.14.
www.thelancet.com Published online April 14, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60293-8
Chronic lymphocytic leukaemia is the most common leukaemia in western countries and mainly affects elderly people: the median age at diagnosis is 72 years. Nonetheless, elderly people have been underrepresented in most landmark trials.1–4 Findings from such studies therefore had little validity for elderly patients with chronic lymphocytic leukaemia. In The Lancet, Peter Hillmen and colleagues5 report results from a trial that enrolled mainly older individuals (median age 69 years, range 35–92). 447 patients with previously untreated chronic lymphocytic leukaemia were enrolled, and were treated with chlorambucil alone (226 patients) or with chlorambucil plus ofatumumab, a type 1 anti-CD20 monoclonal antibody (221 patients). Patients assigned to chlorambucil plus ofatumumab had more complete remissions and significantly improved median progression-free survival, the trial’s primary endpoint, than did those assigned to chlorambucil (22·4 months vs 13·1 months; hazard ratio 0·57 [95% CI 0·45–0·72]). Side-effects such as neutropenia were more common with the combination treatment and infusion-related reactions occurred, but side-effects were manageable and did not greatly affect treatment feasibility. More clinical trials are now being done in elderly patients with chronic lymphocytic leukaemia and various candidate regimens for such patients have emerged.6–11 Several aspects of Hillmen and colleagues’ study5 deserve emphasis and could be key to further improvements in treatment of chronic lymphocytic leukaemia in this population. Systematic assessment and reporting of comorbidities is one of these aspects. Elderly patients with chronic lymphocytic leukaemia are heterogeneous in individual burden of comorbidity—a known determinant of patient survival and perhaps treatment toxicity or feasibility.12,13 Hillmen and colleagues applied a comorbidity score, the cumulative illness rating scale, to quantify and report overall burden of comorbidity in their trial population. This approach allowed assessment of whether elderly patients were more likely to be fit or unfit. We believe that such an approach is worthy of consideration for continuing and future trials in chronic lymphocytic leukaemia. Assessment based on age alone will not be sufficiently informative about patient fitness and vulnerability in
a trial population. However, since many comorbidity scores, and even several versions of single scores such as the cumulative illness rating scale, exist, comorbidity assessment in chronic lymphocytic leukaemia trials will need harmonisation. Comparisons will undoubtedly be drawn between the results of Hillmen and colleagues’ study5 and another large phase 3 trial6 that also included patients with previously untreated chronic lymphocytic leukaemia and comorbidities. This second study compared chlorambucil alone, chlorambucil plus rituximab, and chlorambucil plus obinutuzumab, a glycoengineered type 2 anti-CD20 monoclonal antibody. Median progression-free survival values for the three study groups were 11·1, 15·4, and 29·2 months, respectively.14 It must be emphasised that direct comparisons between the two trials are limited by differences in patient characteristics, study drug dosing, treatment schedules, and methods of data processing. Evidence from these trials does not allow for definitive conclusions on the optimum dose of chlorambucil when combined with anti-CD20 antibodies. Indeed, except for the comparison of obinutuzumab with rituximab (for which head-to-head data exist), conclusions about superiority of one or another antibody with regard to efficacy or tolerability are uncertain. While these debates are relevant to treatment of elderly people with chronic lymphocytic leukaemia, the key achievement of Hillmen and colleagues5 is the firm establishment of chemoimmunotherapy as a standard of care in older and less fit patients with previously untreated chronic lymphocytic leukaemia. Evidence is increasing that anti-CD20 antibodies (when combined with chemotherapy) might even prolong life for such patients.14 Therefore, randomised trials investigating novel front-line regimens in this patient population will now have to use chemoimmunotherapy rather than chemotherapy as a comparator. Backed by phase 3 studies such as the one by Hillmen and colleagues,5 chemoimmunotherapy with chlorambucil and an anti-CD20 antibody can be considered as a good starting point for further treatment advances. The next step forward is combination of anti-CD20 antibodies with backbone therapies other than chlorambucil, including other chemotherapeutics (eg, bendamustine)
www.thelancet.com Published online April 14, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60293-8
Pr J Bernard/CNRI/Science Photo Library
Towards improved frontline treatment of CLL in the elderly
Chronic lymphocytic leukaemia Published Online April 14, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60293-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)60027-7
1
Comment
or targeted drugs (eg, ibrutinib, idelalisib, venetoclax, or lenalidomide). Combinations of such drugs with antiCD20 antibodies have shown promise in elderly patients with chronic lymphocytic leukaemia, and therefore are being investigated in randomised trials. The work by Hillmen and colleagues5 has reinforced the basis for these efforts towards a better front-line treatment of chronic lymphocytic leukaemia in elderly individuals. *Valentin Goede, Michael Hallek German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University of Cologne, Cologne 50924, Germany [email protected] VG has received personal fees from GlaxoSmithKline, Roche, and Mundipharma, and research funding from Roche and Mundiphama. MH has received personal fees from GlaxoSmithKline, Roche, Mundipharma, Janssen, Gilead, AbbVie, and Celgene. 1
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3
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Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–74. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4378–84. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007; 25: 793–98. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107: 885–91.
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Hillmen P, Robak T, Janssens A, et al, for the COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPEMENT1): a randomised, multicentre, open-label phase 3 trial. Lancet 2015; published online April 14. http://dx.doi.org/10.1016/ S0140-6736(15)60027-7. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014; 370: 1101–10. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007. O’Brien S, Lamanna N, Kipps TJ, et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014; 124: abstract 1994. Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014; 124: abstract 1986. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48–58. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011; 118: 3489–98. Baumann T, Delgado J, Santacruz R, et al. Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model. Haematologica 2014; 99: 1599–604. Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014; 99: 1095–100. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015; published online Jan 30. DOI:10.1038/leu.2015.14.
www.thelancet.com Published online April 14, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60293-8
