- Email: [email protected]
B-cell depletion in immune thrombocytopenia
Comment
8
9
10
Chen JY, Eborall H, Armstrong N. Stakeholders’ positions in the breast screening debate, and media coverage of the debate: a qualitative study. Crit Public Health 2013; 19: 1–11. Wegwarth O, Schwartz LM, Woloshin S, Gaissmaier W, Gigerenzer G. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med 2012; 156: 340–49. Heleno B, Thomsen MF, Rodrigues DS, Jorgensen KJ, Brodersen J. Quantification of harms in cancer screening trials: literature review. BMJ 2013; 347: 5334.
11
12
DeFrank JT, Barclay C, Sheridan S, et al. The psychological harms of screening: the evidence we have versus the evidence we need. J Gen Intern Med 2015; 30: 242–48. Edwards AGK, Gurudutt N, Ahmed H, et al. Personalised risk communication for informed decision making about taking screening tests. Cochrane Database Syst Rev 2013; 2: CD001865.
B-cell depletion in immune thrombocytopenia Rituximab is a chimeric monoclonal antibody targeting CD20-expressing B cells that has revolutionised care of patients with B-cell lymphoma. Because of its B cell-depleting effect, rituximab was first hypothesised to be useful to treat autoimmune disorders in the 1990s. Results from many studies have since shown its efficacy in autoimmune disorders, including immune thrombocytopenia.1,2 In The Lancet, Waleed Ghanima and colleagues3 present the first multicentre, randomised, double-masked, placebocontrolled trial testing rituximab as a second-line treatment for immune thrombocytopenia. Patient with immune thrombocytopenia (no rituximab)
In present treatment for immune thrombocytopenia, rituximab is often used for patients who are refractory to corticosteroids or intravenous immunoglobulin, or both, or those who relapse on reduction of corticosteroid dose, and is listed as a second-line treatment in two treatment guidelines.4,5 In view of this endorsement and clinical practice, the absence of supportive evidence is surprising. No licensing or dose finding studies have been done in immune thrombocytopenia. Of the many studies done in this disease, only four were randomised studies, with one assessing rituximab alone, in newly diagnosed or relapsed immune thrombocytopenia,6
Published Online February 5, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61930-9 See Articles page 1653
Patient with immune thrombocytopenia treated with rituximab
57·8
34·5
92·1
2·44 Memory B cells
: CD21
Memory B cells
5·4
2·35 0
10
2
10
3
CD27+
10
4
10
5
4·05
1·44 0
10
2
10 CD27+ 3
10
4
10
5
Figure: Measurement of memory B cells by flow cytometry Prolonged depletion of CD21+ CD27+ memory B cells in patient with immune thrombocytopenia 12 months after rituxumab treatment (right panel) compared with patient who has not received rituxumab (left panel).
www.thelancet.com Vol 385 April 25, 2015
1599
Comment
showing no difference between treatment and placebo for its primary endpoint, treatment failure.6 Other studies compared the effects of rituximab plus dexamethasone and suggested an overall response rate of around 60%, with an increased response in newly diagnosed immune thrombocytopenia and with the addition of dexamethasone.7–11 The accompanying study by Ghanima and colleagues3 is the first attempt to address whether a difference exists between patients receiving rituximab monotherapy versus standard care as a second-line therapy. The data showed no benefit of using rituximab compared with placebo in 109 patients with steroidunresponsive immune thrombocytopenia for the trial’s primary endpoint—incidence of treatment failure as judged by splenectomy, or meeting criteria for splenectomy, by 1·5 years (46% patients assigned to rituximab vs 52% assigned to placebo). Total steroid use and bleeding symptoms were also similar in the two groups by 1·5 years. Despite this absence of efficacy, the rituximab group did show a higher likelihood of a platelet count maintained at more than 30 × 10⁹/L within the first 15 months, and these remissions were longer lasting (36 weeks with rituximab vs 7 weeks for placebo). The authors suggest a 10% difference in response rates, thus needing 10 patients to be treated for every responder. Major strengths of Ghanima and colleagues’ study3 are its clinically relevant endpoints and its rigorous design. Limitations include the small study size (although comparatively large for this rare disease), which might not have been adequately powered to detect small differences between the two groups. Additionally, the definitions of response, needing only one platelet count higher than 30 × 10⁹/L, might explain the notable response rate reported in the placebo group. Further subgroup analyses, health-related quality of life, and assessment of fatigue could have been useful to identify a cohort for which clinical response might be significant. Nonetheless, the absence of a substantial long-term response raises important questions about the role of B-cell depleting therapy, particularly in the era of alternative treatments, such as thrombopoietin receptor agonists. Judgments about the potential benefits of rituximab should be balanced by adverse effects, namely infectious risks. Long-term effects on the memory B-cell population are reported in patients, even years after 1600
treatment (figure). The analysis provided by Ghanima and colleagues shows a non-significant increase in infection in the rituximab group, which continued to increase over time, and other reports have underlined an increased infection rate and reduced vaccine responses after rituximab.12 In view of the availability of non-immunosuppressive treatments, recommendation of rituximab treatment is difficult taking into account these data. However, assessment of responses in a rare and heterogeneous disease such as immune thrombocytopenia is challenging. Although no difference between patient cohorts might exist, individual patients could have a clinically meaningful response to rituximab, with a more rapid and persistent rise in platelet counts, resulting in less corticosteroid use. Although no differences in total dose of corticosteroids between groups were reported by Ghanima and colleagues, the rituximab-treated cohort would have included those who did not respond to rituximab, which could have masked any effects. Furthermore, the response rate in patients in the standard care group was surprisingly high (73%), which might suggest difficulties in defining a response in this disorder. Ghanima and colleagues’ study3 is the first randomised controlled trial of rituximab as a second-line drug, and helps to clarify the use (if any) of single-agent rituximab in patients with steroid relapsed or refractory immune thrombocytopenia. It also suggests further work that is needed in this area. For example, assessment of other clinically significant endpoints and a larger study size enabling subgroup analysis might allow identification of a population of patients in whom rituximab does give real benefits. Also, in view of reports9 of improved responses when used with dexamethasone, the addition of steroids or maintenance rituximab might improve response rates overall. Clearly, further studies are warranted. Bethan Psaila, *Nichola Cooper Department of Haematology, Imperial College London, London W12 0NN, UK [email protected] Nichola Cooper has received honoraria for consultancy work and for speaking at educational events from GSK and Amgen. BP declares no competing interests. 1
2
Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952–57. Saleh MN, Gutheil J, Moore M, et al. A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 2000; 27 (6 suppl 12): 99–103.
www.thelancet.com Vol 385 April 25, 2015
Comment
3
4
5
6
7
Ghanima W, Khelif A, Waage A, et al, on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2014; published online Feb 5. http://dx.doi.org/10.1016/S01406736(14)61495-1. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115: 168–86. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117: 4190–207. Arnold DM, Heddle NM, Carruthers J, et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood 2012; 119: 1356–62. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010; 115: 2755–62.
8
9
10
11
12
Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146: 25–33. Bussel JB, Lee CS, Seery C, et al. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica 2014; 99: 1264–71. Patel VL, Mahevas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012; 119: 5989–95. Khellaf M, Charles-Nelson A, Fain O, et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014; published online Oct 7. http://dx.doi. org/10.1182/blood-2014-06-582346. Nazi I, Kelton JG, Larche M, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122: 1946–53.
Acute flaccid paralysis is a complex clinical syndrome defined by a rapid onset of weakness and has various differential diagnoses, including poliomyelitis characterised by lesions of the anterior horn cells of the spinal cord (anterior myelitis).1 On Sept 12, 2014, physicians notified the Centers for Disease Control and Prevention (CDC) about a cluster of acute limb weakness in children in Colorado, USA.2 These cases coincided with a nationwide outbreak of enterovirus D68 infections associated with severe respiratory illnesses, especially in children.3 The unusual association of clusters of acute flaccid paralysis and the emergence of enterovirus D68 in the USA raised questions about the causal role of this serotype in patients with severe neurological manifestations. In The Lancet, Kevin Messacar and colleagues4 present a detailed description of the clinical and neuroimaging findings identified in the first defined cluster of children presenting with acute flaccid paralysis or cranial nerve dysfunction in the USA. Inclusion criteria were acute onset of focal limb weakness taking place between Aug 1, 2014, and Oct 31, 2014, and MRI findings showing a spinal-cord lesion largely restricted to grey matter. The investigators identified 12 children, with a median age of 11·5 years (range 1–18). All children had a preceding febrile respiratory illness with a median onset of 7 days (range 3–16) before neurological symptoms. The clinical and MRI investigations of the cases of acute flaccid paralysis identified common features: (1) flaccid limb weakness that was mainly proximal, asymmetric, and associated with hyporeflexia, intact sensation, and myalgia; (2) www.thelancet.com Vol 385 April 25, 2015
cranial nerve dysfunction mainly associated with bulbar weakness; and (3) MRI of the spinal cord showing longitudinally extensive lesions of grey matter with predominant anterior horn-cell involvement and brainstem lesions. In the past 4 months, similar cases have occurred in the USA and in Europe.2,5 As of Jan 14, 2015, CDC had verified reports of 107 children in 34 states in the USA who developed a similar neurological illness that is now being referred to as acute flaccid myelitis.6 Together, these data evoke a feeling of déjà vu because the pattern of neurological deficits and neuroimaging abnormalities is consistent with tropism for motor nerve cells and presents striking similarities with infections associated with recognised neurotropic enteroviruses, such as polioviruses and enterovirus A71.7,8 Most importantly, and alarmingly, all ten children with follow-up data in the study had neuromotor sequelae, as did children with enterovirus A71 brainstem encephalitis after the hand, foot, and mouth disease in Taiwan in 1998.9 To date, no targeted therapies or interventions have been effective for treatment of patients with acute flaccid myelitis.10 Messacar and colleagues’ article4 also emphasises important considerations regarding the diagnostic assessment of cases of acute flaccid myelitis, and shows that identification of a pathogen can be challenging. Screening of various respiratory pathogens in nasopharyngeal specimens yielded positive results for rhinovirus and enterovirus in eight (73%) of 11 children and enterovirus D68 was further identified by genotyping in five (45%)
Ramon Andrade 3DCiencia/Science Photo Library
Acute flaccid myelitis and enteroviruses: an ongoing story
Published Online January 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60121-0 See Articles page 1662
1601
8
9
10
Chen JY, Eborall H, Armstrong N. Stakeholders’ positions in the breast screening debate, and media coverage of the debate: a qualitative study. Crit Public Health 2013; 19: 1–11. Wegwarth O, Schwartz LM, Woloshin S, Gaissmaier W, Gigerenzer G. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med 2012; 156: 340–49. Heleno B, Thomsen MF, Rodrigues DS, Jorgensen KJ, Brodersen J. Quantification of harms in cancer screening trials: literature review. BMJ 2013; 347: 5334.
11
12
DeFrank JT, Barclay C, Sheridan S, et al. The psychological harms of screening: the evidence we have versus the evidence we need. J Gen Intern Med 2015; 30: 242–48. Edwards AGK, Gurudutt N, Ahmed H, et al. Personalised risk communication for informed decision making about taking screening tests. Cochrane Database Syst Rev 2013; 2: CD001865.
B-cell depletion in immune thrombocytopenia Rituximab is a chimeric monoclonal antibody targeting CD20-expressing B cells that has revolutionised care of patients with B-cell lymphoma. Because of its B cell-depleting effect, rituximab was first hypothesised to be useful to treat autoimmune disorders in the 1990s. Results from many studies have since shown its efficacy in autoimmune disorders, including immune thrombocytopenia.1,2 In The Lancet, Waleed Ghanima and colleagues3 present the first multicentre, randomised, double-masked, placebocontrolled trial testing rituximab as a second-line treatment for immune thrombocytopenia. Patient with immune thrombocytopenia (no rituximab)
In present treatment for immune thrombocytopenia, rituximab is often used for patients who are refractory to corticosteroids or intravenous immunoglobulin, or both, or those who relapse on reduction of corticosteroid dose, and is listed as a second-line treatment in two treatment guidelines.4,5 In view of this endorsement and clinical practice, the absence of supportive evidence is surprising. No licensing or dose finding studies have been done in immune thrombocytopenia. Of the many studies done in this disease, only four were randomised studies, with one assessing rituximab alone, in newly diagnosed or relapsed immune thrombocytopenia,6
Published Online February 5, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61930-9 See Articles page 1653
Patient with immune thrombocytopenia treated with rituximab
57·8
34·5
92·1
2·44 Memory B cells
Memory B cells
5·4
2·35 0
10
2
10
3
CD27+
10
4
10
5
4·05
1·44 0
10
2
10 CD27+ 3
10
4
10
5
Figure: Measurement of memory B cells by flow cytometry Prolonged depletion of CD21+ CD27+ memory B cells in patient with immune thrombocytopenia 12 months after rituxumab treatment (right panel) compared with patient who has not received rituxumab (left panel).
www.thelancet.com Vol 385 April 25, 2015
1599
Comment
showing no difference between treatment and placebo for its primary endpoint, treatment failure.6 Other studies compared the effects of rituximab plus dexamethasone and suggested an overall response rate of around 60%, with an increased response in newly diagnosed immune thrombocytopenia and with the addition of dexamethasone.7–11 The accompanying study by Ghanima and colleagues3 is the first attempt to address whether a difference exists between patients receiving rituximab monotherapy versus standard care as a second-line therapy. The data showed no benefit of using rituximab compared with placebo in 109 patients with steroidunresponsive immune thrombocytopenia for the trial’s primary endpoint—incidence of treatment failure as judged by splenectomy, or meeting criteria for splenectomy, by 1·5 years (46% patients assigned to rituximab vs 52% assigned to placebo). Total steroid use and bleeding symptoms were also similar in the two groups by 1·5 years. Despite this absence of efficacy, the rituximab group did show a higher likelihood of a platelet count maintained at more than 30 × 10⁹/L within the first 15 months, and these remissions were longer lasting (36 weeks with rituximab vs 7 weeks for placebo). The authors suggest a 10% difference in response rates, thus needing 10 patients to be treated for every responder. Major strengths of Ghanima and colleagues’ study3 are its clinically relevant endpoints and its rigorous design. Limitations include the small study size (although comparatively large for this rare disease), which might not have been adequately powered to detect small differences between the two groups. Additionally, the definitions of response, needing only one platelet count higher than 30 × 10⁹/L, might explain the notable response rate reported in the placebo group. Further subgroup analyses, health-related quality of life, and assessment of fatigue could have been useful to identify a cohort for which clinical response might be significant. Nonetheless, the absence of a substantial long-term response raises important questions about the role of B-cell depleting therapy, particularly in the era of alternative treatments, such as thrombopoietin receptor agonists. Judgments about the potential benefits of rituximab should be balanced by adverse effects, namely infectious risks. Long-term effects on the memory B-cell population are reported in patients, even years after 1600
treatment (figure). The analysis provided by Ghanima and colleagues shows a non-significant increase in infection in the rituximab group, which continued to increase over time, and other reports have underlined an increased infection rate and reduced vaccine responses after rituximab.12 In view of the availability of non-immunosuppressive treatments, recommendation of rituximab treatment is difficult taking into account these data. However, assessment of responses in a rare and heterogeneous disease such as immune thrombocytopenia is challenging. Although no difference between patient cohorts might exist, individual patients could have a clinically meaningful response to rituximab, with a more rapid and persistent rise in platelet counts, resulting in less corticosteroid use. Although no differences in total dose of corticosteroids between groups were reported by Ghanima and colleagues, the rituximab-treated cohort would have included those who did not respond to rituximab, which could have masked any effects. Furthermore, the response rate in patients in the standard care group was surprisingly high (73%), which might suggest difficulties in defining a response in this disorder. Ghanima and colleagues’ study3 is the first randomised controlled trial of rituximab as a second-line drug, and helps to clarify the use (if any) of single-agent rituximab in patients with steroid relapsed or refractory immune thrombocytopenia. It also suggests further work that is needed in this area. For example, assessment of other clinically significant endpoints and a larger study size enabling subgroup analysis might allow identification of a population of patients in whom rituximab does give real benefits. Also, in view of reports9 of improved responses when used with dexamethasone, the addition of steroids or maintenance rituximab might improve response rates overall. Clearly, further studies are warranted. Bethan Psaila, *Nichola Cooper Department of Haematology, Imperial College London, London W12 0NN, UK [email protected] Nichola Cooper has received honoraria for consultancy work and for speaking at educational events from GSK and Amgen. BP declares no competing interests. 1
2
Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952–57. Saleh MN, Gutheil J, Moore M, et al. A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 2000; 27 (6 suppl 12): 99–103.
www.thelancet.com Vol 385 April 25, 2015
Comment
3
4
5
6
7
Ghanima W, Khelif A, Waage A, et al, on behalf of the RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2014; published online Feb 5. http://dx.doi.org/10.1016/S01406736(14)61495-1. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115: 168–86. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117: 4190–207. Arnold DM, Heddle NM, Carruthers J, et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood 2012; 119: 1356–62. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010; 115: 2755–62.
8
9
10
11
12
Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146: 25–33. Bussel JB, Lee CS, Seery C, et al. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica 2014; 99: 1264–71. Patel VL, Mahevas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012; 119: 5989–95. Khellaf M, Charles-Nelson A, Fain O, et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014; published online Oct 7. http://dx.doi. org/10.1182/blood-2014-06-582346. Nazi I, Kelton JG, Larche M, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122: 1946–53.
Acute flaccid paralysis is a complex clinical syndrome defined by a rapid onset of weakness and has various differential diagnoses, including poliomyelitis characterised by lesions of the anterior horn cells of the spinal cord (anterior myelitis).1 On Sept 12, 2014, physicians notified the Centers for Disease Control and Prevention (CDC) about a cluster of acute limb weakness in children in Colorado, USA.2 These cases coincided with a nationwide outbreak of enterovirus D68 infections associated with severe respiratory illnesses, especially in children.3 The unusual association of clusters of acute flaccid paralysis and the emergence of enterovirus D68 in the USA raised questions about the causal role of this serotype in patients with severe neurological manifestations. In The Lancet, Kevin Messacar and colleagues4 present a detailed description of the clinical and neuroimaging findings identified in the first defined cluster of children presenting with acute flaccid paralysis or cranial nerve dysfunction in the USA. Inclusion criteria were acute onset of focal limb weakness taking place between Aug 1, 2014, and Oct 31, 2014, and MRI findings showing a spinal-cord lesion largely restricted to grey matter. The investigators identified 12 children, with a median age of 11·5 years (range 1–18). All children had a preceding febrile respiratory illness with a median onset of 7 days (range 3–16) before neurological symptoms. The clinical and MRI investigations of the cases of acute flaccid paralysis identified common features: (1) flaccid limb weakness that was mainly proximal, asymmetric, and associated with hyporeflexia, intact sensation, and myalgia; (2) www.thelancet.com Vol 385 April 25, 2015
cranial nerve dysfunction mainly associated with bulbar weakness; and (3) MRI of the spinal cord showing longitudinally extensive lesions of grey matter with predominant anterior horn-cell involvement and brainstem lesions. In the past 4 months, similar cases have occurred in the USA and in Europe.2,5 As of Jan 14, 2015, CDC had verified reports of 107 children in 34 states in the USA who developed a similar neurological illness that is now being referred to as acute flaccid myelitis.6 Together, these data evoke a feeling of déjà vu because the pattern of neurological deficits and neuroimaging abnormalities is consistent with tropism for motor nerve cells and presents striking similarities with infections associated with recognised neurotropic enteroviruses, such as polioviruses and enterovirus A71.7,8 Most importantly, and alarmingly, all ten children with follow-up data in the study had neuromotor sequelae, as did children with enterovirus A71 brainstem encephalitis after the hand, foot, and mouth disease in Taiwan in 1998.9 To date, no targeted therapies or interventions have been effective for treatment of patients with acute flaccid myelitis.10 Messacar and colleagues’ article4 also emphasises important considerations regarding the diagnostic assessment of cases of acute flaccid myelitis, and shows that identification of a pathogen can be challenging. Screening of various respiratory pathogens in nasopharyngeal specimens yielded positive results for rhinovirus and enterovirus in eight (73%) of 11 children and enterovirus D68 was further identified by genotyping in five (45%)
Ramon Andrade 3DCiencia/Science Photo Library
Acute flaccid myelitis and enteroviruses: an ongoing story
Published Online January 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60121-0 See Articles page 1662
1601