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B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment.

Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O - PLoS ONE (2015)

Bottom Line: We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment.The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.

ABSTRACT

Background: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

Methods: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

Findings: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

Conclusion: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

Trial registration: ClinicalTrials.gov NCT01156909.

No MeSH data available.


Related in: MedlinePlus

Historic comparison of Fatigue scores for nine patients given placebo in KTS-1-2008, and rituximab maintenance in KTS-2-2010.Nine patients from the placebo group in the previous randomized KTS-1-2008 study were included in the present KTS-2-2010 study with rituximab induction and maintenance treatment. The mean Fatigue scores for consecutive 3-months intervals, until 12 months follow-up, were compared using General Linear Model (GLM) for repeated measures. Four time intervals with mean Fatigue scores in each were included in the comparison. Main effect for the interaction between time and intervention group (rituximab maintenance versus the patient’s own “historic” placebo) was assessed.
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pone.0129898.g004: Historic comparison of Fatigue scores for nine patients given placebo in KTS-1-2008, and rituximab maintenance in KTS-2-2010.Nine patients from the placebo group in the previous randomized KTS-1-2008 study were included in the present KTS-2-2010 study with rituximab induction and maintenance treatment. The mean Fatigue scores for consecutive 3-months intervals, until 12 months follow-up, were compared using General Linear Model (GLM) for repeated measures. Four time intervals with mean Fatigue scores in each were included in the comparison. Main effect for the interaction between time and intervention group (rituximab maintenance versus the patient’s own “historic” placebo) was assessed.

Mentions: Nine patients from the placebo group in the previous randomized phase II study KTS-1-2008 [7] were included in the present open-label phase II study (KTS-2-2010) with rituximab induction and maintenance infusions (Table 1). None of these nine patients had experienced a clinical response during 12 months follow-up after two placebo infusions two weeks apart. Six out of these nine had clinical response during the first 12 months after rituximab infusions in the present study, and in addition one patient with gradual improvement fulfilled the criteria for a clinical response after 12 months follow-up (Table 1). The Fatigue scores for these nine patients, with means for consecutive three-months intervals until 12 months follow-up are shown in Fig 4. There was a significant interaction between time and intervention group (p = 0.003), i.e. there was a difference in course of Fatigue scores until 12 months follow-up in favor of rituximab-intervention as compared to “historic” data when the same patients were given placebo.


B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment.

Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O - PLoS ONE (2015)

Historic comparison of Fatigue scores for nine patients given placebo in KTS-1-2008, and rituximab maintenance in KTS-2-2010.Nine patients from the placebo group in the previous randomized KTS-1-2008 study were included in the present KTS-2-2010 study with rituximab induction and maintenance treatment. The mean Fatigue scores for consecutive 3-months intervals, until 12 months follow-up, were compared using General Linear Model (GLM) for repeated measures. Four time intervals with mean Fatigue scores in each were included in the comparison. Main effect for the interaction between time and intervention group (rituximab maintenance versus the patient’s own “historic” placebo) was assessed.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488509&req=5

pone.0129898.g004: Historic comparison of Fatigue scores for nine patients given placebo in KTS-1-2008, and rituximab maintenance in KTS-2-2010.Nine patients from the placebo group in the previous randomized KTS-1-2008 study were included in the present KTS-2-2010 study with rituximab induction and maintenance treatment. The mean Fatigue scores for consecutive 3-months intervals, until 12 months follow-up, were compared using General Linear Model (GLM) for repeated measures. Four time intervals with mean Fatigue scores in each were included in the comparison. Main effect for the interaction between time and intervention group (rituximab maintenance versus the patient’s own “historic” placebo) was assessed.
Mentions: Nine patients from the placebo group in the previous randomized phase II study KTS-1-2008 [7] were included in the present open-label phase II study (KTS-2-2010) with rituximab induction and maintenance infusions (Table 1). None of these nine patients had experienced a clinical response during 12 months follow-up after two placebo infusions two weeks apart. Six out of these nine had clinical response during the first 12 months after rituximab infusions in the present study, and in addition one patient with gradual improvement fulfilled the criteria for a clinical response after 12 months follow-up (Table 1). The Fatigue scores for these nine patients, with means for consecutive three-months intervals until 12 months follow-up are shown in Fig 4. There was a significant interaction between time and intervention group (p = 0.003), i.e. there was a difference in course of Fatigue scores until 12 months follow-up in favor of rituximab-intervention as compared to “historic” data when the same patients were given placebo.

Bottom Line: We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment.The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.

ABSTRACT

Background: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

Methods: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

Findings: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

Conclusion: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

Trial registration: ClinicalTrials.gov NCT01156909.

No MeSH data available.


Related in: MedlinePlus