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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

Clinical response durations after rituximab maintenance therapy, within 36 months follow-up.In panel A, response durations within the three years (156 weeks) follow-up are shown, for 14 major responders and four moderate responders. In panel B, time points for start of clinical responses are shown, for major and moderate responders. In both panels A and B, the 11 red dots denote patients with still ongoing clinical response at 156 weeks (end of study), while the 7 black squares denote patients experiencing partial or full relapse during the 36 months follow-up period. The overall response criterion was a Fatigue score ≥ 4.5 for a minimum of six consecutive weeks, which must include at least one recording of Fatigue score > 5.0 during the response period. Single response periods and the sum of response periods during follow-up were recorded as response duration.
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pone.0129898.g003: Clinical response durations after rituximab maintenance therapy, within 36 months follow-up.In panel A, response durations within the three years (156 weeks) follow-up are shown, for 14 major responders and four moderate responders. In panel B, time points for start of clinical responses are shown, for major and moderate responders. In both panels A and B, the 11 red dots denote patients with still ongoing clinical response at 156 weeks (end of study), while the 7 black squares denote patients experiencing partial or full relapse during the 36 months follow-up period. The overall response criterion was a Fatigue score ≥ 4.5 for a minimum of six consecutive weeks, which must include at least one recording of Fatigue score > 5.0 during the response period. Single response periods and the sum of response periods during follow-up were recorded as response duration.

Mentions: For major responders the mean of sum of response durations was 105 weeks, and for moderate responders 69 weeks (Fig 3A) within the 156 weeks study period. For 18 patients with post-hoc defined clinically significant responses the mean of sum of response durations within 156 weeks follow-up was 97 weeks (SD 32 weeks). The mean duration of the longest continuous response (i.e. continuous Fatigue score ≥ 4.5) was 83 weeks for major responders, and 48 weeks for moderate responders.


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)

Clinical response durations after rituximab maintenance therapy, within 36 months follow-up.In panel A, response durations within the three years (156 weeks) follow-up are shown, for 14 major responders and four moderate responders. In panel B, time points for start of clinical responses are shown, for major and moderate responders. In both panels A and B, the 11 red dots denote patients with still ongoing clinical response at 156 weeks (end of study), while the 7 black squares denote patients experiencing partial or full relapse during the 36 months follow-up period. The overall response criterion was a Fatigue score ≥ 4.5 for a minimum of six consecutive weeks, which must include at least one recording of Fatigue score > 5.0 during the response period. Single response periods and the sum of response periods during follow-up were recorded as response duration.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0129898.g003: Clinical response durations after rituximab maintenance therapy, within 36 months follow-up.In panel A, response durations within the three years (156 weeks) follow-up are shown, for 14 major responders and four moderate responders. In panel B, time points for start of clinical responses are shown, for major and moderate responders. In both panels A and B, the 11 red dots denote patients with still ongoing clinical response at 156 weeks (end of study), while the 7 black squares denote patients experiencing partial or full relapse during the 36 months follow-up period. The overall response criterion was a Fatigue score ≥ 4.5 for a minimum of six consecutive weeks, which must include at least one recording of Fatigue score > 5.0 during the response period. Single response periods and the sum of response periods during follow-up were recorded as response duration.
Mentions: For major responders the mean of sum of response durations was 105 weeks, and for moderate responders 69 weeks (Fig 3A) within the 156 weeks study period. For 18 patients with post-hoc defined clinically significant responses the mean of sum of response durations within 156 weeks follow-up was 97 weeks (SD 32 weeks). The mean duration of the longest continuous response (i.e. continuous Fatigue score ≥ 4.5) was 83 weeks for major responders, and 48 weeks for moderate responders.

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