How important is it to predict lymphopenia in pwMS starting DMTs?
Mult Scler Relat Disord. 2017 Dec 14;20:51-57. doi: 10.1016/j.msard.2017.12.003. [Epub ahead of print]
Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count.
Baharnoori M, Gonzalez CT, Chua A, Diaz-Cruz C, Healy BC, Stankiewicz J, Weiner HL, Chitnis T.
There is limited data regarding the predictors of hematological abnormalities in multiple sclerosis (MS) patients treated with dimethyl fumarate (DMF) or fingolimod (FNG), and the impact of treatment switch on lymphocyte and leukocyte count METHODS: We identified 405 patients on DMF and 300 patients on FNG (treatment duration: at least 12 month) within a large prospective study of MS patients conducted at the Partners MS Center, Brigham and Women's Hospital (CLIMB study) between Jan 2011 to Feb 2016. Patients had complete blood counts with differentials at baseline and every 6 months while on treatment. Most participants had a clinical visit with complete neurologic examinations every 6 months and brain MRI scan every 12 months. T cell subset profile was available for subgroup of patients (n = 116).
In the FNG group, the risk of developing lymphopenia grade 4 (< 200) was higher in female patients (p = 0.0117) and those who were previously treated with natalizumab (p = 0.0116), while the risk of lymphopenia grade 3b+4 (< 350) was higher in female patients (p = 0.0009). DMF treated patients with lower baseline lymphocyte count had a higher chance of developing lymphopenia grade 2 (< 800) (p < 0.0001) or 2+3 (< 500) (p < 0.0001). We examined the effect of treatment switch between DMF and FNG. No significant recovery in lymphocyte and leukocyte count was observed after treatment switches. Reduced dosing of FNG in patients with lymphopenia led to increase in lymphocyte count but also increased disease activity in 25% of patients.
Female sex and prior exposure to natalizumab increased the probability of lymphopenia on FNG, while low absolute lymphocyte count was associated with increased risk of lymphopenia on DMF. Parallel switch did not lead to recovery from hematological abnormalities. Long-term studies with larger number of patients are required to confirm our findings and to establish guidelines for prediction and management of hematological abnormalities.
Our understanding of treatment-relates side effects in MS, in particular that of immunosuppression, at times seems to deify probability. I suppose if we were privy to the answers, we wouldn't need to predict the antecedent events that lead to it in the first place. The word prediction in itself implies that there is a degree of accuracy involved, but again this would be inaccurate. Baharnoori et al., have attempted to predict the factors involved in treatment related lymphopenia (low lymphocyte count) in their article, so we'll see.
Lymphopenia leaves the person affected by it exposed to opportunistic infections (from colds to pneumonia) and even possibly cancers in the long-term. Drugs, in particular dimethyl fumarate, DMF (aka tecfidera) and fingolimod (aka gilenya) result in severe lymphopenia with lymphocyte counts <500/mm3. Lymphopenia is graded as follows: Grade 1 - 800/mm3; Grade 2 - 800-500/mm3; Grade 3 - 500-200/mm3; and Grade 4 - <200/mm3. Although, in the Phase III clinical trials of DMF Grade 3 lymphopenia was observed in 4% of those who received the treatment, real-life data now shows this figure to be much higher ~20%, particularly in those who are older. The lymphopenia is also persistent in those experiencing Grade 2, or Grade 2+3 lymphopenia with little recovery over the long-term. With fingolimod, there is ~70% reduction in lymphocyte counts (around a quarter develop Grade 4 lymphopenia) within the first month, which then continues for the course of the treatment.
In this study, they found that the main predictors of profound lymphopenia (Grade 4) on fingolimod treatment was female gender (uncertain whether this is a statistical blip as MS is more prevalent in women than men) and prior use of natalizumab. The latter finding has implications as fingolimod is often used as de-escalation therapy from highly active therapies. Reducing the dose of fingolimod to lessen this effect appears to lead to a resurgence in disease activity. A lower absolute lymphocyte count before starting treatment (although this did not reach statistical significance with fingolimod in this study) was also predictive of likelihood of reaching >Grade 2 lymphopenia. It goes without saying, that switching between therapies with known long-term impact on lymphocyte counts is a risky strategy (see Figure below)!
Figure: Absolute lymphocyte count (ALC) (A) and white blood cell (WBC) (B) count on reduced dose of FNG over 42 month (6 month interval). Yearly ALC (C) and WBC (D) on FNG and after switch to DMF. Redline corresponds to the baseline ALC and WBC prior starting FNG. Yearly ALC (E) and WBC (F) on DMF and after switch to FNG. Redline corresponds to the baseline ALC and WBC.
Labels: dimethyl fumarate, fingolimod, lymphopaenia