Cheer-I don't think that there is any reason to suspect that alemtuzumab is neurotoxic as it is not an anti-metabolite, alkylating agent, anti-DNA repair agent-it is specific to leukocytes.
Do you understand what I am saying? It makes sense that cyclophosphamide can be neurotoxic because it causes DNA injury which occurs in all cells but has a more dramatic effect in rapidly dividing cells. Hematopoetic stem cell transplant involves multiple cytotoxic drugs. alemtuzumab is a monoclonal antibody against CD52 which isn't present on neurons/oligodendrocytes, so there is no a priori reason to think it would be neurotoxic. Of course, any medication could have any side effect.
Accelerated brain atrophy occurs in SPMS normally (and in RRMS as well), and alemtuzumab does not stop this from occurring. Whether or not alemtuzumab has a sustained effect on slowing brain atrophy in RRMS remains to be seen. Dr. G seems to be optimistic, but I am more skeptical. We will have to wait and see the extension phases of the randomized trials many years out.
To anyone who is curious, here is the link to the full text of the article cheer is referring to with campath in SPMS: http://www.neurology.org/content/53/4/751.full.pdf+html
Here is the discussion from the authors below:
This study shows that a single pulse of treatment with the humanized monoclonal antibody Campath 1H is associated with a major and sustained reduction in inflammatory MS disease activity as demonstrated by the suppression of Gd-enhancing lesion formation. No such reduction in activity was seen in the four untreated control subjects. Such a small control group cannot provide definitive comparative data, and indeed may by chance have had a lower level of enhancement during the pretreatment period. However, the baseline-treatment crossover design that we used has successfully shown a treatment effect on enhancing MRI activity using another agent, interferon β-1b,24 which was subsequently confirmed using the more robust parallel-group, placebo-controlled design.25 That both the treated and control group patients were blinded to the level of MRI activity throughout the study reinforces our impression that the reduction in Gd enhancement reflects a therapeutic effect.
In this analysis we have combined conventional MRI parameters (Gd enhancement and T2 lesion volume) with new approaches (hypointense T1 lesion volume, brain volume, and spinal cord area quantification) in an attempt to identify the effect of treatment on individual pathologic elements. These results should be interpreted with some caution due to the small numbers of control patients and the potential for measurement drift over time. However, all quantitative analyses were performed by the same experienced observer, in randomized order, without knowledge of patient identity or scan order, in an attempt to minimize the potential for bias.
We found no significant correlation between T2 lesion volume changes and clinical findings. This emphasizes the low pathophysiologic specificity of focal T2 signal hyperintensity, and is concordant with the weak correlations found between T2 abnormalities and disability in other studies.26-28 Although significant correlations between hypointense T1 lesion volume have been reported elsewhere,6 we found no overall correlation between hypointense T1 lesion volume and EDSS score changes. However, those with a sustained increase in EDSS score exhibited a significant increase in hypointense T1 lesion volume compared with those with stable disability. Furthermore, a moderate longitudinal correlation between the infratentorial T1-to-T2 ratio and EDSS score was identified. There is emerging evidence that those areas of high signal on a T2 sequence that are hypointense on a corresponding T1 image represent more severe structural loss.7 Therefore progressive loss of structure in functionally eloquent areas such as the brainstem and cerebellum might be expected to result in an increase in disability, as suggested by our results.
We also found a clear relationship between sustained increase in EDSS score and the development of cerebral (p < 0.009) and spinal cord atrophy (p < 0.01), although the significance of the latter is qualified by the smaller cohort of patients who could be analyzed for methodological reasons. Furthermore, those patients with a sustained increase in disability and brain atrophy had significantly smaller cerebral volumes at baseline. This finding suggests that an ongoing atrophic process is already more established in this cohort, and that loss of brain volume is predictive of subsequent clinical progression.
Those patients with a significant increase in EDSS score showed a much higher cumulative Gd-enhanced volume during the pretreatment period than the clinically stable patients. This indicates that although Campath 1H was able to suppress new lesion formation, it did not prevent the secondary consequence of inflammatory lesions that had already developed during the immediate pretreatment period. Increasing disability has been associated with higher Gd-enhancing lesion frequencies,28,29 and it is possible that inflammation might compromise repair mechanisms within demyelinated regions and thereby expose axons to the immunologic and biological consequences of persistent demyelination. Thus, even if inflammation is stopped, previously acquired extensive areas of damage may still undergo secondary degeneration with disease progression. Severe atrophy is likely to represent the final irreversible sign of axonal loss, leading to progression of disability.10 The recent interferon-β trials also suggest that suppression of active inflammation delays but does not prevent progression of disability,25,30 perhaps indicating ongoing axonal loss in established areas of pathology. A key issue in current MS research is to identify whether earlier intervention with therapies aimed at suppressing inflammation will delay or prevent later irreversible atrophy.31
Measurements of cerebral atrophy, spinal cord area, and T1 hypointense lesion volume represent important new approaches to the assessment of therapeutic efficacy. These techniques are objective, have high serial reproducibility, and are both simple and quick to apply. They can supplement the more traditional MRI measures and provide a means of assessing the impact of therapeutic intervention on destructive pathology and tissue loss.