Sunday, March 1, 2015

Lemtrada Clinical Trial Data Overview

I am working on vacation here because I think this information will be of interest to everyone who has just received Lemtrada or will in the near future.

Short personal update. This time last year I could not drive and did not have the energy to even go to the grocery store. This morning I swam along a reef in rip tide conditions and found a sea turtle and swam along with him for 20 minutes- after about 1 hour of swimming along the reef. No flotation device, just fins and some snorkeling gear- moments only made possible by Lemtrada!

I must thank Beth (Lem patient infused in London May 2014). She sent me this article.

This is a fairly technical article but I did try to par it down and add explanations. What I find most interesting is the info on the AE (adverse events aka side effects) but I really think you should try to understand all these points, take notes, and follow your own labs and symptoms.

I truly believe a well informed patient makes the best medical decisions for themselves. This is the real purpose of this blog- so you can understand this treatment and make the informed decision if it is right for you.

Article from Medscape on Lemtrada

Here is the direct link: http://www.medscape.com/viewarticle/838091_print

 Here is the Text with My Summary Points

Intro:

It was granted licensing approval by the European Medicines Agency (EMA) in September 2013.

In November 2014, alemtuzumab was approved by the FDA for relapsing forms of MS

How Lemtrada Works

Alemtuzumab (Lemtrada) targets CD52, an antigen of unknown function that is expressed on lymphocytes, monocytes, some dendritic cell populations and, to a lesser degree, on natural killer (NK) cells and other leukocytes

Alemtuzamab primarily depletes circulating T and B lymphocytes via antibody-dependent cytolysis and complement-dependent cytolysis (ie- Lem lyses- breaks apart- T & B cells) see other posts on immune system in general).

Depletion is followed by lymphocyte repopulation, which begins within weeks.

B-lymphocyte counts typically return to baseline by 6 months post-treatment. This is when sensory symptoms returned for me. I was treated with Ritux which depletes B cells. And it worked :)

CD4+ T-cell repopulation is particularly delayed. In a long-term follow-up of 37 patients who had received alemtuzumab treatment in the 1990s for MS, median recovery time to normal levels was 8.4 months for B cells, 20 months for CD8+ T cells and 12 years for CD4.

The therapeutic effect of alemtuzumab is likely not solely a consequence of lymphocyte depletion, but also of repopulation features. This is what is meant when lay people say "the immune system resets.

Early studies on when to retreat after the initial 2 doses:
CAMMS223 phase II study design. Alemtuzumab was infused intravenously (IV) on 5 consecutive days at baseline and on 3 consecutive days at year 1. The third treatment course at year 2 was given at the discretion of the investigator if CD4+ T-cell counts were ≥100 × 106 cells/l.

Safety
Long-term safety data for alemtuzumab are not yet available. However, safety data up to 4 years (CARE-MS extension), 7 years (CAMMS223 extension) or up to 12 years (Cambridge cohort) have thus far been consistent with what was observed in the core clinical trials. Whether any new safety signals emerge beyond this point remains to be seen.

Infusion-associated Reactions- IARs

IARs were the most common AEs in all three studies and those associated with alemtuzumab are thought to be mainly attributable to cytokine-release syndrome.

Cytokine release occurs as a result of target cell lysis and recruitment of inflammatory cells. (ie, Lem lyses cells, they fall open, release their contents- cytokines).

The incidence of IARs was ≥90% across studies.

Serious IARs were reported in up to 1–3% of patients in each alemtuzumab treatment group.

Most common were as follows:
headache (43–56%);
rash (39–89%);
pyrexia- fever (16–36%);
nausea (14–20%);
urticaria- rash (11–26%);
pruritus- itch (10–28%);
flushing (8–11%);
insomnia (10–19%);
fatigue (7–24%);
chills (7–18%);
chest discomfort (6–14%); and
dyspnea (6–13%).

There were no cases of anaphylaxis and no IARs resulted in death in the core studies.

The IARs were most frequent during the first treatment course (85%), and decreased during course 2 (69%) and course 3 (63%) [Mayer et al. 2014]. Few patients (2–6.6% per infusion day) required infusion interruption or infusion rate adjustment.

Infusion-associated reactions are common with alemtuzumab, but rarely serious.

Infections

Most were mild or moderate in severity.

Serious infections were rare, but slightly elevated with alemtuzumab versus injectable interferons.

The most common infections were those of the respiratory tract and urinary tract.
Herpetic infections (herpes viruses- fever blisters, chicken pox- so you need vaccination if you did not have the disease, also shingles). These infections declined after the introduction of acyclovir prophylaxis- now standard practice.

Follow-up for up to 7 years shows Infection incidence did not increase with each course of alemtuzumab. Most infections (96%) were mild or moderate over the follow-up period and upper respiratory tract infections were most common.

Is PML a problem?
Alemtuzumab has not been associated with any cases of progressive multifocal leukoencephalopathy (PML) in studies of patients with MS. There have been several cases of PML in patients treated with alemtuzumab for transplant rejection or for CLL. In these cases, however, patients had been heavily treated with immunosuppressive therapies before receiving alemtuzumab.

Cancer Risks?

Of 1486 alemtuzumab-treated patients in the clinical development program, 29 have been diagnosed with a cancer of any kind.

Six were thyroid cancers caught due to the routine monitoring.
     Five were in patients with known thyroid disease.
     One patient who developed thyroid cancer did not have thyroid disease prior to cancer diagnosis.

Other cancers included:
basal cell carcinoma (n = 6),
breast (n = 5) and
malignant melanoma (n = 4).

Autoimmune AEs

Autoimmune AEs represent the most important risk associated with alemtuzumab treatment. Autoimmune sequelae are thought to arise from the way in which lymphocyte repopulation proceeds.

Stay with me while I try to break this down.

 If T lymphocytes repopulate from mature T cells that are not killed, lyses, etc patients who go on to develop autoimmune AEs.

In contrast, patients without autoimmune AEs tend to generate relatively more new T lymphocytes in the thymus- the new baby T cells created from scratch are associated with fewer autoimmune problems.

Thyroid.

In 5-year follow-up Thyroid problems occurred in:

39% of patients treated with alemtuzumab 12 mg and
29% of those who received the 24-mg dose.

In total, 102 episodes were reported in 73 alemtuzumab patients.

Graves' hyperthyroidism (65.8%), hypothyroidism (20.5%) and subacute thyroiditis (12.3%) were most common.

Onset ranged from 6 to 61 months after the first treatment course.

When:
Incidence peaked at year 3 and declined in subsequent years.

Thyroid disorders responded to conventional therapy with antithyroid drugs, radioactive iodine, thyroid hormone or surgery.

Overall, thyroid AEs were reported in 36% of patients
Serious thyroid AEs in 3.8% of patients over 4 years of follow-up
Hyperthyroidism, hypothyroidism, goiter and thyroiditis were most common. These are also the easiest to treat.

ITP

Alemtuzumab is associated with a unique form of ITP characterized by delayed onset, responsiveness to conventional ITP therapies, and prolonged remission. So in English- comes on late, responds to treatment & goes into a long term remission that does not require ongoing treatment.

The first case of ITP occurred when a patient presented with intracranial hemorrhage (brain bleed) and died.

This prompted the implementation of a risk-management plan that comprised patient and physician education, monthly complete blood count (CBC) and monthly symptom surveys offset from the CBC by 2 weeks.

How ITP was defined in the studies:
Either a confirmed platelet count between 50 and 100 × 109/l on ≥2 consecutive occasions over a period of at least 1 month, or
A confirmed platelet count <50 × 109/l without clumping documented on two or more consecutive occasions over any period of time

This gets into the weeds but if you are watching your own labs you can make a note of these numbers and know where you stand. I personally treated HIV patients with low platelet counts. We would closely monitor at a level of 30, and treat at 10- for reference.

The incidence of ITP was 2.0% (n = 30/1486).

A further 21 patients did not meet the protocol definition but had platelet counts below normal limits.

When:
ITP onset occurred a mean of 16 months (range: 1–34) after the last dose of alemtuzumab.

Most patients responded to first-line therapy with corticosteroids, intravenous immunoglobulin or platelet transfusion. Other therapies were rituximab (n = 4) and splenectomy (n = 1), and several events (n = 2) resolved spontaneously.

Nephropathy. ie- Kidney Disease

In pilot studies, two patients developed antiglomerular basement membrane (anti-GBM) disease that ultimately required renal transplant.

Incidence 4 cases out of 1486 treated patients occurred:
Including 1 case of anti-GBM disease,
1 case of glomerulonephritis with positive anti-GBM antibody, and
2 cases of membranous glomerulonephritis

When:
Onset ranged from 4 to 39 months after the last dose of alemtuzumab. Each case responded to medical treatment.

Pregnancy and Fertility
Women of childbearing potential are advised to use contraception during a course of alemtuzumab and for 4 months afterwards.

Males: CD52 is expressed in the male reproductive system, including the epididymis and seminal vesicle, sperm and seminal fluid, posing a theoretical risk of alemtuzumab for male fertility.

However, developing sperm are negative for CD52 expression, and although mature sperm express CD52, an abundance of CD52 antigen in seminal plasma effectively competes with sperm for alemtuzumab binding, making an adverse impact on male fertility unlikely. A limited data set (n = 13) showed that at baseline, and 1, 3 and 6 months post alemtuzumab treatment, there was no evidence of defects in sperm motility or morphology, and no patient had a consistently depressed sperm count.

Choosing the Right Patient for Alemtuzumab

Alemtuzumab is not for every patient with MS and the decision to use it should be carefully considered.

Study data suggest that alemtuzumab may be ineffective in patients with secondary progression.

Although the safety profile is generally manageable for the right patient, risks probably outweigh benefits in patients with mild disease or clinically isolated syndrome, and there are no available data on these populations.

Alemtuzumab should be reserved for patients with active inflammatory disease (early in disease) Active disease was defined as:
 ≥1 relapse in the past year and
≥2 relapses in the past 2 years,
plus the presence of MRI lesions;

Patients with active disease despite treatment (relapses on other therapies) benefited from alemtuzumab and are clearly candidates for more powerful therapy.

For patients who meet criteria for active disease but are early in their disease course and treatment-naive benefits from alemtuzumab.

Although some clinicians may be hesitant to use alemtuzumab as first-line therapy, the current lack of established neuroprotective or neuroregenerative therapies leaves only the option of preserving existing neural tissue before extensive pathology occurs. USE LEMTRADA EARLY!!!

In patients with early MS who are clearly on a path of rapidly advancing disease, high-efficacy antiinflammatory therapy must be considered. USE LEMTRADA EARLY!!!

The Decision to Re-treat With Alemtuzumab

The issue of retreatment with alemtuzumab beyond the initial two courses of therapy will become important as the second anniversary of its approval in Europe approaches.

Labeling guidelines do not currently address whether or how retreatment with alemtuzumab should be undertaken. In phase III studies, alemtuzumab treatment beyond the initial two courses was offered if a relapse occurred or if a patient accumulated ≥2 unique MRI lesions (either Gd-enhancing lesions and/or new or enlarging T2 lesions).

Lymphocyte reconstitution rate does not appear to predict breakthrough disease activity, and use of lymphocyte counts as a biomarker to indicate retreatment has been discouraged [Kousin-Ezewu et al. 2014]. ie no particular lab can tell you when to retreat at this time.

In clinical practice, it may be appropriate to monitor alemtuzumab efficacy by MRI. MRI scans were performed annually in clinical trials and helped to guide the decision to re-treat during the extension study.

The maximal number of alemtuzumab courses that may be safely given is unknown. Some have suggested the use of a platform therapy (I believe they are referring to another DMT after you finish 2 Lem courses) after alemtuzumab but there are currently no data addressing this approach.

Summary
Alemtuzumab is a highly effective therapy for patients with active RRMS who are either treatment-naive (never been treated) or who have had breakthrough disease on DMT.

The available safety data from the phase II and III clinical studies span about 5 years and are consistent with the 12-year data from the Cambridge cohort.

The safety profile is manageable with continued monitoring. Further experience with alemtuzumab in the clinic will provide the needed long-term data.

A comprehensive monitoring program lasting at least 4 years after the last alemtuzumab dose allows early detection and effective management of autoimmune adverse events. Further experience with alemtuzumab in the clinic will provide needed long-term data.