For many pwMS, autologous hematopoietic stem cell therapy (AHSCT) is considered as the holy grail to control MS disease activity. Based on the outcomes in people with very active disease, AHSCT is definitely more effective than any other DMT we currently have in our armamentarium, especially when used early. Comparative studies revealed that the proportion for whom no evidence of disease activity (NEDA) was achieved at 2 years was 7–16% for placebo, 13–27% for platform therapies (e.g. interferon) and 22–48% for other active drugs. Among patients who underwent AHSCT, the proportion was at 70–92% and thus considerably higher. Evidently, these numbers spark discussions at many internet fora and MS communities, and many have taken the shot and booked tickets to Moscow. At least until one week ago.
As nobody wants the feeling of having ignored the existence of such an effective therapy, the more hesitant pwMS often discuss the matter with their MS consultant. In pwMS who are very active and have failed on second line MS treatments, there is expert consensus about the usefulness of AHSCT. However, very often also pwMS who are stable on anti-CD20 or who fail on first line therapies wonder whether they should consider AHSCT. In this situation, it’s important to be aware about the short and long term burden of AHSCT.
There are the obvious facts such as the small but existing mortality risk with AHSCT (in the most recent cohorts 0.3% but most likely higher in more disabled pwMS) and the frequent adverse events related to immune suppression (e.g. neutropenic fever, sepsis, urinary infections and viral reactivations) which will affect almost all individuals. The bulk of these severe adverse events took place in the first month after the conditioning regimen which is clearly the eye of the storm.
Alkylating agents such as cyclophosphamide, busulfan and melphalan fulfill an import role in lymphodepletive stem cell regimens. They are part of the initial stem cell mobilisation procedures and of the conditioning regimens before the actual stem cell infusion. However, alkylating agents are toxic to both ovaries and testes and the degree of toxicity is dependent on age, sex and cumulative dose. Cyclophosphamide is most studied agent.
In female pwMS, cyclophosphamide may lead to infertility and premature menopause which manifests as an irregular or absent menstrual cyclus (amenorrhea). Treatment-induced damage includes depletion of ovarian follicles and shrinkage and fibrosis of the ovaries. Some pwMS who develop amenorrhea during treatment may subsequently recover ovarian function. Conversely, some women with apparent preservation of ovarian function during and after treatment may develop premature ovarian insufficiency years later. Women treated before the age of 25 are at lower risk of infertility than those treated after the age of 30.
The following data illustrate these points:
- A meta-analysis including 1388 women (mean age 27.7) receiving IV cyclophosfamide for systemic rheumatic diseases found that sustained absence of menstrual cycle occurred in 273 women (19.7%).
- A report of 84 women who were menstruating prior to IV cyclophosphamide treatment for lupus or vasculitis demonstrated the importance of age. Chronic absence of menstrual cycle did not develop in any of the 22 women younger than 26 years of age but occurred 14 of the 20 women older than age 35.
- Out of 43 female pwMS who underwent AHSCT, 30 (70%) recovered menses after a mean time of 6.8 months. Among pwMS who recovered menstrual cycle, 1 experienced premature menopause at 31, 3 years post-AHSCT.
In male pwMS, cyclophosphamide causes a decrease in sperm count (oligospermia) and in some individuals also irreversible absence of sperm cells (azoospermia). Overall, approximately 70% of male patients who receive less than 7.5 g/m2 will regain fertility. As an example, a study of 35 men with lupus found that 86 percent of those with prior cyclophosphamide treatment had very poor sperm quality, compared with 45 percent of the men without prior cyclophosphamide.
Secondary autoimmune diseases
Secondary autoimmune diseases have been reported after AHSCT between one in ten to twenty individuals. One of the hypothesis about their occurrence is an imbalance between B and T cell regeneration. The secondary autoimmune diseases have mainly included hyper/hypothyroidism but also less frequent occurrences of immune thrombocytopenic purpura and acquired factor VIII deficiency (hemophilia) which both manifest with a tendency to bleed or bruise easily. Higher incidence of secondary autoimmune diseases (around 20%) have been reported but apply to regimens with CD34+ selection which are not frequently used.
Accelerated brain volume loss has been noted following aHSCT in pwMS. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, which refers to brain volume loss due to resolution of brain edema rather than loss of brain parenchyma. However, early spikes in neurofilament concentrations (and thus brain debris) have clearly indicated that the initial brain volume loss post-AHSCT exceeds what can be expected from its anti-inflammatory effect. A large study on untreated pwMS showed values of annual brain volume loss of −0.49% and −0.64 % for pwRRMS and pwSPMS, respectively. After AHSCT, the rates of annual brain volume loss are about four to six times higher in the first 12-24 months compared to baseline. “Chemo brain” or “chemo fog” are terms used to describe cancer treatment–related cognitive impairment and also applies to the brain volume loss shortly after AHSCT. For most pwMS, its effects are short-lived but for some can be permanent.
Cyclophosphamide has been associated with bladder carcinoma and the development of hematological malignancies. In an AHSCT trial with long-term follow-up, 9 of 281 treated patients were diagnosed with a malignancy. However, no organ-specific prevalence was detected excepted for myelodysplastic syndromes (3/9 cases) which are associated with exposure to cytotoxic drugs.
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
- Have you ever considered AHSCT while being stable on first or second line MS treatment?
- Have you ever dismissed AHSCT because of the long term side effects?
- If you have had AHSCT or if you seriously considered AHSCT:
- Were you informed about these long term consequences?
- Where did you find most useful information on the topic?