Autologous hematopoietic cell transplantation in multiple sclerosis

Figures & data

Figure 1. This figure highlights the new classification structure for MS used in clinical trials as suggested by Lublin et al 2014 [3]. * Active disease refers to the presence of a relapse or measureable active disease on MRI imaging. ** Progression refers to a sustained change in the patients EDSS over a set time period, often longer than 6 months.

Table 1. The Kurtzke Expanded Disability Status Scale (EDSS).

EDSS score
0.0	Normal neurological exam
1.0	No disability, minimal signs in more than one FS
1.5	Minimal disability in one FS
2.0	Minimal disability in two FS
2.5	Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in three or four FS (three or four FS grade 2, others 0 or 1) though fully ambulatory
3.0	Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; or two FS grade 3 (others 0 or 1) or five grade 2 (others 0 or 1)
3.5	Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; or two FS grade 3 (others 0 or 1) or five grade 2 (others 0 or 1)
4.0	Fully ambulatory without aid, self-sufficient, up and about some 12 h a day despite relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 m
4.5	Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance; able to walk without aid or rest some 300 m
5.0	Ambulatory without aid or rest for about 200 m; disability severe enough to impair full daily activities (e.g. to work a full day without special provisions)
5.5	Ambulatory without aid for about 100 m; disability severe enough to preclude full daily activities
6.0	Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 m with or without resting
6.5	Constant bilateral assistance (canes, crutches, braces) required to walk about 20 m without resting
7.0	Unable to walk beyond approximately 5 m even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair some 12 h a day
7.5	Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day
8.0	Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has effective use of arms
8.5	Essentially restricted to bed much of day; has some effective use of arm(s); retains some self-care functions
9.0	Helpless bed patient; can communicate and eat
9.5	Totally helpless bed patient; unable to communicate effectively or eat/swallow
10.0	Death due to MS

This scale is often used in MS research to monitor progression of the disease. FS stands for functional status. The overall EDSS score is calculated from different parts of the neurological examination. Each part of the neurological exam gives a separate FS, which is then used to calculate the overall EDSS.

Figure 2. This figure highlights the possible biochemical changes to the immune system that may explain why AHCT halts MS.

Table 2. Outcomes from various cohort studies and trials performed concerning MS patients who have undergone Autologous Hematopoietic Cell Transplantation (AHCT).

Study	Number of patients	Relapse-free survival at 1 year	New Gad-positive MRI lesions at 1 year	EDSS change at 1 year median	No evidence of disease activity (NEDA)	Conditioning regimen	Justification for AHCT	Notes
Burman et al. [29]	48	87% at 5 years	8 new lesions in entire cohort during all follow up	−0.75 (All patients) −1.5 (progressive patients excluded)	68% at 5 years	BEAM/ATG (n = 41) Cyclophosphamide/ATG (n = 7)	Patients treated as rescue therapy for severe RRMS^a	Cohort study based on responses to a survey
HALT-MS Nash et al. [23]	24	86.3% at 3 years	0 at 3 years 2 patients developed lesion thereafter	−0.5 at 3 years	78.4% at 3 years	BEAM/ATG	Failure of DMT (2 or more clinical relapses during past 18 months) associated with increased EDSS score	Single arm phase 2 clinical trail (HALT-MS)
Burt et al. [13]	21	62% at 3 years	5 patients by end of follow up (3 years)	−0.9 at 1 year and −1.7 at 4 years	62% at 3 years	Cyclophosphmide/Mesa/ Alemtuzumab/ Methylprednisolone	Interferon beta treatment plus corticosteroid-treated relapses past 12 months, or 1 relapse and gadolinium-enhancing lesions seen on MRI	Prospective cohort study
Burt et al. [30]^b	145	89% at 2 years and 80% at 4 years	*	−1.0 at 1 year and −1.5 at 5 years	68% at 4 years	Cyclophosphomide plus with Alemtuzumab or ATG	Interferon beta treatment plus corticosteroid-treated relapses past 12 months, or 1 relapse and gadolinium-enhancing lesions seen on MRI	Observational cohort study
Shechenko (2008) [31]	45	*	None in patients who did not have relapse	28 patients had a drop of EDSS of 0.5 at 6 months	*	BEAM/ATG	Confirmed diagnosis of MS with an EDSS between1.5 and 8.0	Prospective Cohort study

*: indicates information not available in study.

NCG means no comparator group as this was a cohort study.

^a In the Burman et al. [29] study, eight patients where included who did not have RRMS and instead had a diagnosis of SPMS.

^b Burt et al. [30] is a follow-up study that uses the same patients who are in Burt et al. [13], but with increased recruitment.

Table 3. Outcome measures of Randomized Controlled Trials for Disease Modifying Therapies used in MS.

Study	Number of patients	Relapse-freesurvival at 1 year	New Gad-positive MRIlesions at 1 year	EDSS change at 1 year median	No evidence of diseaseactivity (NEDA)	Notes
AFFIRM Polman et al. [32]	627	68% reduction in relapse ratecompared to placebo	245 patients had at leastone new lesion	−^a	37% at 2 years	Randomized control trial
CARE-MS-1 Cohen et al. [33]	386	77.6% at 2 years	176 patient had new ofenlarging lesions at 2 years	−0.14 at 2 years	39% at 2 years	Randomized control trial
CARE-MS-II Coles et al. [34, 35]	436	65% at 2 years	186 patient had new lesions at 2 years	−0.17 at 2 years	32% at 2 years	Randomized control trial
FREEDOMS Kappos (2010) [36]	854	60% in relapse rate comparedto placebo^b	35 patients had new lesions at 2 years^b	−0.03 at 2 years^b	48% at 2 years	Randomized control trial

^aData was not displayed.

^bPatients taking 1.24 mg of fingolimod.

Table 4. Factors that are associated with a more favorable outcome after AHCT in MS.

Favorable outcome for AHCT in MS is seen in
RRMS Young patients (≤45 years) Short disease duration (≤10 years) Active disease (two or more relapses in 12 months in the preceding 12 months) Evidence of gadolinium enhancement on MRI scans EDSS of 5.5 or less

Table 5. Common side effects reported in each of the main AHCT studies post transplant.

Study	Number of deaths secondary to AHCT	Infection rate	Other complications	Mean length of follow up
Burman et al. [29]	No deaths	Seventeen neutropenic fever Eight herpes zoster infections Three Clostridium difficile One Candida	Four hypothyroid disease One Crohn’s disease One Alopecia areata One incontractable epilepsy One deep vein thrombosis	47.4 months
HALT-MS Nash et al. [23]	Two deaths one secondary to asthmaand one secondary to MS progression	Sixteen neutropenic fevers OneClostridium difficile	Three deep vein thrombosis One pulmonary embolism	46.5 months (median)
Burt et al. [13]	No deaths	Five neutropenic fevers Two zoster infections OneClostridium difficile	Two immune thrombocytopenia	37 months
Burt et al. [30]^a	No deaths	Four Clostridium difficile	Seven immune thrombocytopenia Seven thyroid disease	30 months
Shechenko et al. [31]	One death due to intracranial hemorrhage	–^b	–^b	19 months

^aBurt et al. [39] is a follow-up study that uses the same patients who are in Burt et al. [13], but with increased recruitment.

^bInformation was not in this particular study.

Table

1. Mobilization and harvest. In the first stage, the patient is given a short course of granulocyte-colony stimulating factor (G-CSF) which releases hematopoietic stem cells into the peripheral circulation. Most centers performing this step will supplement the G-CSF infusion with chemotherapy, often cyclophosphamide 2–4 g/m^2, which not only mobilizes the stem cells for harvest by apheresis but also provides some interim suppression of disease activity.

2. Conditioning and stem cell re-infusion. In this stage, the patient is given a high dose of cytotoxic therapy (i.e. chemotherapy, radiotherapy, and/or serotherapy, such as ATG or monoclonal antibodies such as alemtuzumab) to eliminate the majority, if not all, of their bone marrow and immune system. Conditioning regimens can be of differing intensities, as described above.

3. Following conditioning, the stem cells collected in the mobilization stage are re-infused into the patient. Engraftment is confirmed when the patient starts producing peripheral blood cells again.

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