General principles

Centre experience and accreditation

aHSCT is an intensive procedure with a level of immediate transplant-related risks and other toxicities. Registry studies support a positive impact of JACIE accreditation [86] on PFS, whilst the centre experience in ADs resulted in a statistically significant improvement of TRM/NRM, PFS and overall survival [15, 21]. Such improvement is likely related to progressively improved patient selection, a dedicated pattern of care and the full integration between the HSCT and disease specialists. Experience is important as conditioning regimens used in aHSCT in ADs induce more profound immunosuppression than in haemato-oncological indications due to ATG, with a higher incidence of acute reactions, viral reactivations and infections. In addition, administration of DMTs before aHSCT may have an impact on the graft characteristics and immune reconstitution and further studies are required. There is a need for an extended competency and package of care for neurological patients, including specific pre-transplant work-up with attention to cardio-respiratory function, specific neurological supportive care measures, prolonged infective monitoring after the procedure, consideration of physiotherapy/rehabilitation [26]. Centre experience and accreditation may improve patient care and outcomes via implementation of specific staff training, procedures and audit in the institutional quality management system [21, 86].

Recommendations

aHSCT should be delivered in transplant units that provide high quality care and are accredited by JACIE or equivalent organisations (level II).

Units should be experienced with close collaboration between HSCT and neurology specialists throughout the patient journey including medium- and long-term follow up (level II).

Multidisciplinary teams (MDTs) and patient consent

Any decision to proceed must assess the balance of benefits and risks particularly in terms of reversibility or stabilisation of disability and other neurological features. Decision-making requires critical multidisciplinary input from neurology and haematology specialities and may also involve other core members, such as nursing and professions allied to medicine (PAMs).

Informed consent should be obtained for all phases of the transplant procedure, A frank discussion about potential risks, including TRM risk, transient worsening of function and other early and late transplant-related toxicities is an essential part of the consent process. The discussion should also include the risk-benefit of alternative treatments, including DMTs. Patients with childbearing potential should be counselled appropriately as temporary or permanent ovarian/testicular failure and infertility following aHSCT are known risks [87, 88]. Fertility preservation strategies should be discussed. All patients should be invited to provide separate consent for submission of their anonymised/pseudonymised personal data to the EBMT, or equivalent, registry in accordance with relevant data protection and other regulations.

Transplant technique

A variety of transplant techniques have been used, both in mobilisation and conditioning (Table 3). In accordance with previous EBMT guidelines [21, 26], two ‘intermediate-intensity’ conditioning regimens have been used most commonly in MS: BEAM-ATG and cyclophosphamide 200 mg/kg + ATG (Fig. 4). Data on transplant technique for aHSCT in other immune-mediated neurological disorders outside MS is limited and heterogeneous.

Table 3 Categorisation of conditioning regimens used for autologous HSCT, with examples used in MS and other immune-mediated neurological diseases [20, 21, 26] Full size table

Fig. 4 Trends in transplant conditioning used for autologous HSCT in Multiple Sclerosis: BEAM-ATG versus Cy-ATG (EBMT Registry 1995–2018) Full size image

Pre-transplant ‘wash-out’

Prior to mobilisation, DMTs and other immunomodulatory drugs should be discontinued as early as possible, which may help minimise risks and inhibitory effects on successful mobilisation. ‘Wash-out’ periods, commonly used in neurological practice for switching between DMTs, aim to reduce the risks of PML and other infections [89]. There is no consensus to support duration of wash-out periods. The following ‘wash-outs’ are examples; at least 6 weeks for dimethyl fumarate, fingolimod and natalizumab, and 6 months for alemtuzumab, ocrelizumab and cladribine given the more profound lymphopenia and risk of infection. Accelerated elimination should be considered in patients on teriflunomide (https://www.aubagiohcp.com/content/pdf/drug_elimination_guide.pdf). No wash-out is necessary for interferon and glatiramer acetate. There have been no reports of PML following aHSCT in current EBMT registry data, but CSF JCV-PCR should be done on patients transitioning from natalizumab if they have high JCV antibody Index. Steroid pulses may be used to reduce the risk of relapses during the wash-out period.

Peripheral blood stem cell [PBSC] mobilisation and leukapheresis

Most patients treated for AD have received priming doses of cyclophosphamide of 2–4.5 g/m2 with uromixetan (Mesna) and/or cautious hyperhydration followed by G-CSF 5–10 μg/kg prior to leukapheresis [26, 29,30,31,32,33,34,35,36,37,38, 41]. Administration of G-CSF alone may induce disease flare, but its combined administration with ‘priming’ chemotherapy usually prevents flares, reduces T-cell numbers in the graft and improves PBSC yields [90]. There are no data in terms of efficacy, but cyclophosphamide at a dose of 2 g/m2 is likely to be safer than higher doses but potentially less effective in terms of both mobilisation potential and disease control. The procedure can usually be carried out as an outpatient regimen, but in disabled patients hospital admission may be considered. The need for repeat harvest appears to be rare, with little data to support the need for off-licence use of plerixafor.

In line with EBMT recommendations, the minimum dose of CD34+ cells for re-infusion is 2.0 × 106/kg, although other generic recommendations have proposed 4−5 × 106/kg as the optimal dose [91, 92]. Considering that MS and neurological disorders are non-malignant indications, it would be pragmatic to aim for 5 × 106/kg as an optimal target before freezing, with 2.0 × 106/kg as a minimum safety threshold. Doses higher than 8 × 106/kg are unlikely to improve the rate of engraftment and have a theoretical risk of increased T cell contamination of the graft.

Neurological patients undergoing mobilisation are at risk of febrile neutropenia during mobilisation, and, if fever occurs, there may be a related transient worsening of neurological function, referred to as the Uhthoff phenomenon [93]. Oral antibiotic prophylaxis should be considered with a rapid pathway for hospital readmission and treatment of fever including use of steroids. Where disability precludes rapid readmission, patients can be hospitalised for the mobilisation phase.

Conditioning regimens

Previous EBMT ADWP recommendations recommended the use of ‘intermediate intensity’ regimens namely cyclophosphamide 200 mg/kg with T-cell depleting serotherapy (most commonly ATG) as a generic regimen across ADs, and, for MS, ‘BEAM-ATG’, was specifically recommended (Table 3) [26]. The use of ‘high-intensity’ regimens including TBI or busulfan was not recommended on grounds of short and long-term toxicity, whilst the ‘low-intensity’ regimens were considered to be less efficacious [21, 26]. Higher intensity regimens, such as the ‘BuCy-ATG’ regimen, are efficacious but have been associated with potentially serious side effects, including veno-occlusive disease [34]. TBI, with its greater short and long-term risks, including infections, secondary malignancies, NRM and EDSS progression possibly due to radiation neurotoxicity, is now rarely used, if at all, and was reported as ineffective in advanced MS [94]. Regimens of a lower intensity such as cyclophosphamide 120 mg/kg with ATG seem to be associated with an increased rate of relapse [95]. There is experience in Mexico of a low-intensity regimen where cyclophosphamide at 100 mg/kg has been used prior to re-infusion with unfrozen PBSC, with and without post-transplant rituximab. However, long-term outcome data are limited [96, 97].

Since the publication of the EBMT 2012 guidelines [26], there has been an increase in the use of Cy-ATG regimen in MS whilst BEAM-ATG usage has also been maintained (Fig. 4). At present, there is no comparative data as to the relative efficacy and safety of these two most commonly used intermediate-intensity conditioning regimens. Therefore, EBMT guidelines advocate using either of these two regimens for MS. The question of relative safety and efficacy between these two intermediate treatment regimens may be resolved through an ongoing EBMT registry analysis.

With respect to T-cell depleting serotherapy, the majority of MS patients have been treated with rabbit ATG (rATG) from various sources (Thymoglobulin/Sanofi-Genzyme and Grafalon/Neovii). Despite potential immunomodulatory advantages in non-transplant settings [98], the use of horse-ATG (hATG) has been limited compared with rATG and associated with a greater level of toxicity in one early study running from 2001–2006 [99]. However, in a more recent study the safety of a specific type of hATG (ATGAM, Pfizer) was assured with outcomes comparable to recent data using rATG [100]. The choice of type and dose of rATG depend on availability and centre preference, but in the published literature has been most commonly polyclonal rATG of Thymoglobulin type given in dose range of 5–7.5 mg/kg. Higher serum levels and type of ATG have been linked with infection and other outcomes in allogeneic HSCT [101,102,103] and non-transplant aplastic anaemia [104] settings, but this has not been systematically investigated in relation to aHSCT for ADs. Other forms of serotherapy, such as alemtuzumab, have been used, although data suggest a higher rate of complications including secondary autoimmunity [33]. Given the heterogeneity of types of ATG and other serotherapy, further evaluation of their use in conditioning regimens is urgently warranted.

Although HSCT units are likely to be experienced in the administration of ATG, it requires special attention given the potential for severe allergic-type reactions. These risks can be minimised with pre-medication consisting of antihistamines, paracetamol and steroids along with consideration of graduated dosing regimens and slow infusion rates. Varying doses of methylprednisolone (up to 1000mg [41]) have been used as pre-medication, but a minimum of methylprednisolone 2 mg/kg intravenously is recommended with a sufficient time interval (e.g. 30–60 min) before the start of the ATG infusion. As there is ongoing risk of ATG-related fever and other reactions after the infusion a tapering dose of oral or intravenous steroid is often used routinely, with breakthrough febrile or other episodes treated with additional pulses of intravenous methylprednisolone (e.g. 250 mg) whilst ensuring that infection is fully covered.

CD34+ selection and other graft manipulation

The question of graft manipulation is unclear and is confounded with inevitable but unquantifiable degree of in vivo depletion of T cells and other immune effector cells when ATG is included in the conditioning regimen. In MS, both unmanipulated and manipulated autologous grafts have been used. CD34+ selection has featured in some clinical trials, including in combination with the higher intensity BuCy-ATG regimen. Whether this contributes to the reported benefits and toxicity is unclear. An EBMT retrospective analysis failed to show benefit of graft manipulation in MS [105], and use in most other ADs [26]. Moreover, CD34+ selection may be associated with excess infection and the selection procedure adds significantly to the costs and logistics of aHSCT. In the absence of firm evidence of benefit, the recommendation is that CD34+ selection or other graft manipulation is not used outside a clinical trial setting in MS and other neurological diseases.

Supportive care, nursing and rehabilitation aspects

Most patients have nursing and supportive care (including transfusion) requirements common to patients undergoing aHSCT for other indications. The main difference in patients is the degree of baseline disability. In addition, the administration of conditioning chemotherapy and ATG with high-dose steroids and hyperhydration in most regimens requires close inpatient observations, including fluid and electrolyte balance. Twice-daily weighing is recommended. As some neurology patients are prone to seizures, some units incorporate prophylaxis against seizures during conditioning. The risk of potential physical and psychological side effects of high-dose steroids should be highlighted to both patients and nursing staff.

Urinary bladder dysfunction is common in MS, and residual volumes of urine represent not only a risk of infection, but also a risk of retaining cyclophosphamide metabolite, acrolein, which may cause haemorrhagic cystitis. All patients should be assessed for residual volume with ultrasound and, if necessary, a urinary catheter should be in situ for the period of cyclosphophamide administration. This should be accompanied by uromixetan (Mesna) as per departmental standard operating procedures. Patients with long-term indwelling catheters should be managed appropriately, with vigilance for the higher level of infection risk.

Occurrence of fever may affect the physical and mental state of the patient, and increase nursing needs to a greater degree in MS than in most other febrile transplant patients. Causes include ATG reactions, sepsis, urinary infections and viral reactivations. Fever of any type may temporarily compromise neurological function, referred to as the Uhthoff phenomenon [93], and sustained fever during the transplant period have been reported to affect long term efficacy [33]. Fever should be pro-actively managed appropriate to the clinical picture to induce rapid defervescence.

Vitamin D may have an impact on health and immune responses in MS and HSCT, and, given that patients are hospitalised during HSCT, routine supplementation should be considered [106].

Assessment and planning for rehabilitation should be performed prior to the transplant, for both the inevitable deconditioning effect of the aHSCT procedure and specific to neurological function of the patient. This area is currently the subject of a detailed EBMT ADWP review and guidance.

Recommendations