Burt et al. JAMA Neurol 2005:62:6
Hematopoietic stem cell transplantation (HSCT) was proposed as a treatment for multiple sclerosis (MS) in 1995 based on favourable results in animal models including experimental autoimmune encephalomyelitis.These initial or first-generation trials were developed by medical oncology subspecialists, used malignancy-specific myeloablative transplantation regimens, and selected patients with secondary progressive MS with rapid progression of disability. In general, these trials suffered from higher than anticipated toxic reactions including treatment-related and disease-related mortality, continued loss of brain volume as seen on magnetic resonance imaging (MRI), and, at least in some patients, continued progressive disability despite marked attenuation or absence of gadolinium-enhancing lesions on MRI. Learning from these experiences, second-generation transplantation trials for MS are using MS-specific nonmyeloablative transplantation regimens and selecting for active relapses despite the use of interferon treatment in patients with less accumulated disability. While still preliminary, results using second-generation nonmyeloablative HSCT regimens are encouraging with minimal treatment-related morbidity and improvement in Expanded Disability Status Scale (EDSS) scores. The following 3 variables seem important in predicting the benefit and minimizing the toxic effects from an autologous stem cell transplantation in patients with MS: the selection of patients who still have inflammatory disease (ie, gadolinium enhancement on MRI and/or frequent active relapses), treatment early in the course before the onset of significant irreversibly progressive disability, and the use of a safer lymphoablative but nonmyeloablative HSCT conditioning regimen.
The first partial misconception that HSCT is a high-risk procedure needs to be placed in perspective with the drug regimen utilized, as well as with the risks of current FDA-approved disease-modifying therapies. There are three variables that determine the safety of HSCT: 1) the regimen (drugs) used; 2) patient selection; and 3) a center effect (experience with transplant for MS).It is important to recognize that the terminology ‘autologous hematopoietic stem cell transplantation’ is in reality a misnomer. There is no transplant, only the infusion of an autologous supportive blood product, analogous to a surgeon collecting before and then reinfusing autologous packed red blood cells after an operation. Before receiving the stem cell infusion (transplant), patients with autoimmune diseases receive a ‘conditioning regimen’ of drugs (chemotherapy, biologics, and/or radiation). The early and late toxicity from HSCT depends upon the specific drugs in the conditioning regimen and not the infused autologous blood product, i.e. hematopoietic stem cells.
BACKGROUND
The current therapies for MS consist of immune-modulating agents, such as interferons or glatiramer acetate, and anti-inflammatory and immune suppressive drugs such as glucocorticoids, methotrexate, and mitoxantrone (Novantrone; Immunex Corporation, Seattle, Wash).Autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is a form of immune suppressive therapy in that immune suppression is maximized to the point of transient immune ablation. In theory, the transplantation conditioning regimen ablates the aberrant disease causing immune cells while hematolymphopoietic stem cells (HSCs) regenerate a new and antigen naive immune system. Therefore, all of the toxic reactions and efficacy of an autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is likely a consequence of the conditioning regimen.
MOBILIZATION
The most common method of collecting HSCs is by mobilization from the peripheral blood. Since negligible HSCs are detectable in the peripheral blood during the steady state, either a hematopoietic growth factor such as granulocyte colony-stimulating factor or chemotherapy (usually cyclophosphamide) with or without granulocyte colony-stimulating factor is necessary to mobilize HSCs into and subsequently collect HSCs from the blood. Hematopoietic growth factors used to mobilize HSCs also have immune-modulating effects and unlike malignancies may exacerbate disease depending on the growth factor. Granulocyte colony-stimulating factor may precipitate clinical flares of MS sometimes with significant and irreversible neurologic deterioration.Colony-stimulating factor–induced MS flare may be prevented by either administration of corticosteroids or mobilization using the combined therapy of cyclophosphamide and granulocyte colony-stimulating factor.
COLLECTING STEM CELL
Most mononuclear cells collected by peripheral blood apheresis are immune cells such as lymphocytes and monocytes not HSCs. While the true identity of human HSCs remains elusive, either purified CD34+ or AC133+ hematolymphopoietic progenitor cells are sufficient for hematopoietic and immune reconstitution. In general, a minimum number of 2 × 106 CD34+ cells per kilogram of recipient weight will ensure engraftment. Hematopoietic stem cells may be positively selected or enriched ex vivo using antibodies to CD34+ or AC133 or purified by negative selection by using antibodies to remove lymphocytes. In practice, the most common method of purging lymphocytes is via CD34-positive selection using either the Miltenyi CliniMACS (Bergish Gladbach, Germany) or the Baxter Isolex (Deerfield, Ill) cell separator device. Whether enriching the graft for CD34+ HSC is necessary or even superior to infusion of an unmanipulated graft remains unclear. CD34+ selection by removing lymphocytes is perhaps best viewed as another method of immune suppression. For an intense conditioning regimen, CD34+ selection may be unnecessary or even detrimental by increasing the risk of treatment-related infection.#The rationale for autologous HSCT of MS is to regenerate an antigen-naive immune system from the patient’s own HSCs. Therefore, the goal of the conditioning regimen is lymphoablation not myeloablation. The autologous HSCT regimen should be based on immune suppressive drugs that are well tolerated at conventional nontransplantation doses and are expected to remain safe and nonmyeloablative at higher transplantation doses. The regimen must also avoid further damage to already injured axons and oligodendrocytes. By definition, myeloablative agents are lethal to HSCs and, apart from their myeloablative effect on bone marrow, may be similarly cidal to tissue-specific stem cells such as oligodendrocyte progenitor cells or neural stem cells. In animal models, cranial irradiation impairs the mechanism of CNS repair by neural stem cell apoptosis, alteration in cell cycle progression, and/or destruction of the neural stem cell niche or milieu through invasion of macrophages and microglia. This raises concerns about using total body irradiation based, or any other stem cell ablative regimen, in the treatment of MS.
Nonmyeloablative HSCT regimens that are as immune suppressive as myeloablative regimens but without myeloablative adverse effects may be designed by using agents or combinations of agents such as fludarabine, cyclophosphamide, antilymphocyte antibodies such as Alemtuzumab or anti-thymocyte globulin, and/or by the use of CD34+ selection of the graft. Fever-related deterioration of neural function in MS, termed “pseudoexacerbations,” due to conduction blocks in marginally functioning demyelinated axons should be avoided during transplantation by minimizing pyrogenic agents in the conditioning regimen. Similarly, the risk of infection-related fever should be minimized during transplantation by use of prophylactic antibiotics.
In summary, for MS the rationale behind the HSCT conditioning regimen should be to (1) dose-escalate agents that work as conventional therapy, (2) maximize immune suppression without myeloablation, (3) avoid conditioning regimen agents that may cause injury to already disease-affected and damaged CNS tissue, (4) avoid injury to tissue-specific stem cell compartments that may be important for CNS repair, (5) minimize the risk of fever, and (6) design regimens that are justified for the risk of the disease being treated.
So if positive what next? Will the regulators say: HSCT in place of current second line? (it would be cheaper in the long-run), HSCT in addition to second line; great but where is the second trial to confirm the results as we wouldn't want to favour academics over pharma or you are comparing apples with pears its obvious that HSCT is better than compound X in the standard second line or will they say the trial isn't properly done, like they did initially with Alemtuzumab (recently "We recognize that blinding during the first year will be compromised by patient hair loss but efforts will be made to mask hair loss by covering the heads of study patients during their first year neurology assessments" was removed from clinical trials .gov. Did they give up blinding the assessor?). If you agree to be randomised to HSCT and don't get it, do you loose the placebo effect. all sort of thng to think about.
I personally hope the regulators say yes this can be another treatment option choice.....(it will be approved for RRMS....will progressive MSers seek it a a base on which to layer neuroprotection and repair?).
However, I suspect there will be a lot of pharma out there who will not be so happy. Alternatively will it take so long to get HSCT approved, especially if more trials are needed the landscape will have changed by the time this happens.
If you do a trial against Alemtuzumab, in the two years to get the trial off the ground Ocreluzimab will probably come along. Will people therefore want Alemtuzumab? Will this be available as standard care, because if not, you will need to buy the drug for a trial of 110 people (based on the powering of MIST) the costs with be about £10-15,000,000 plus the costs of the HSCT and monitoring so who can fund a trial at this cost?
The first partial misconception that HSCT is a high-risk procedure needs to be placed in perspective with the drug regimen utilized, as well as with the risks of current FDA-approved disease-modifying therapies. There are three variables that determine the safety of HSCT: 1) the regimen (drugs) used; 2) patient selection; and 3) a center effect (experience with transplant for MS).It is important to recognize that the terminology ‘autologous hematopoietic stem cell transplantation’ is in reality a misnomer. There is no transplant, only the infusion of an autologous supportive blood product, analogous to a surgeon collecting before and then reinfusing autologous packed red blood cells after an operation. Before receiving the stem cell infusion (transplant), patients with autoimmune diseases receive a ‘conditioning regimen’ of drugs (chemotherapy, biologics, and/or radiation). The early and late toxicity from HSCT depends upon the specific drugs in the conditioning regimen and not the infused autologous blood product, i.e. hematopoietic stem cells.
BACKGROUND
The current therapies for MS consist of immune-modulating agents, such as interferons or glatiramer acetate, and anti-inflammatory and immune suppressive drugs such as glucocorticoids, methotrexate, and mitoxantrone (Novantrone; Immunex Corporation, Seattle, Wash).Autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is a form of immune suppressive therapy in that immune suppression is maximized to the point of transient immune ablation. In theory, the transplantation conditioning regimen ablates the aberrant disease causing immune cells while hematolymphopoietic stem cells (HSCs) regenerate a new and antigen naive immune system. Therefore, all of the toxic reactions and efficacy of an autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is likely a consequence of the conditioning regimen.
MOBILIZATION
COLLECTING STEM CELL
Most mononuclear cells collected by peripheral blood apheresis are immune cells such as lymphocytes and monocytes not HSCs. While the true identity of human HSCs remains elusive, either purified CD34+ or AC133+ hematolymphopoietic progenitor cells are sufficient for hematopoietic and immune reconstitution. In general, a minimum number of 2 × 106 CD34+ cells per kilogram of recipient weight will ensure engraftment. Hematopoietic stem cells may be positively selected or enriched ex vivo using antibodies to CD34+ or AC133 or purified by negative selection by using antibodies to remove lymphocytes. In practice, the most common method of purging lymphocytes is via CD34-positive selection using either the Miltenyi CliniMACS (Bergish Gladbach, Germany) or the Baxter Isolex (Deerfield, Ill) cell separator device. Whether enriching the graft for CD34+ HSC is necessary or even superior to infusion of an unmanipulated graft remains unclear. CD34+ selection by removing lymphocytes is perhaps best viewed as another method of immune suppression. For an intense conditioning regimen, CD34+ selection may be unnecessary or even detrimental by increasing the risk of treatment-related infection.#The rationale for autologous HSCT of MS is to regenerate an antigen-naive immune system from the patient’s own HSCs. Therefore, the goal of the conditioning regimen is lymphoablation not myeloablation. The autologous HSCT regimen should be based on immune suppressive drugs that are well tolerated at conventional nontransplantation doses and are expected to remain safe and nonmyeloablative at higher transplantation doses. The regimen must also avoid further damage to already injured axons and oligodendrocytes. By definition, myeloablative agents are lethal to HSCs and, apart from their myeloablative effect on bone marrow, may be similarly cidal to tissue-specific stem cells such as oligodendrocyte progenitor cells or neural stem cells. In animal models, cranial irradiation impairs the mechanism of CNS repair by neural stem cell apoptosis, alteration in cell cycle progression, and/or destruction of the neural stem cell niche or milieu through invasion of macrophages and microglia. This raises concerns about using total body irradiation based, or any other stem cell ablative regimen, in the treatment of MS.
Nonmyeloablative HSCT regimens that are as immune suppressive as myeloablative regimens but without myeloablative adverse effects may be designed by using agents or combinations of agents such as fludarabine, cyclophosphamide, antilymphocyte antibodies such as Alemtuzumab or anti-thymocyte globulin, and/or by the use of CD34+ selection of the graft. Fever-related deterioration of neural function in MS, termed “pseudoexacerbations,” due to conduction blocks in marginally functioning demyelinated axons should be avoided during transplantation by minimizing pyrogenic agents in the conditioning regimen. Similarly, the risk of infection-related fever should be minimized during transplantation by use of prophylactic antibiotics.
In summary, for MS the rationale behind the HSCT conditioning regimen should be to (1) dose-escalate agents that work as conventional therapy, (2) maximize immune suppression without myeloablation, (3) avoid conditioning regimen agents that may cause injury to already disease-affected and damaged CNS tissue, (4) avoid injury to tissue-specific stem cell compartments that may be important for CNS repair, (5) minimize the risk of fever, and (6) design regimens that are justified for the risk of the disease being treated.
The current ongoing Multiple Sclerosis International Stem cell Transplant (MIST) trial (www.clinicaltrials.gov NCT00273364) randomizes patients with two or more steroid-treated relapses within 12 months despite first-line therapy with interferon or copaxone to either HSCT (cyclophosphamide/ATG) or best available approved second-line therapy (Novantrone, Tysabri, or Gilenya) with a target of n=110.
So if positive what next? Will the regulators say: HSCT in place of current second line? (it would be cheaper in the long-run), HSCT in addition to second line; great but where is the second trial to confirm the results as we wouldn't want to favour academics over pharma or you are comparing apples with pears its obvious that HSCT is better than compound X in the standard second line or will they say the trial isn't properly done, like they did initially with Alemtuzumab (recently "We recognize that blinding during the first year will be compromised by patient hair loss but efforts will be made to mask hair loss by covering the heads of study patients during their first year neurology assessments" was removed from clinical trials .gov. Did they give up blinding the assessor?). If you agree to be randomised to HSCT and don't get it, do you loose the placebo effect. all sort of thng to think about.
I personally hope the regulators say yes this can be another treatment option choice.....(it will be approved for RRMS....will progressive MSers seek it a a base on which to layer neuroprotection and repair?).
However, I suspect there will be a lot of pharma out there who will not be so happy. Alternatively will it take so long to get HSCT approved, especially if more trials are needed the landscape will have changed by the time this happens.
If you do a trial against Alemtuzumab, in the two years to get the trial off the ground Ocreluzimab will probably come along. Will people therefore want Alemtuzumab? Will this be available as standard care, because if not, you will need to buy the drug for a trial of 110 people (based on the powering of MIST) the costs with be about £10-15,000,000 plus the costs of the HSCT and monitoring so who can fund a trial at this cost?
Nobody only Pharma?
Food for thought.
Food for thought.