Maintenance in Autologous Stem Cell Transplant for Crohn's Disease (MASCT - CD)

Crohn's Disease Inflammatory bowel disease, encompassing Crohn's disease (CD) and ulcerative colitis (UC), represent incurable chronic inflammatory disorders of the intestinal tract. Patients with IBD experience a chronic relapsing and remitting course of their disease, with little ability to predict when these flares will occur. The primary symptoms of IBD are related to inflammation of the gastrointestinal (GI) tract and include diarrhea, hematochezia, and abdominal pain. Patients also frequently suffer from systemic inflammatory symptoms such as fatigue, arthritis, uveitis, and erythema nodosum.

Current therapies for CD are directed at symptom control by suppressing the immune system or surgical resection of the damaged bowel. The most efficacious medical therapy, the combination of an anti-tumor necrosis factor alpha (anti-TNFα) monoclonal antibody and an immunomodulator (6-MP or azathioprine), results in a 56% clinical remission rate at 6 months, leaving a large portion of patients with active disease. Unfortunately, even among initial responders to this therapy a large proportion of responders eventually relapse, requiring that the majority of patients with Crohn's disease ultimately need new therapeutic modalities.

The most promising treatment for CD patients refractory to anti-TNFα therapy, are inhibitors of T-cell trafficking to the GI tract. The first of these, natalizumab, was approved by the FDA in 2008 and is indicated for CD and multiple sclerosis. Natalizumab binds to the α4 integrins (α4β1 and α4β7), disrupting interaction with its ligands VCAM-1 and MAdCAM-1 and impeding leukocyte adhesion and trafficking to the CNS and GI tract respectively. The ENACT study demonstrated a 6% improvement in clinical response in patients receiving natalizumab compared to placebo (56% vs 49%, p = 0.05) in 905 patients with moderate to severe Crohn's disease defined as a CDAI score of between 220-450. While the overall therapeutic efficacy was modest, in a subgroup analysis of patients refractory to anti-TNFα therapy 55% of patients in the treatment arm responded compared to 35% in the placebo arm (P < 0.05). One negative feature of natalizumab is that general blockade of α4 integrins inhibits T-cell trafficking to the CNS in addition to the intestine and has been shown to increase the risk of progressive multifocal leukoencephalopathy (PML), a fatal infection caused by the JC Virus (JCV).

A newer monoclonal antibody, vedolizumab, binds only to α4β7 which results in selective inhibition of leukocyte trafficking to the intestine and theoretically eliminates the risk of PML. Vedolizumab was approved by the FDA in 2014 based on a randomized controlled trial of 368 patients with refractory CD treated with vedolizumab which demonstrated a significant induction of clinical remission in this cohort (14.5% vs 6.8%, p=0.02) . Similar to natalizumab, a subgroup analysis demonstrated that 10.5% of patients refractory to anti-TNFα therapies will respond to vedolizumab. Among vedolizumab responders who were randomized to maintenance vedolizumab, responders were more likely to be in clinical remission at week 52 compared to patients not on maintenance therapy (39% vs 22%, p=0.001).

Autologous hematopoietic stem cell transplantation (HCT) is a procedure used to treat and/or cure a number of malignant conditions including lymphoma and myeloma. Briefly, following collection and cryopreservation of hematopoietic stem cells, very high doses of chemotherapy to overcome tumor resistance are given followed by reinfusion of the collected hematopoietic stem cells. The transplanted HSC reconstitute the marrow and restore normal blood cell production and reconstitute the immune system. More recently, autologous HCT has been shown to be an effective treatment in a number of autoimmune disorders such as multiple sclerosis, scleroderma, and CD. For autoimmune disorders, the presumptive mechanism of action is that intensive immunoablation followed by reinfusion of hematopoietic cells results in an immunological "reset" without recurrence of the autoimmune disease. The most common chemotherapy regimen used for autoimmune disorders is a combination of cyclophosphamide with anti-thymocyte globulin. The safety of this regimen is well established and has been recommended for the previously mentioned conditions by the European Group for Blood and Marrow Transplantation (EBMT).