Autologous Stem Cell Transplant for Crohn's Disease
Autologous Stem Cell Transplant for Crohn's Disease
Crohn's Disease (CD) is an inflammatory bowel disease. It can lead to significant
 complications and discomfort in the stomach and intestines. Crohn's disease is a
 debilitating, incurable disease of immune cells; it affects almost 1 million people in the
 United States. CD is characterized by inflammation of the stomach and intestine as well as
 organs outside of the intestines such as the skin, eyes, and joints. Current therapies to
 treat CD aim to suppress the patient's immune cells but these therapies become ineffective
 for the majority of patients and lead to complications including the requirement for surgical
 bowel resection, impaired quality of life, and lifelong disability. Hematopoietic stem cell
 transplantation (HCT) is a procedure used to treat a number of medical conditions including
 Crohn's disease. To improve success of HCT in CD doctors considered combining transplant with
 other drugs to improve the chances of achieving remission and also maintaining the remission.
 The Investigators' plan in this study is to incorporate the drug Vedolizumab after transplant
 to test if this drug will improve remission and make patients healthier.

 Patients may qualify to take part in this research study because Crohn's disease is active,
 because surgery is not a treatment option and because there is evidence that the disease has
 failed to respond to treatments for Crohn's disease including the following:

 -  corticosteroids

 -  azathioprine, 6-mercaptopurine, methotrexate

 -  Anti-TNFα (infliximab, adalimumab, certolizumab, golimumab)

 -  Anti-integrin agents (natalizumab, Vedolizumab) If patients meet entry criteria will
 undergo a baseline endoscopy, colonoscopy and MR or CT enterography. If documentation of
 active mucosal disease patients will then be tapered off of current medications and
 undergo stem cell mobilization. Mobilization will involve low dose chemotherapy, growth
 factors and require 1-2 week hospitalization. Patients will then undergo stem cell
 transplant which will involve high dose chemotherapy and require a 2-4 week
 hospitalization. After restoration of the immune system patients will be placed on
 vedolizumab per standard dosing (0,2,6 then 8 every weeks) for a total of 8 doses.
 Patients will have monthly study visits and a repeat colonoscopy and MR/CT scan at 6
 months.
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).

 Stem cell transplantation for CD has been recognized as a potential therapeutic modality
 since the 1980s. Northwestern University treated 24 patients with CD where stem cells were
 mobilized with cyclophosphamide 2 mg/m2 and G-CSF 10 mcg/kg/day followed by an immunoablative
 transplant using cyclophosphamide 200 mg/kg (50 mg/kg daily for 4 days) and ATG (30 mg/kg) as
 per the previously referenced consensus statement by EBMT. In this study there was no
 treatment related mortality and clinical relapse-free survival (defined as not restarting CD
 therapy) was 73% (17/23) at 1 year but declined to 19% at 5 years demonstrating the problem
 of durable disease control with autologous transplant alone. Interestingly, 8/15 (53%)
 patients who restarted therapy for recurrent Crohn's symptoms were able to achieve clinical
 remission, highlighting the possibility that efficacy of medications previously used can be
 restored following autologous HSCT. Autologous Stem-Cell Transplantation in Crohn's Disease
 (ASTIC) trial randomized patients either to autologous transplantation or stem cell
 mobilization chemotherapy without transplantation. This trial design allowed for the benefit
 of autologous HCT to be assessed independently of the potential benefit of the
 immunosuppression from high dose cyclophosphamide used to mobilize stem cells. The primary
 endpoint of the trial was assessed by the Crohn's Disease Activity Index (CDAI), the most
 prevalent method of assessing Crohn's disease clinical activity, where a level <150 is
 considered to represent disease remission. The ASTIC trial demonstrated at 1 year in patients
 who underwent transplant 44% were in clinical remission compared to 9% of patients who
 underwent mobilization only (p = 0.017). One death occurred in this study believed secondary
 to cyclophosphamide induced sinusoidal obstructive syndrome. Across all studies there has
 been one treatment related death out of 69 transplanted patients (1%), which is approximately
 the rate expected with autologous HCT for a malignancy such as multiple myeloma and
 significantly lower than the 5-10% expected transplant related mortality for other
 malignancies like lymphoma. Additional support for the safety of autologous HCT for
 autoimmune disorders comes from similarly designed studies using the same conditioning
 regimen of cyclophosphamide and ATG for other autoimmune or connective tissue disorders. For
 example, the one year mortality rate following autologous transplantation in 129
 relapsing-remitting multiple sclerosis patients was 0%.

 The discrepancy in response rates between the ASTIC study (44%) and the Northwestern study
 (73%) are likely due to several factors. First, the Northwestern population included patients
 with less severe Crohn's disease than the ASTIC trial. The Northwestern patients were
 eligible provided that the patient failed anti-TNF therapy while the ASTIC trial used
 stricter eligibility criteria. In addition, the ASTIC trial required endoscopic evidence of
 active Crohn's disease and therefore excluded patients whose disease activity scores
 reflected causes other than active inflammatory Crohn's disease, while the Northwestern trial
 did not. The CDAI score can be inflated from symptoms related to functional bowel disease and
 not the active inflammatory disease which is the target of immunosuppressive therapies.
 Active inflammatory mucosal disease is the greatest predictor of disease free survival and
 improves the reliability of the CDAI as a disease activity index. Finally, in an unknown
 number of patients the primary endpoint for the Northwestern patients was assessed on the
 basis of telephone report from patients that were asymptomatic and not on immunosuppressants,
 rather than the more rigorous CDAI score.

 Based on the successes described in transplanting Crohn's disease patients and guidelines on
 transplant utilization developed by the EBMT, other centers have begun to open their own
 transplant programs under the auspices of clinical trials.

 High doses of cyclophosphamide (high-CY), at a dose of 50 mg/kg/day X 4 days has become a
 standard dosing regimen in transplantation, a standard dosing for other transplant studies in
 Crohn's Disease, and the chemotherapeutic agent proposed for this clinical trial's Crohn's
 disease conditioning regimen. In this study, high-CY will be combined with an additional
 immunosuppressant, rabbit anti-thymocyte globulin (thymoglobulin, ATG), which has become part
 of the autologous transplant approach for autoimmune diseases including Crohn's disease.
 Thymoglobulin is a rabbit-thymocyte globulin obtained from the serum of rabbits immunized
 with human thymus lymphocytes. ATG is a lymphocyte-selective immunosuppressant that acts by
 causing in vivo T-cell depletion in blood and lymphoid tissues . There are sustained shifts
 in T and B cell subpopulations from memory to naïve cell dominance, supportive of thymic
 reprocessing and reeducation of the reconstituting immune system. This, in essence, resets
 the immune system of patients with autoimmune diseases, of which Crohn's disease may be
 considered. Thymoglobulin, the brand of ATG being used in this study, has a half-life of 2-3
 days. This allows for further delay in the return of activating T cells which contribute to
 the pathophysiology of Crohn's disease.

 Rationale for Incorporating Vedolizumab to Maintenance post Autologous Transplantation: While
 the results of the ASTIC trial suggest autologous BMT for CD is an effective therapy, there
 is still room for improvement as sustained remission is achieved in only 44% of patients. The
 reasons for the failure of induction of remission and the lack of sustained response in a
 portion of patients are unknown, but presumably recapitulation of the autoimmune response
 after transplant plays an important role. Vedolizumab is appealing to test after autologous
 stem cell transplant as it targets inflammatory T cells destined for the intestine
 (expressing α4β7). These T cells would be expected to be present in the graft and their
 blockade may improve the induction of remission achieved by the graft and leave the majority
 of protective T cells in the graft available to the recipient's recovering immune system. The
 addition of vedolizumab not only has the potential to improve induction of remission from the
 transplant itself but, as an adjunct therapy post-transplant, it may also help to maintain
 remission in this patient cohort. The need to provide patients with maintenance therapy post
 inductive therapy is well established both for medical therapeutics as well as
 post-operatively and vedolizumab has been established as an effective maintenance agent. The
 restoration of response to previously failed medications observed in other studies suggests
 that patients who did not respond to vedolizumab previously may now respond post HCT. This
 study will test the hypothesis that vedolizumab maintenance therapy will improve outcomes at
 1 year post-transplant by decreasing the portion of patients whose disease recurs and
 increasing the portion of patients for whom the transplant induces remission.
Inclusion Criteria:

 -  Diagnosis of Crohn's disease by standard criteria

 -  Active disease based on clinical symptoms, defined as CDAI >250. In patients with an
 ostomy, the number of liquid stools score in the CDAI will be replaced by the number
 of times that the ostomy bag is emptied daily.

 -  Active disease based on endoscopic evaluation, defined as SES-CD score > 3 in at least
 one bowel segment

 -  Failure to respond to (or intolerant/adverse reaction to or declines) a member of each
 of the class of drugs listed below:

 1. corticosteroids

 2. azathioprine,

 3. 6-mercaptopurine, methotrexate

 4. Anti-TNFα (infliximab, adalimumab, certolizumab, golimumab)

 5. Anti-integrin agents (natalizumab, vedolizumab)

 6. Ustekinumab

 -  Failure to respond refers to ongoing objective inflammation with symptoms and, as is
 traditional, is defined by the gastroenterologist evaluating the patient.

 -  No surgical therapeutic option secondary to risk of short bowel syndrome or patient
 refusal

 Exclusion Criteria:

 -  History of significant toxicity to any medications used in trial (cyclophosphamide,
 thymoglobulin, vedolizumab)

 -  Pregnant or breastfeeding

 -  Age <18

 -  Karnofsky Performance Score <60

 -  Patients who have an uncontrolled infection (presumed or documented) despite
 appropriate therapy for at least one month

 -  Patients with symptomatic coronary artery disease or uncontrolled congestive heart
 failure.

 -  HIV infected

 -  Ejection fraction <30% or requiring supplemental continuous oxygen.

 -  DLCO <35% or requiring supplementary oxygen.

 -  Patients for whom an insufficient number of stem cells (<2 X 10^6/kg) have been
 collected.