Transcript Hematopoietic stem cell transplant as a therapy for severe, anti

Hematopoietic Stem Cell Transplant
as a Therapy for Severe, anti-TNF-α
Resistant Inflammatory Bowel
Disease
Christopher Sweat, MD
Resident, PGY1
University of Washington Dept. of
Surgery
July 10, 2014
Patient XH
 2½ year old male with severe early onset
inflammatory bowel disease, unresponsive to
Remicaid and steroids.
Course
• Initially mild, intermittent bloody diarrhea
starting at 7 months of age
• Progressively worsening and painful since fall
2013, at which time he was diagnosed with
allergic colitis.
• By April 2014, was having 20+ painful, bloody
bowel movements per day.
• Diagnosed with inflammatory bowel disease.
Course, cont.
• Started on sulfasalazine, high dose
corticosteroids, and Remicade.
• Initial significant improvement, with complete
remission of symptoms.
• After several weeks, tapered off steroids, and
symptoms returned in full.
• Given additional doses of Remicade, but no
response.
Course, cont.
• 6/20, endoscopic biopsies performed
– Severe lymphocytic inflammation extending from
the rectosigmoid past the transverse colon, with
severe crypt abscess formation
– Mild lymphocytic inflammation of gastric antrum
– Severe ulcerative or indeterminate colitis.
• 7/2, total colectomy with Brooke ileostomy
Course, cont.
• Pathology 7/7/14- severe chronic colitis
limited to the mucosa and submucosa, not
extending into the distal ileus, most consistent
with ulcerative colitis.
• Discharged home on 7/9/14.
Conventional Therapies
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Salicylates
Antibiotics
Steroids
TNF-α inhibitors
– Infliximab
– Adalibumab
Stem cell transplant in IBD
In the 1980s, it was found that several patients
being treated for leukemia would achieve
complete remission of their coexisting
autoimmune diseases after receiving bone
marrow transplants, (including SLE, IBD, and
systemic sclerosis.)
HCST in IBD
• Long term case series of 11 patients being treated
for AML and CML, 1994-2002, 4 with UC, 7 with
Crohn’s.
• All received allogeneic SCT from matched donors.
• All but one achieved complete and lasting
remission of their IBD, with one exception
– 1 pt with Crohn’s had incomplete myeloablation
resulting in immune chimerism- had some recurrence,
but it was very mild.
Allogeneic Stem Cell Transplant
• Stem cells from a matched donor, again
enriched via CD34+ selection.
• Total Myeloablation/Immunoablation
• Post-transplant Immunosupression to prevent
GVHD.
Advantages
1. Possibility of long-term, complete remission.
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Multiple small studies have shown complete and
lasting remission of IBD symptoms- longest
follow up was 15 years.
Disadvantages
1. Requires post-transplant immunosuppression
to prevent GVHD
2. More danger of sepsis and a more prolonged
recovery of cell counts 2/2 the need for
complete myeloablation.
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Incomplete myeloablation in one case led to
chimerism and return of symptoms 1.5 years
post transplant.
HSCT in IBD, cont.
• Starting in the early 2000s, RCT studies explored the
possibility of autologous stem cell transplants as a way
to treat severe, medication resistant IBD- specifically
Crohn’s- and were partially successful.
• While complete remission was only rarely achieved,
(only ~20% after 5 years) short term outcomes were
excellent- 91% completely symptom free for first year.
• More importantly, when symptoms did return,
previously treatment intractable Crohn’s would actually
respond to conventional medications.
Autologous Stem Cell Transplant
1. Patient’s own stem cells are mobilized using
cyclophosphamide 2g/m2 and Filgrastim, (GCSF) 10 μg/kg/day.
2. Enriched via CD34+ selection
3. Stem cells are reinfused after partial
immunosupression using cyclophosphamide
200 mg/kg in conjunction with
antithymocyte globulin.
Advantages of Autologous SCT
• 1- Autologous Cells- no risk of GVHD
• 2-Nonmyeloablative- bone marrow is
suppressed rather than ablated, leading to a
faster recovery, less neutropenia, and overall
less risk of infection
• 3- Significantly more responsive to
conventional therapies even after recurrence.
Disadvantages of Autologous SCT
• Remission is temporary
– Rates in one RCT 91% remission at 1 year post
HSCT, 63% at 2 years, 57% at 3 years, 39% at 4,
and 19% at 5.
• Infection risk 2/2 immune compromise (less
than allograft due to suppression rather than
destruction of marrow, but still present)
Conclusions
• Allogenic HSCT is a potentially curative method of
treatment for severe, anti-TNFα resistant IBD,
though it’s use is limited due to the high risks of
myeloablation and post-transplant GVHD.
• Though not curative, autologous SCT may provide
short term relief of symptoms and, more
importantly, lead to the patient having a better
response to conventional IBD treatment
regimens.
• Regardless, it’s effectiveness provides interesting
insite into the disease.
References
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Lopez-Cubero S., et al. Course of Crohn’s Disease after allogeneic marrow
transplantation (1998)
Ditschkowski M., et al. Improvement of inflammatory bowel disease after
allogeneic stem-cell transplantation (2003)
Elding H, et al. Refinement in localization and identification of gene regions
associated with Crohn's Disease (2013)
Burt R., Craig R., et al. Autologous nonmyeloablative hematopoietic stem cell
transplantation in patients with severe anti-TNF refractory Crohn disease: long
term follow-up (2010)
Snowden J.A., Ansari A., et al. Autologous stem cell transplantation in severe
treatment-resistant Crohn's disease: long-term follow-up of UK patients treated
on compassionate basis. (May 5, 2014)
Sostegni R., Daperno M., et al. Review Article: Crohn’s Disease: monitoring
disease activity.
Kriván G., Szabó D., et al. Successful autologous haemopoietic stem cell
transplantation in severe, therapy-resistant childhood-onset Crohn's disease.
Report on the first case in Hungary (May 18, 2014)
McGovern
D.
Crohn
Disease
and
NOD2/CARD15.
http://emedicine.medscape.com/article/1790325-overview#a30
Supplement: Crohn’s/ NOD2
• Very complex genetic and immunologic basis
– Over 70 loci identified
– Incidence: 3-7/100,000 diagnoses per year.
– 15x more likely if 1st degree relative affected, 30x with an
affected sibling, and a 67% concordance rate in identical
twins.
• Genetic relation definitively shown in 2001 with
discovery of the NOD2 gene.
– Risk for Crohn’s goes up 2x if heterozygous for mutant
NOD2, 20x if homozygous.
– Has a leucine rich sequence that interacts with bacterial
compounds- exact purpose unclear, but suggests
autoimmune