The purpose of this study is to find out if a stem cell transplant is safe for patients with a very rare disease. The stem cell transplant is called AHSCT (for "allogeneic hematopoetic stem cell transplantation"). The rare disease is called MNGIE (for "Mitochondrial NeuroGastroIntestinal Encephalomyopathy").
In this study, we plan to perform AHSCT on at least 3 and at most 12 patients with confirmed MNGIE. We will evaluate mortality, the success of the transplant, biochemical parameters, gastrointestinal function, and nerve functions.
- Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE)
MNGIE is a rare, severe genetic disease. It usually begins to affect patients in their late teenage years. Major symptoms are gastrointestinal (difficulty swallowing, diarrhea, abdominal pain, inability to eat normal size meals), weight loss, droopy eyelids, reduced ability to move eyes, numbness, tingling, and weakness in the hands and feet due to nerve damage. The disease occurs when a person inherits two DNA mutations in the TYMP gene that produces the protein thymidine phosphorylase (TP). Low levels of TP activity, or no TP activity, cause toxic accumulations of thymidine (Thd) and deoxyuridine (dUrd). These toxic accumulations prevent the mitochondria, the energy producing parts of the cell, from producing enough energy.
The therapeutic efficacy of AHSCT is supported by preliminary results in 10 surviving, successfully transplanted MNGIE patients who have shown restoration of circulating TP activity, marked reductions of the toxic metabolites, Thd and dUrd, and time-dependent clinical improvements.
The Single Primary Aim is to confirm that primary graft failure by day 42 post-transplant and mortality from initiation of conditioning regimen through day 100 post-transplant are acceptable in a one-arm safety study of the consensus AHSCT protocol for MNGIE.
There are 5 Secondary Aims:
- To confirm that additional safety outcomes do not reach an unacceptable level through day 100 post-transplant.
- To evaluate the change in key biological and clinical outcome measures from baseline through day 100 post-transplant.
- To collect preliminary safety data through two years post-transplant.
- To evaluate the change from baseline through two years post-transplant in key biological and clinical outcome measures.
- To assess, and revise as appropriate, the recruitment, retention, patient management, and data management procedures for the planned biological allocation Phase II trial comparing AHSCT to standard of care for MNGIE patients.
About this Study
This is a prospective, non-randomized, interventional Phase I adaptive safety study. There will be 3-12 participants enrolled over the course of 2 years.
Participants in this study will receive chemotherapy prior to undergoing an allogeneic Stem Cell Transplant (alloSCT). Following alloSCT participants will be assessed for neurogastrointestinal clinical response. Participants' blood will also be evaluated for signs of improvement in typical biochemical abnormalities of MNGIE.
Participants will be enrolled in the study for 2 years.
To be eligible to participate, you must:
- Have laboratory-confirmed MNGIE: thymidine phosphorylase (TP) defect (a and/or b):
- homozygous or compound heterozygous mutations in the TYMP gene, and/or
- TP enzyme activity of <20% of normal.
- Increased plasma thymidine (Thd) > 3 micromole/L
- Increased plasma deoxyuridine (dUrd) > 7.5 micromole/L
- Age at least 5 and no greater than 55 years.
- Karnofsky performance status ≥50%; Lansky >40%
- Be ambulatory
- Be able to grant consent
- Have insurance coverage of the AHSCT and related care
- Have agreement of investigators that alloHSCT is appropriate after discussion at Adult or Pediatric SCT Conference.
Additionally, there must be an available HLA-10/10 related or unrelated 10/10 HLA-matched donor.
You are not eligible to participate if you have:
- Severe cognitive impairment (I.Q. <70).
- Severe psychiatric illness (depression, anxiety, etc. impairing work or activities of daily living).
- Moderate to severe lung disease (vital capacity <50% of predicted normal, diffusion capacity of carbon monoxide or forced expiratory volume in one second <70%).
- Prior episode of peritonitis due to perforated diverticula.
- Prior episode of intestinal pseudo-obstruction.
- Moderate to severe hepatopathy (AST and ALT >2x ULN, bilirubin >2x ULN, liver cirrhosis on ultrasound).
- Moderate to severe diabetes mellitus.
- Moderate to severe cardiomyopathy (congestive heart failure, ejection fraction <50%).
- Moderate to severe nephropathy (serum creatinine>2mg/dL, on dialysis).
- For women of childbearing potential, participant cannot be pregnant, lactating, or plan to become pregnant over the course of the study.
- Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients with fever despite broad-spectrum antimicrobials but no clinical or hemodynamic evidence of sepsis will be allowed.
- Know hypersensitivity to E. coli-derived products.
- HIV disease.
- Positive for anti-donor HLA-DP antibodies >1000 in adults.
To be eligible to be a donor, you:
- May be an HLA-10/10 related or unrelated donor using high resolution DNA based typing.
- Must be healthy and an acceptable donor as per institutional standards for marrow or stem cell donation.
- Must have no significant cardiopulmonary, renal, endocrine or hepatic disease.
- No donor age restriction if donor is a matched sibling.
- Syngeneic donors are not eligible.
How to participate
In order to participate, you may contact the study coordinator:
Kris Engelstad, MS, CGC
Columbia University, New York, NY