Abstract
Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.
Keywords: allogeneic hematopoietic SCT, mitochondrial neurogastrointestinal encephalomyopathy, MNGIE, consensus, recommendation
Introduction
Background and rational for allogeneic HSCT in MNGIE
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder of nucleotide metabolism due to TYMP gene mutations that cause loss of activity of thymidine phosphorylase (TP). TP deficiency results in greatly elevated thymidine (Thd) and deoxyuridine (dUrd) plasma and tissue levels,1 which lead to nucleotide pool imbalances causing instability of mitochondrial DNA (mtDNA) with loss of mitochondrial respiratory chain functions. MNGIE manifests clinically as a multisystemic disease mainly affecting the gastrointestinal and nervous systems with: (1) severe gastrointestinal dysmotility, (2) cachexia, (3) ptosis, ophthalmoparesis or both, (4) peripheral neuropathy and (5) leukencephalopathy.2
Although the biochemical defect is present from birth, patients develop initial symptoms at a mean age of 19 years with a wide range from 5 months to more than 50 years.2,3 The disease course is relentlessly progressive with death occurring at a mean age of 37 years.
Currently, fewer than 200 patients (M.Hirano, personal communication) without apparent ethnic restrictions are known to be affected with MNGIE, but the true incidence of the disease and its distribution among ethnic groups are unknown, and may be underestimated. First, this rare disease was initially described only 22 years ago4 and therefore, is under-recognized. Second, it may masquerade as other diagnoses including anorexia nervosa, inflamma-tory bowel disease, superior mesenteric artery syndrome, Whipple disease, chronic intestinal pseudo-obstruction, chronic inflammatory demyelinating polyneuropathy and Charcot Marie Tooth disease.5 Third, rare cases with atypical features such as absence of gastrointestinal dysmotility, presence of cognitive dysfunction and hypogonadism, or with unusually late-onset may be misdiagnosed.3,6,7
The relatively late-onset of MNGIE compared with other mitochondrial diseases that typically present in infancy or childhood is thought to be due to the progressive accumulation of mtDNA defects induced by toxic levels of Thd and dUrd.8,9 Once the proportion of defective mtDNA has reached a critical threshold, tissue-specific mitochondrial dysfunction manifests clinically. While TP is not expressed in all tissues, cellular and plasma Thd and dUrd levels appear to be in equilibrium among all body compartments.10
Therefore, correction of the TP deficiency in a readily accessible compartment such as blood may be sufficient to eliminate the toxic nucleosides and to control the disease. Replacement of circulating enzyme should catabolize the toxic metabolites in plasma, create a diffusion gradient and subsequently clear these freely diffusible substrates from the tissue compartments, normalize the cellular nucleotide pools and prevent further damage of mtDNA. Symptoms or disease progression might be improved with or without mtDNA repair as has been observed in other metabolic diseases treated with stem cell replacement therapies.11
Clinical evidence for enzyme replacement strategies
Both Thd and dUrd are freely diffusible across cell membranes. Lowering of plasma levels of both of these agents can be achieved by direct removal of the metabolites or replacement of the missing enzyme. Both approaches have been explored.
Current evidence from heterozygote carriers suggests that TP activity between 25 and 30% of normal is sufficient to prevent disease manifestations. Below this level there is a correlation between the extent of TP deficiency and severity of clinical phenotype.3
Direct removal of metabolites from the blood compartment by peritoneal dialysis
Both Thd and dUrd can be removed by dialysis. In contrast to haemodialysis, in which only a short-term effect can be observed with routine dialysis frequency, peritoneal dialysis may be more effective.12,13
In a 16-year-old girl with MNGIE, symptoms improved with continuous ambulatory peritoneal dialysis,13 her weight increased and menstruation resumed. Although tissue concentrations of Thd and dUrd were not measured, the improvement of the symptoms under continuous ambulatory peritoneal dialysis suggests that the elimination of plasma Thd and dUrd had a clinically relevant beneficial effect. Symptoms reappeared rapidly, when peritoneal dialysis was interrupted. Despite elimination of about 100 mmol of Thd and dUrd daily, it was observed that there was no decrease in the plasma levels most likely explained by a continuous equilibrium with the tissue nucleoside pool. Therefore, it remains unclear if the clinical improvement was due to the changes in the nucleoside pool or to other factors.
Substitution of the missing enzyme by platelet transfusions
Because plts are rich in TP, platelet transfusions to two MNGIE patients were performed to test the biochemical response of patients to a circulating source of TP activity.14 Repeated platelet transfusions restored circulating TP activity and clearly reduced plasma Thd and dUrd concentrations. The clinical symptoms were not monitored because no effect was expected in such a short treatment, but the biochemical effects observed indicated that permanent restoration of circulating TP would ameliorate the nucleoside imbalances that cause the disorder.
Preliminary published experience of enzyme replacement by allogeneic HSCT
Allogeneic hematopoietic SCT (HSCT) offers the possibility of sustained correction of enzyme deficiency and has become an established treatment for many different storage diseases.11 Nine patients with MNGIE have so far been treated with allogeneic HSCT.15–19 Early data showed a rapid restoration of the enzyme activity together with a reduction or disappearance of plasma Thd and dUrd in those patients who engrafted. Although the observation period in most patients was too short to evaluate a clinical benefit but it was sufficient to show biochemical improvement.
Consensus proposal
Reasons for a consensus proposal
As outlined above, six teams have investigated allogeneic HSCT as a possible treatment for patients with MNGIE. Members from all these teams participated in the first international symposium and consensus conference, which took place in Bern Switzerland on 7 November 2008. Preliminary data from all nine patients who were known at that time to have undergone allogeneic HSCT worldwide were presented and discussed in detail. The data confirmed the proof of principle of allogeneic HSCT as a tool to replace the missing enzyme. Rapid restoration of the TP activity and reduction or disappearance of plasma Thd and dUrd was observed in all patients with engraftment. Several different transplant regimens were used. Engraftment as well as rejections, infections, GVHD and post-transplant lymphoproliferative disease were observed. The heterogeneity of the approaches precluded definitive analysis and follow-up was too short in most cases to evaluate clinical benefit. Therefore an important goal of this conference was to propose a common transplant protocol which should allow a reliable evaluation of this therapy for MNGIE and help to determine the best treatment regimen in the future.
General considerations
To date, clinical benefit from allogeneic HSCT for patients with MNGIE has not yet been shown. There are several challenges in administering this treatment: (1) patients are generally in poor medical condition with limited capacity to tolerate transplant-related complications, (2) the risk of graft rejection necessitates adequate conditioning and immunosuppression, (3) gastrointestinal function is disturbed with potential impairment of absorption, that is, there is a need for parenteral application of drugs, (4) drugs with possible mitochondrial toxicity must be avoided, and (5) for many drugs used in HSCT (and even more for their potential interactions) their effects on mitochondrial function are not known.
Given these challenges and the clinical experiences from the first patients, the next step should be to follow a common standardized transplant regimen, which is based on established transplant protocols.
The first goal remains to demonstrate a clinical benefit of allogeneic HSCT. This can only be achieved by studying patients with clinical disease confirmed by biochemical assays preferably with genetic confirmation by identification of TYMP mutations20 and with severe clinical manifestations that justify the risk of the procedure. Patients should not have irreversible end-stage disease, which may prevent clinical benefit from the procedure. In addition, all risks from HSCT should be minimized. Thus, HSCT should currently only be offered to patients with an optimal donor (see section 2.3.3. donor type). Once the clinical benefit of alloHSCT has been shown, these recommendations may be widened.
Written informed consent from the patients or their guardians is necessary and approval of the treatment protocol by local institutional review boards is recommended.
A data safety monitoring board will evaluate the results of the treatment protocol after each cohort of five patients. If HSCT fails in three consecutive patients, the clinical study protocol will be halted.
All participants agreed that these recommendations are provisional and should be evaluated at regular intervals.
Treatment protocol
Standardized pre-treatment evaluation
All patients should undergo standardized pre-treatment evaluation as outlined in Table 1 to evaluate clinical efficacy and potential toxicities.
Table 1.
Standardized disease-specific pre-treament evaluation
| Baseline assessments should be comprehensive. Video or photographic documentation is recommended, provided the patient/guardian gives written informed consent. |
| Recommended examinations and tests for patients include: |
| Personal and family history |
| Clinical examination including: |
| Performance status (Karnofsky or Lansky) |
| Weight and height |
| Complete neurological evaluation |
| Cognitive evaluation: modified mini-mental state (3 MS) evaluation and Wechsler Scale 3rd edition |
| Laboratory evaluations: |
| Complete blood count |
| Blood chemistry including liver function tests and metabolic evaluation for lactate and pyruvate before and after a light standardized meal |
| Thymidine phosphorylase (TP) activity and TYMP mutations, plasma |
| Thd and dUrd, urine Thd/creatU and dUrd/creatU |
| Peripheral nerve conduction studies |
| OXPHOS activities and mtDNA analyses in cultured skin fibroblasts and if available myoblasts |
| MRI of the brain and the spinal cord |
| MRS (MR spectroscopy) of leukoencephalopathic area and ventricular CSF |
| Audiometry |
| Ophthalmological examination |
| Abdominal ultrasound |
| ECG |
| Optional: |
| EMG |
| Lumbar puncture (lactate, pyruvate, protein) |
| Muscle biopsy (histology, biochemical measurements of respiratory chain enzymes, and mtDNA analyses) |
| Gastrointestinal motility studies |
Timing of transplantation
Patient evaluation for allogeneic HSCT should be performed as early as possible after definitive diagnosis of MNGIE. Given the current knowledge, transplantation should be considered early in the disease when there may be greater potential for optimal recovery and the patient's medical fitness minimises the risks associated with HSCT. Further studies are needed to determine the optimal time point for transplantation.
This recommendation is based on data that are limited by three factors. First, it is not clear yet to what extent the disease burden might be reversible and over what period. Second, there are no established prognostic factors for disease progression. Third, it is known from studies of other diseases that transplant-related morbidity and mortality increases with progression of the disease, increasing number of comorbidities and/or reduced performance score.21,22
Donor type
Careful donor selection is required to minimize both the risk of graft rejection and GVHD.
If available, a HLA-identical sibling would be the first choice. Given the fact that TYMP mutation carriers are asymptomatic23 both non-carriers and heterozygous carriers would be accepted as a donor but non-carriers are preferred to maximize potential enzyme replacement.
If no sibling donor is identified, a HSCT with a 10/10 allele matched unrelated donor is recommended (HLA-A, B, C, DRB1 and DQB1 phenotypically identical).
Based on current results, use of a donor with a HLA allele match less than 10/10 is discouraged.19
If more than one HLA-identical donor is available further donor selection for gender, CMV serostatus and blood group should be performed according to the centers’ guidelines.
Source of transplant and cell dose
The cell dose is an important predictor to prevent graft rejection and secondary graft failure.24 Given the fact that patients with MNGIE are typically underweight, an adequate stem cell dose should be achievable for BM as well as G-CSF-mobilized PBSC.
As MNGIE is a non-malignant disease, BM is the recommended stem cell source because it is associated with less GVHD than PB;25 however, if the donor only agrees to PB donation, PB would be acceptable.
In view of the current results, the use of CB cannot be recommended until graft rejection can be better controlled in this disease. Both, the limited number of cells in the graft as well as HLA disparity might contribute to this problem.
Backup of autologous hematopoietic stem cells
Because of the high rate of rejections that was observed in the first nine patients,19 an autologous backup of hematopoietic stem cells for rescue should be considered before the start of conditioning.
Autologous stem cells should be mobilized with G-CSF alone. We recommend storing a minimum number of 2 × 106 CD34+ cells per kg before start of conditioning.
Current experience and knowledge suggests that the apheresis procedure does not represent an increased risk in MNGIE patients. If infusion of the cryopreserved cells becomes necessary, DMSO is not expected to harm residual mitochondrial function.
Manipulation of the graft
Manipulations other than minimal manipulations (for example, depletion of RBC or plasma in case of ABO-incompatibility in BM transplants) are not recommended, including T-cell depletion (TCD) as discussed below.
Conditioning for the transplant
It is important to find an optimal balance between the cytoreductive effect to prevent rejection and minimal toxicity. Beside the usual toxicities of the drugs used, their potential mitochondrial toxicity has to be considered:
No clinically relevant mitochondrial toxicity has been described for fludarabine and BU.
In contrast, clinically relevant mitochondrial toxicity has been described in either animals or humans for CY, melphalan and TBI.26–29 Therefore these agents or procedures are not currently recommended for conditioning.
The group recommends conditioning with fludarabine 30 mg/m2 for 5 days (day –6 to day –2, total dose 150 mg/m 2) and BU 3.2 mg/kg i.v. in divided doses (0.8 mg/kg/dose i.v. every 6 h) daily for 4 days (day –5 to day –2, total dose 12.8 mg/kg). Owing to the gastrointestinal dysmotility, there is erratic and often decreased transit time with possible malabsorption, therefore, oral BU is not recommended.
Immunosuppression and GVHD prophylaxis
Various techniques of immunosuppressive regimens or in vitro or in vivo TCD have been used in allogeneic HSCT to prevent graft rejection and GVHD. Owing to an increased risk of infection, no clear advantage in survival could be shown when compared with standard approaches with CYA with or without methotrexate. The pros and cons of TCD were discussed extensively during the conference with the knowledge that problems such as rejection, GVHD and opportunistic infections including post-transplant lymphoproliferative disease occurred in the patients discussed. Finally, the participants agreed that if the recommended donor selection criteria are fulfilled, no TCD is recommended for either HLA-identical sibling HSCT or unrelated 10/10 matched HSCT.
Leukoencephalopathy as well as peripheral neuropathy are well-recognized side effects of calcineurin inhibitors (for example, CYA and tacrolimus (FK506)),30,31 which could limit the use of these drugs in MNGIE because these are also manifestations of MNGIE. CYA prevents mitochondrially mediated apoptosis by blocking the permeability transition pore,32 but may inhibit mitochondrial respiratory chain enzymes.33 Similarly, tacrolimus prevents apoptosis34 but can also act as a mitochondrial toxin.35 Despite its potentially toxic effects on mitochondria, CYA was well tolerated by 4 of 9 MNGIE patients without any obvious exacerbation of the neuropathy or the metabolic status by strict monitoring and maintenance of plasma levels of CYA or tacrolimus within the therapeutic range.
Some patients have been treated with methotrexate in addition to a calcineurin inhibitor. Theoretically, methotrexate could exacerbate the nucleotide pool imbalances in MNGIE patients because it inhibits thymidylate synthase, which depends on N5,N10-methylene-tetrahydrofolate. However, methotrexate toxicity was not observed in this cohort of patients possibly due to the preferential action of the drug on mitotically active cells, whereas MNGIE primarily affects post-mitotic cells. We were also concerned that the action of methotrexate may be reduced in MNGIE patients because excess Thd may be converted to TMP by the action of thymidine kinase, which is not inhibited by methotrexate. Nevertheless, this drug appeared to be effective for GVHD prophylaxis in three transplanted MNGIE patients. Therefore, we recommend methotrexate in our protocol.
Instead of methotrexate, mycophenolate was used in some patients. Data about mitochondrial toxicity of mycophenolate are controversial but gastrointestinal adverse effects are well-known and may contribute to post-transplant gastrointestinal problems in these patients.
An alternative drug for calcineurin inhibitors would be rapamycin, though mitochondrial toxicity has been described for it.36,37 Current evidence suggests that the immunosuppressive effect of a rapamycin-based regimen without a calcineurin inhibitor is less efficient than a calcineurin inhibitor-based regimen. Hence, the potential increase in the risk of rejection might outweigh the potential benefits.
In conclusion, current experience does not favor any one immunosuppressive regimen over another. Therefore, the group recommends using the most established regimen: CYA with careful therapeutic monitoring to avoid trough levels above 250 mg/L in combination with methotrexate 10 mg/m2 on days 1, 3 and 6 with leucovorine rescue38 with dose modification for renal insufficiency. The day 6 dose of methotrexate is optional in the setting of severe mucositis.
Tapering of CYA will commence at 6 months in the absence of active GVHD. Depending on chimerism results, the taper schedule may be initiated earlier.
Supportive care
For BU conditioning, antiepileptic prophylaxis with benzodiazepines is recommended. Phenytoin is not recommended as an antiepileptic prophylaxis because of the potential for many drug interactions and its mitochondrial toxicity as well.39,40
Standard infectious prophylaxis for pneumocystis jiroveci pneumonia and toxoplasmosis is recommended.
For patients with positive serology for HSV or VZV, prophylaxis with acyclovir or valacyclovir is recommended. Although data from animal models suggest mitochondrial damage,41 the potential for mitochondrial toxicity seems to be relatively low in uninfected cells.42 Most patients received this prophylaxis or treatment without detectable clinical deterioration.
Regular monitoring for CMV and EBV reactivations is recommended according to the center's own practice. If CMV reactivation occurs, antiviral treatment should be initiated. There is no apparent advantage from one antiviral drug (ganciclovir, foscarnet or cidofovir) over the other.
Azoles should be avoided because of their negative impact on mitochondrial function in animal models.43,44 Echinocandins or amphotericin B formulations might be used as an alternative.
Antibiotic treatment should be guided by the presumptive or proven cause of infection and the local susceptibility data. Even if there is theoretical concern about the use of aminoglycosides, this should not prevent their use if clinically required. In this case, close monitoring of the patients (serum levels of aminoglycosides, drug-associated toxicity) is necessary. Use of linezolide should be avoided; if it is clinically necessary, the application should be limited to 2 weeks because it inhibits mitochondrial protein synthesis.45,46
Transfusion triggers for RBC and plts should not be different from other patients undergoing allogeneic HSCT and should be guided by the center's practice. Neither regular platelet transfusions for enzyme substitution nor regular IVIG substitutions are recommended.
For analgesic treatment, paracetamol is the standard treatment, whereas opiates should be used with caution. Typically, bowel movements in MNGIE are hyperactive but if mucositis occurs the risk for paralytic ileus might be increased and could be further increased by opiates. Non-steroidal anti-inflammatory drugs are not recommended due to their adverse effects on renal and platelet function.
A summary of drugs commonly used in HSCT is provided in Table 2.
Table 2.
Drug usage in MNGIE
| (a) Drugs without clinically apparent toxic effect on mitochondrial function in MNGIE |
| Chemotherapeutics: |
| Fludarabine |
| Busulfan |
| Immunosuppressants: |
| Cyclosporine A |
| Tacrolimus |
| Sirolimus |
| Mycophenolic acid |
| Methotrexate |
| Antibiotics: |
| Penicillins, cephalosporins, β-Lactamase inhibitors and carbapenems |
| Quinolones |
| Others: metronidazole, trimethoprim sulfamethoxazole |
| Virostatics: |
| (Val)acyclovir |
| Antifungals: |
| Echinocandines: for example, caspofungin |
| Amphotericin B formulations |
| Others: |
| Benzodiazepines |
| Metoclopramide |
| Selective 5HT3 receptor antagonists |
| Paracetamol |
| Fentanyl (but may decrease intestinal motility) |
| (b) Drugs which should be used only after careful risk-benefit analysis: |
| Chemotherapeutics: |
| Cyclophosphamide |
| Melphalan |
| Antibiotics: |
| Aminoglycosides |
| linezolide |
| Virostatics: |
| (Val)ganciclovir |
| Foscavir |
| Cidofovir |
| Antifungals: |
| Fluconazole |
| Voriconazole |
| Others: |
| Opiates (decrease of intestinal motility) |
| Phenytoin |
| Valproic acid |
| Conventional neuroleptics |
Standard dosing of drugs is recommended in MNGIE unless dose adaptions are otherwise indicated. Data on mitochondrial toxicity of individual drugs are mainly based on in vitro or animal data. For many drugs little is known on their usage in MNGIE. Recommendations for certain drugs are based on the successful use in humans without a detectable deterioration of metabolism. If vitally indicated every drug should be used with careful monitoring of the clinical symptoms and the metabolic status. Even if the plasma level of TP normalizes post transplant it is not clear yet whether this will also reduce the toxic effect on the mitochondria in the organs. Therefore careful observation is also mandatory in the post-transplant period. This list is neither complete nor is the safety profile from many drugs known extensively. Careful re-evaluation is therefore necessary in each patient.
Post-transplant follow-up
Standardized post-transplant monitoring is as essential as pre-transplant evaluation for the assessment of short- and long-term outcome. The proposed steps are outlined in Table 3.
Table 3.
Standardized disease-specific pre-transplant evaluation
| Post-transplant follow-up should be performed according to the centers' guidelines but include: |
| Monitoring for chimerism: |
| Cell-specific chimerism analysis is recommended on day 30, day 100, 6 months and 1 year. Further annual chimerism analysis is encouraged to document that the donor engraftment is stable on long term |
| If chimerism on day 30 is less than 90% donor type the analysis should be repeated every month and immunosuppression should be rapidly tapered if donor type chimerism decreases. Donor lymphocyte infusions (DLI) in incremental doses are recommended according to local institutional protocols |
| Recommendations for minimal follow up of the disease |
| Post-transplant follow-up assessments of disease-associated clinical and biochemical characteristics should occur according to institutional guidelines. It can be restricted to findings that have been abnormal at baseline but should include at least: |
| (a) Monthly follow up during the first 6 months: |
| History |
| Performance status (Karnofsky or Lansky) |
| Clinical examination including weight |
| Perform storage for analysis of enzyme levels of thymidine phosphorylase (TP) and metabolites (deoxyuridine, thymidine) in plasma at the same time |
| (b) After 6 and 12 months and yearly thereafter: |
| History |
| Performance status (Karnofsky or Lansky) |
| Clinical examination including: |
| Weight and height |
| Complete neurological evaluation |
| Cognitive evaluation: modified mini-mental state (3 MS) evaluation and Wechsler Scale 3rd edition |
| Laboratory evaluations: |
| Complete blood count |
| Blood chemistry including liver function tests and metabolic evaluation for lactate, lactate and pyruvate |
| Thymidine phosphorylase enzyme (TP) activity, plasma Thd and dUrd. Urine Thd/creatU and dUrd/creatU are optional |
| Peripheral nerve conduction studies of the same nerves as in the baseline assessment |
| OXPHOS activities in cultured skin fibroblasts |
| Audiometry (if pathological at baseline) |
| Ophthalmological examination |
| Abdominal ultrasound |
| Brain MRI and MRS for lactate yearly |
| Diary of gastrointestinal signs and symptoms47 (Supplementary appendix 1) |
Disease evaluation, data reporting and trial planning
Data collection and data analysis are necessary to evaluate treatment. We propose that data be collected in an international registry (currently under development). For patients treated in EBMT centers data collection will be integrated into the EBMT ProMISe database. Collaborative projects covering all aspects of the disease (basic science, epidemiology, natural course and treatment) are necessary and under development.
The group will meet at least once a year or after every five patients with allogeneic HSCT—whichever occurs first—to reevaluate the current recommendations.
Conclusion
Allogeneic HSCT offers a novel treatment of MNGIE, a rare fatal disease with limited therapeutic options. It is important to perform HSCT with a standardized protocol to facilitate further analysis of the clinical effects of this therapy for MNGIE. Full ascertainment of patients including negative data is necessary. We hope that our proposal promotes efficient collaborative optimization of HSCT to allow effective treatment of this otherwise debilitating and lethal disease.
Supplementary Material
Acknowledgements
RM is supported by a grant from Instituto de Salud Carlos III (PI06/0735). MH is supported by US National Institutes of Health (NIH) Grants HD32062 and RCNS070232 by grants from the Muscular Dystrophy Association, and by the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF). The consensus conference was supported by a travel grant from Swiss Blood Stem Cells and a grant from the Swiss Foundation for Research on Muscle Diseases.
Footnotes
Conflict of interest The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
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