Matched unrelated bone marrow transplant for severe combined immunodeficiency
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- Roifman, C.M., Grunebaum, E., Dalal, I. et al. Immunol Res (2007) 38: 191. doi:10.1007/s12026-007-0042-y
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Severe combined immunodeficiency (SCID) is a lethal disease unless allogeneic bone marrow transplantation (BMT), preferably from a family related HLA identical donor (RID) is given. Previously, some patients received HLA-mismatched related donors (MMRD) BMT, which often resulted in slow immune reconstitution and variable survival. Alternatively, HLA-matched unrelated donors (MUD) BMT have been suggested. Recently, we have directly compared outcome of patients with SCID who received either MMRD or MUD BMT. Survival after MUD BMT was significantly better than after MMRD BMT. Patients who received MUD BMT also had better engraftment of donor cells and immune reconstitution. Recent reports from other centers confirm these results finding that MUD BMT provides excellent survival and better immune reconstitution for patients with SCID. In conclusion, MUD BMT appears vastly superior to MMRD BMT and should be offered as first choice of treatment for patients with SCID when RID is unavailable.
KeywordsBone marrow transplantMatched unrelated severe combined immunodeficiencyT+ SCID
Severe combined immune deficiency (SCID) is a heterogeneous group of inherited diseases characterized by significant impaired immunity leading to death in infancy unless treated by hematopoietic stem cell transplantation. The optimal treatment for patients with SCID is bone marrow transplantation (BMT) from a related, HLA-identical donor (RID) [1, 2]. Unfortunately, such donors are found for only a minority of patients with SCID [3, 4].
As an alternative, stem cell transplantations from HLA-mismatched related donors (MMRDs) have been commonly attempted . However, compiled experience of BMT for SCID from Europe revealed that in 294 recipients of MMRD BMT, 3-year survival was only 54% . Furthermore, in another study careful analysis of survival according to the degree of HLA indentity showed that frank haploidentical (half-matched) transplantation resulted in only 25–30% long-term survival in patients with primary immunodeficiency . This low success rate may reflect the intense T-cell depletion required to prevent graft-vs-host disease, which contributes to slower immune reconstitution with prolonged periods of increased susceptibility to infections [7–9]. Recent studies have suggested a time-dependent loss of function following T-cell depleted MMRD BMT, associated with progressive lymphopenia, a restricted T-cell repertoire, decreased thymic output as indicated by reduced levels of T-cell receptor excision circles and abnormal humoral immunity .
Experience was similar at the hospital for Sick Children, Toronto. By the mid 1980s it became apparent that success rate using MMRD was at best 50% regardless of the T-cell depletion method used (C. M. Roifman, unpublished). In an attempt to improve the outcome of BMT in SCID we have searched for an alternative to MMRD.
The establishment of bone marrow registries in the US and Canada created the opportunity to try matched unrelated donors (MUD) instead of T-cell depleted related donors. In 1987 we have created the Hospital for Sick Children protocol for the use of MUD in BMT for SCID. Based on previous protocols used in patients with leukemia, the SCID protocol uniquely included strict isolation techniques, aggressive pre-transplant antimicrobial treatment, nutritional support, and the use of cyclosporine A/prednisone rather than Methotraxate as GVHD prophylaxis.
Study 1: Matched unrelated BMT for patients with SCID and residual T-cell function (T+ SCID)
A substantial number of SCID patients may present with variable degrees of cell-mediated function. In recent years, patients with mutations in Jak-3, Zap-70, IL-2Rα, and CD3 [11–13], were reported to have residual T-cell function. We and others have shown that R222C mutation in the IL-2Rγ is consistently associated with an atypical presentation [14–16]. Such patients have normal numbers of circulating T cells as well as normal response to mitogens and a normal thymus morphology . Omenn syndrome  related or unrelated to cartilage hair hypoplasia  as well as ‘partial’ ADA deficiency  may also have residual T-cell function. Experience with the application of BMT to patients with SCID and residual function is extremely limited . Among T+ SCID patients transplanted with T-cell depleted bone marrow, engraftment rates have been poor, ranging from 14% to 30%, and short-term survival rates reached 47% , but long-term survival as low as 10% have been recorded. These discouraging results point to a pressing need for better transplant alternatives to ensure a full engraftment and reconstitution of immunological function, and a better long-term survival rate.
From 1990 to 1999, we prospectively enrolled infants and children with SCID and residual T-cell function with no sibling donor into a protocol using MUD in an attempt to develop a better alternative to MMRD bone marrow transplantation. Seven consecutive patients with SCID with residual function were included. One of these patients was a sibling of a patient with T+ SCID but she had no substantial residual T cells. Patients diagnosed in the Division of Immunology at the Hospital for Sick Children, Toronto who lacked histocompatible siblings or closely matched related donors, were referred to the Canadian Unrelated Bone Marrow Donor Registry for an unrelated donor search. All donors and recipients were matched by DNA genotype analysis.
Four out of seven patients were diagnosed with Omenn’s syndrome, one of them had cartilage hair hypoplasia. Two other patients were siblings who demonstrated delayed symptoms related to T cell immunodeficiency. The first sibling was diagnosed at the age of almost 4 years, but his sister was diagnosed immediately after birth because of the positive family history. An additional patient had normal in vitro immune function and a normal thymic morphology. Diagnosis of profound immunodeficiency was established after he failed to reject a skin graft. Recently the molecular defect has been identified as a novel mutation in the common γ chain of the IL2 receptor . One patient with Omenn syndrome was excluded because the unrelated donor bone marrow harvested (outside of the international registry) was poor and it had all the characteristics of peripheral blood. In addition, parents stopped GVHD treatment against medical advice.
Four out of seven patients had a pulmonary infection before transplant, which is considered a poor prognostic factor, and three of them were very high-risk transplants. One patient received a bone marrow infusion during his admission to the intensive care unit due to severe pneumocystic carinii pneumonitis requiring prolonged mechanical ventilation. Prior to her MUD transplant another patient failed to engraft a MMRD BMT. Another patient who received an HLA-identical MUD donor, lost the graft within 4 weeks. He was re-conditioned with a cyclosphophamide and irradiation protocol and was re-transplanted using a harvest obtained from the same donor. The mean age at transplantation was 22 months (range 10–59).
Neutrophil engraftment was achieved in all patients at a mean of 16.5 days (range 13–22), including the patients who failed previous BMTs. Engraftment of platelets was achieved within a mean of 31.8 day (range 11–60 days). All seven cases demonstrated virtually 100% engraftment of donor cells, without any evidence of residual recipient cells; including the patient who had previously failed a haploidentical T-cell depleted BMT. In one other patient karyotyping analysis showed 100% female donor cells in peripheral blood.
Cell-mediated immunity including total lymphocyte counts and subsets of T cells, studied by flow cytometry, 1–2 months after BMT showed early signs of engraftment in all patients. All patients showed eventually normal absolute lymphocyte count, absolute CD3+ and CD4+ and CD8+ cells. Proliferative responses of T cells to stimulation with different mitogens and in vivo candida skin test were within normal limits in all surviving patients. Humoral immune reconstitution was also normal in all surviving patients.
During hospitalization a total of four episodes of fever were recorded for all patients. They all occurred within a few days after BMT, while patients were severely neutropenic. In three episodes bacterial agents were recovered from blood cultures including Pseudomonas aeruginosa and Staphylococcus coagulase negative. Blood cultures obtained from patients during the rest of the febrile episodes failed to detect bacterial fungal or viral infection. All patients recovered after administration of antibiotic therapy.
Four out of seven (57%) developed GVHD of grade II or more, possibly due to their advanced age. GVHD was reversed in three out of four by using a pulse of methylprednisolone. One patient did not have any symptoms of GVHD for more than 2 months post BMT. She developed a full blown, three organ involvement GVHD several days after GVHD prophylaxis was switched from i.v. to an equivalent dose of oral medication resulting in a sharp decline in cyclosporine A serum levels. A pulse of high-dose steroids was administered but had to be discontinued due to a massive gastrointestinal bleed. She responded partially to repeated courses of antithymocyte globulin (ATG). A trial of anti-IL-2R antibody was unsuccessful and she subsequently died 7 months post BMT. The rest of the cases subsequently resolved after treatment with topical steroids.
Six out of seven (86%) patients are alive and well. This is an outstanding survival as compared with MMRD BMT (Fig. 1). Further 17/19 patients with Wiscott–Aldrich syndrome have successfully engrafted with MUD transplants in our Institution (C. Roifman unpublished). There is no clear explanation for this excellent outcome of T+ SCID after MUD BMT. Historically, protocols for MMRD BMT did not include conditioning schemes. It can be assumed that in T+ SCID recipients engraftment could be compromised possibly leading to increased microbial colonization and infections. On the other hand using MUD after conditioning offered rapid engraftment, and therefore very low rates of infection which, may increase survival of these patients.
Little information is currently available on long-term restoration of immune function in infants with SCID treated by MUD transplantation. We compared the long-term outcomes of a large group of patients diagnosed as having SCID who received RID, MUD, or MMRD BMT during a particular period of time.
The best treatment for SCID remains BMT using an HLA-identical related donor. In agreement with previous studies, the long-term survival rate for patients who received RID BMT in our study is 92.3%. Unfortunately for most patients with SCID, including more than 85% of our patients, such donors were not available and other solutions, such as MMRD or MUD BMT, had to be considered. We have compared here the outcomes between groups of 41 and 40 SCID patients who received MUD BMT or MMRD BMT, respectively between 1990 and 2004 in two major referral centers, The Hospital for Sick Children, Toronto, and the Nocivelli Centre in Brescia. This study which contains the largest group of patients with SCID to have undergone MUD BMT, reveals a survival rate of 80.5% for MUD BMT, which is consistent with or better than results previously reported with smaller cohorts [22–24].
We found that the survival of patients with B- SCID, such as those with Omenn syndrome or mutations in the RAG-1, RAG-2, and ARTEMIS genes, was not different from the survival of B+ SCID. Previous studies had shown disappointing outcomes, with as low as 35% disease-free survival for those with B- SCID undergoing MMRD BMT .
Perceived limitations of MUD BMT as a therapy have been the delay in treatment dictated by the time required to obtain bone marrow and the concern of failing to identify a donor in the registries . However, the latter concern has been greatly alleviated by the continuous expansion of the international unrelated donor base . For all but one patient, we were able to find an acceptable donor. The median time from diagnosis to MUD BMT in this study was only 4 months. This is shorter than previously reported , probably due to the expansion and improvement of bone marrow donor registries . Still, the median time from diagnosis to transplantation in the MMRD BMT group was only 2 months. However, 30% of patients receiving MMRD BMT required repeat transplantation. Thus, the actual median time from diagnosis to final MMRD transplantation increased by 1 month, eliminating some of the potential advantage of MMRD.
Contrary to common belief, we did not observe clinical deterioration while waiting for a transplant, and no patient was lost because of such delay. On the contrary, in many cases we used this time to control infections and to improve patients’ nutritional status, factors well known to affect outcome . Even among patients who required assisted ventilation prior to MUD BMT, we did not observe increased mortality. In addition, mortality rates were not different for patients who were rushed to receive MMRD transplant because of a perceived urgency in clinical condition versus those who were in stable clinical condition. Together these results may challenge the instinct to rush to BMT while patients are clinically unstable, especially when myeloablation is prescribed.
Acute graft-vs-host disease has been reported at lower incidence (46–66%) after MMRD BMT [32, 33]. In full agreement, 45% of the patients in our MMRD BMT group developed acute graft-vs-host disease, significantly lower than the frequency of acute graft-vs-host disease in MUD BMT recipients. However, there was no significant difference in the frequency of grade III or higher acute graft-vs-host disease between patients receiving MUD and MMRD transplants (Fig. 6). Assessment of larger groups of patients with high-grade acute graft-vs-host disease will be required to reveal whether there is a significant difference in the pathogenesis and consequences of graft-vs-host disease arising from MUD and MMRD BMT. Thus, MUD BMT may be a particularly attractive alternative for patients with B- SCID, although further study with larger patient groups will be required to confirm these findings.
In conclusion, we have demonstrated that MUD is superior to MMRD BMT for SCID and is associated with long-term robust immune reconstitution , indicating that this mode of treatment should be preferred for patients with SCID when RID is not available. The continuing expansion of donor registries, advances in HLA analysis, and better management of graft-vs-host disease are expected to further improve outcomes of MUD transplantation.