Transplantation in common variable immunodeficiency - a new therapeutic option?

Published Online: September 20, 2011

Introduction
Common variable immunodeficiency (CVID) is a rare disease with a prevalence of 1 in 25,000 to 50,000. It is characterized by an immune disorder called hypogammaglobulinemia and increased susceptibility to infections. The spectrum of the disease can vary from mild forms to very severe ones with several co-morbidities such as autoimmunity, sarcoid-like granulomas, lymphoproliferation, and malignancies. The therapeutic options to date are limited to immunoglobulin substitution, immunosuppressants and substitution with blood derivates. Allogeneic stem cell transplantation (ASCT) has occasionally been reported as treatment in case of occurring malignancy, but the outcome of ASCT as a potentially curative approach in CVID with poor prognosis is unknown.

Description of the study
In The Journal of Allergy and Clinical Immunology, Rizzi et al report on the longterm outcome of four adult patients with CVID (3 males, 1 female; age 30 to 44 years) who received reduced intensity-conditioned ASCT (Fludarabin, BCNU, Melphalan, Alemtuzimab). Of the 4 patients described two were transplanted for newly occurring malignancy (P1, P2), and two for severe CVID with impending organ failure (P3, P4). None of the known mutations associated with CVID were demonstrated. P1, P2 and P3 received stem cells from matched familial donors while P4 was treated with stem cells from a matched, unrelated donor. Cyclosporin A was given for graft versus host disease (GvHD) prophylaxis in all patients. This is the biggest cohort of transplanted CVID patients ever reported, and represents a milestone for future application of ASCT in antibody deficiency.

Results
Clinical Outcome

Three of 4 patients (P1,P2,P4) survived long-term (currently at 5.5, 7.0 and 4.5 years of follow up, respectively) whilst one patient (P3) suffered a treatment-related death. The best outcome was achieved for P2, in whom ASCT secured so far 7 years of disease-free survival from lymphoma and underlying CVID without any GvHD; ASCT resolved in this patients all CVID-related signs such as susceptibility to infections, hypogamma-globulinemia, lymphoadenopathy, splenomegaly and cytopenia. So far only a residual asymptomatic selective IgA deficiency persists. The patient responded well to vaccination with tetanus toxoid (Tetanol®) against which no titers were measurable before ASCT. In P1 the primary goal to cure large granular lymphocyte (LGL) syndrome and the associated anaemia requiring weekly transfusions , was achieved. However, ASCT did not improve CVID, which persists with hypogammaglobulinemia and susceptibility to infections. P4 achieved the primary goal of halting the inexorable decline of her pulmonary function with a reduction in steroid dose from 15mg to 3.5mg/d. She also experienced a subjective improvement of her respiratory function but without detectable improvement on pulmonary function testing. Furthermore, IgM and IgA (previously undetectable) became normal. Prior to ASCT, P1 and P4 had been unsuccessfully treated with immunosuppressive drugs at acceptable and tolerable dosages for immunodeficient patients. Possibly, the resolution of anaemia and LGL in P1, and the stabilization of the lung function in P4 can be ascribed to the beneficial effect of the immunosuppressive, ‘reduced intensity’ conditioning regimen. P3 was transplanted because of a severe course of CVID, with splenomegaly, consequent blood pooling and cytopenia, severe infections and chronic diarrhoea with recurrent Giardiasis and Salmonella infections. P3 also had multiple sarcoid like lesions in lung, spleen and liver, leading to portal hypertension with oesophagus varicosis grade III to IV and associated splenomegaly. After transplantation an intestinal GvHD stage 3, grade III in colon, grade I in stomach developed with 3-4 stools per day. Finally patient P3 died 100 days after ASCT of intractable hemorrhagic pneumonia.

Chimerism and immune reconstitution
All patients engrafted normally, with the exception of P3 that did not achieve platelet engraftment. The three surviving patients all achieved good levels of donor chimerism in all compartments. On long-term immunological assessment T and NK cells of P1 and P2 exhibited normal reconstitution kinetics leading to a normalization of the naïve recent thymic emigrants counts. In P2 a normal reconstitution of the B cell compartment was observed, whereas in P1 ASCT did not change the B cell phenotype: persistent B lymphocytopenia with high percentages of naïve B cells and almost undetectable transitional B cells indicated a poor B cell output from bone marrow (BM). In P4 the pre-existing pattern of B and T lymphocytopenia with normal NK cells persisted post transplant despite the 99% donor chimerism. Ongoing B and T lymphocytopenia may point to abnormalities in the stromal and/or cytokine environment, which are not amenable to ASCT.

Summary
Rizzi et al report for the first time on feasibility and outcome of ASCT in 4 patients suffering from severe CVID. One of the 4 patients died after 3 months due to over-whelming hemorrhagic pneumonia. Three patients have now survived between 4.5 to 7 years. One patient is cured from his lymphoma and the underlying CVID; he is free of recurrent infections, has normalized his serum immunoglobulin levels (except IgA) and responds for the first time to vaccines. In two patients ASCT reached the end point of resolving the lymphoproliferative disease in one, and reducing the steroid dose with stabilization of pulmonary disease in the second, but had scarce effect on the underlying immunodeficiency. The importance of the report lies in the evidence that CVID can be cured in selected patients. The unsolved questions relate to patient and donor selection, risk predictors and the timing of ASCT. Clearly, more efforts are needed to make ASCT a new therapeutic option for CVID.

The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

AAAAI - American Academy of Allergy Asthma & Immunology