eMedicine Specialties > Hematology > Disorders of Lymphocytic Function

Combined B-Cell and T-Cell Disorders: Treatment & Medication

Author: Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo
Coauthor(s): Mohammad Muhsin Chisti, MD, Staff Physician, Department of Internal Medicine, Sisters of Charity, University at Buffalo State University of New York (SUNY) School of Medicine and Biomedical Sciences; Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; David Claxton, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology-Oncology, Hershey Medical Center, Pennsylvania State University; James O Ballard, MD, Kienle Chair for Humane Medicine, Professor, Departments of Humanities, Medicine, and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine
Contributor Information and Disclosures

Updated: Jun 24, 2008

Treatment

Medical Care

Patients with combined immunodeficiencies, such as SCID, XHM, Good syndrome, and WAS, may benefit from intravenous immunoglobulin (IVIG) replacement therapy. Appropriate supportive care, such as early identification of opportunistic infections or nutritional support, are necessary.

• In WAS, other than prophylactic antibiotics and IVIG, splenectomy for thrombocytopenia and platelet transfusion in acute life-threatening bleeding can be used.
• NOTE: Do not immunize these patients with live attenuated vaccines.
• Focus efforts on the treatment of infections, allergic reactions, and autoimmune and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering Streptococcus pneumoniae and Haemophilus influenzae is indicated. Prophylactic antibiotic therapy has been recommended for patients with frequent infections. A course of metronidazole may result in dramatic improvement of the patients' diarrhea and, to a certain extent, of malabsorption syndrome. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.
• Patients with ADA deficiency may benefit from substitution with pegademase bovine ADA. The maximum effect on immunologic function does not occur for several months. (see the package insert for details.)
• Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. This treatment strategy is highly successful when a human leukocyte antigen (HLA)-matched sibling donor is available; if such a donor is not available, however, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunologic complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative (see below). Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) may be helpful for patients with SCID. Survival rates in these previously fatal conditions are around 90% in some case series.
  • The discovery of the HLA system in 1968 led to successful bone marrow transplantations. Patients with immunodeficiency syndromes were the first to benefit from this novel therapy.
  • Allogeneic bone marrow transplantation has become the standard of care for certain patients with SCIDs (eg, XSCID, ADA deficiency). Patients with other immunodeficiency syndromes may benefit from bone marrow transplantation or HSCT, including those with WAS or XHM.
    • There are many groups that are exploring the potential benefits of HSCT based on alternative donors. There are several advantages of umbilical cord blood stem cell transplantation (UCBSCT), which include ready availability of the unit, a lower risk of transmitting viral diseases, no risk to the donor, and a lower risk of GVHD even in the absence of a perfect HLA match.
    • Another possibility for patients without a suitable sibling donor is a matched unrelated donor (MUD) HSCT. But in clinical practice, this therapy is limited due to high rates of GVHD and transplant-related mortality.
    • To facilitate the identification of a suitable MUD, there have been recent advances, including the following:
      • The continuous growth of volunteer donors worldwide
      • High-resolution molecular techniques for HLA typing, which permits a better selection of donors
      • Advances in critical care have resulted in a significant decrease in MUD-HSCT transplant related mortality and an increase in the survival of SCID infants who are severely infected at the time of diagnosis.
    • Early diagnosis before the development of permanent lung and liver damage and referral to a specialized center for bone marrow transplantation/HSCT are essential for therapeutic success.
    • Bertrand et al reported on a European experience with 178 patients in 18 centers who were treated with HLA, nonidentical, T-cell–depleted bone marrow transplantation.⁹ With a median follow-up of 57 months, disease-free survival was shown to be significantly better for patients with B-positive SCID (60%) than for patients with B-negative SCID (35%).⁹
    • Buckley et al found that the survival rate was not affected by the genetic type, but it was affected by race (ie, more white patients than black or Hispanic patients survived [P <0.001]) and sex (all girls survived [P = 0.047]).¹⁰
    • Another report noted the inefficacy of bone marrow transplantation in correcting Job syndrome.¹¹
  • Despite the success that has been seen in some SCID patients treated with bone marrow transplantation, in some cases, failure to restore B-cell function or failure or rejection of the graft over time occurrence. A novel alternative strategy to circumvent graft failure/rejection is the use of gene transfer into autologous stem cells using retroviruses.
    • Gene therapy is a viable therapeutic option; advances in biotechnology have enabled the performance of this highly complex treatment for several immunodeficiency syndromes.
    • Cavazzana-Calvo et al published reports of the successful results of gene therapy for SCID-X1 disease in 2 children, opening new horizons for the future of these patients.³ This therapy resulted in complete immune reconstitution of the lymphoid system, with T-, B-, and NK-cell counts comparable to age-matched controls.³ An update on these 2 patients by the same authors and a report on 3 others confirmed the previous results.
    • Patients with ADA deficiency were the first to be enrolled in gene therapy trials. Until recently, no successful sustained expression of ADA occurred in treated patients. A trial conducted by Kohn et al is under way.¹²
    • Novel forms of gene therapy are being tested in clinical studies.^5,13 One approach known as gene-modified autologous HSCT has shown some promising results; this therapy has the potential to circumvent the significant limitations of allogeneic bone marrow transplantation and gene therapy by using postthymic differentiated cells.
    • RNA viruses are the most commonly used vectors to introduce genetic information into hematopoietic stem cells and/or progenitor cells. There have been reports of spontaneous, partial corrections of the phenotype of severe T-cell immunodeficiencies (eg, ADA deficiency, SCID-X1, WAS, RAG1 deficiency, CD3 deficiency) within the past decade. It has been demonstrated that several T-cell precursors which carry a wild-type sequence of the disease-causing gene or mutation with less harmful effects can mature into functional mature T cells that provide adequate immunity. The selective advantage conferred by the expression of either gamma C or ADA in lymphocyte progenitors was confirmed in 3 gene therapy clinical trials.
    • It is striking to note that gene therapy for ADA deficiency was only successful in patients who did not concomitantly receive polyethylene glycol–ADA (PEG-ADA) enzymatic substitution.¹⁴

Consultations

Consultations should be obtained with specialists from the following specialties:

• Bone marrow transplantation
• Gastroenterology
• Nutrition
• Infectious diseases

Diet

In view of the presence of chronic diarrhea, patients often require enteral or parenteral supplementation.

Activity

Physical activity should be encouraged. Patients may need isolation to decrease the risk of common viral and bacterial infections, such as avoiding crowded places. Strict hygienic practices are important.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Blood Products/Immunoglobulins

Blood products/immunoglobulins provide immediate passive immunity. These agents can be used as replacement therapy in patients with antibody-deficiency states.

Immune globulin, intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P)

Provide an immediate rise of antibodies that have a proven protective effect against bacterial and viral infection (passive immunity). Because antibodies are not produced by the host, these products must be readministered monthly. This treatment may increase CSF IgG (10%).

Metabolic Enzymes

Metabolic enzymes are used to replace ADA.

Pegademase bovine (Adagen)

ADA is an enzyme of the purine salvage pathway that is responsible for adenosine and deoxyadenosine deamination to inosine and deoxyinosine, respectively. ADA deficiency leads to accumulation of the metabolites dATP and 2'-deoxyadenosine, both of which are toxic to lymphocytes.

Treatment is indicated in patients with SCID secondary to ADA deficiency whose conditions proved refractory to bone marrow transplantation or who are not candidates for transplantation. Individualize therapy (based on plasma levels) to achieve the following: trough plasma levels of 15-35 mmol/h/mL and a decline in erythrocyte dATP to <0.005-0.015 mmol/mL packed erythrocytes or to <1% of total erythrocyte adenine nucleotide content (ATP + dATP). Plasma levels >35 mmol/h/mL are not associated with additional clinical benefit. This treatment has no role in preparatory regimen for bone marrow transplantation.

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