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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2012 December 1.
Published in final edited form as:
PMCID: PMC3370408

Malignancies after hematopoietic cell transplantation for primary immune deficiencies: a report from the Center for International Blood and Marrow Transplant Research


We describe the incidence of malignancy in patients with primary immunodeficiency disorders (PIDD) following hematopoietic cell transplantation (HCT). From the Center for International Blood and Marrow Transplant Research, 2266 PIDD patients who had undergone allogeneic HCT between 1968 and 2003 were identified. Patient, disease and transplant factors for development of malignancy were examined and pathology reports for reported malignancies reviewed independently by a pathologist for confirmation. The incidence of malignancy was highest for Wiskott-Aldrich syndrome (3.3%) with an overall incidence of 2.3% for PIDD. Post-HCT malignancy was confirmed for 52 of 63 reported cases. Forty-five of 52 patients developed a lymphoproliferative disorder (PTLD) at a median of 3 months post-HCT. Of these, 26 had received T-cell depleted (TCD) bone marrow. Three patients who developed myelodysplastic syndrome had received TCD marrow and total body irradiation. Three patients developed a solid tumor. Patients with PIDD are at a relatively low risk of developing malignancies post-HCT compared to their historical risk of cancer. The most frequent malignancy or lymphoproliferative disorder was early-onset PTLD. As in other HCT recipients, TCD appears to correlate with PTLD development. Our results lend support to the hypothesis that immune reconstitution in PIDD following HCT leads to a decrease in cancer risk.


Children with primary immune deficiency diseases (PIDD) such as severe combined immune deficiency (SCID) and Wiskott-Aldrich syndrome (WAS) die prematurely as a result of serious infections or malignancies. Although the number of children with PIDD who develop cancer every year is small, it has been estimated that the overall risk for cancer in these children is about 4%, or about 10,000 times greater than expected in age-matched healthy controls.1,2

Allogeneic hematopoietic cell transplantation (HCT) is currently the only curative therapy available for a number of prematurely lethal PIDD. Since 1968, when the first successful allogeneic bone marrow transplant was reported in a child with SCID3, several thousand children with PIDD have undergone HCT. SCID and WAS represent the most frequent indications for allogeneic HCT amongst these patients. Complete reconstitution of the immune system with full donor hematopoietic chimerism can be achieved in patients with PIDD after myeloablative chemotherapy with or without irradiation and HCT. It is not known whether this impacts the risk of malignancies for these patients. We hypothesize that allogeneic HCT for PIDD results in a decreased risk of malignancy because of improved immune surveillance as a result of achieving immune competence.

There is little specific data in the published literature regarding the incidence of malignancies post-HCT in patients with PIDD. Post-transplant lymphoproliferative disorders have been reported in a number of patients with SCID following thymic epithelial transplants and haplo-identical T-cell depleted (TCD) bone marrow transplants.4 A retrospective analysis performed by Neudorf et al in 1984 had documented no cases of cancer in SCID patients following successful bone marrow transplantation.5

Whether HCT decreases the risk of cancer in patients with PIDD is unknown. Little is known about the incidence of cancer or the risk factors associated with development of cancer in these HCT survivors. Here, we present a descriptive report of risk factors that may have contributed to the development of a malignancy after allogeneic HCT in a large cohort of children with PIDD reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).


Data collection

The CIBMTR is a working group of over 500 transplant centers worldwide that voluntarily contribute detailed patient-, disease- and, transplant-characteristics and outcome data on HCT recipients to a Statistical Center at the Medical College of Wisconsin. Participating centers register consecutive transplants and provide relevant patient, disease and transplant characteristics and outcome data including graft-versus-host disease, development of malignancy post-HCT, survival and for deceased patients, cause of death. Detailed demographic, disease and transplant characteristics and outcome data are collected on allogeneic transplants. Patients are followed annually until death. Computerized error checks, physician review of submitted data and on-site audits of participating centers ensure data quality. This study was approved by the Institutional Review Board of the Medical College of Wisconsin.

Statistical Analysis

The incidence of malignancy post-HCT was determined using the cumulative incidence estimator with death as the competing risk. 95% confidence intervals were calculated using standard techniques.6


The study population consisted of 2266 patients with PIDD who had undergone allogeneic HCT between 1968 and 2003 and reported to the CIBMTR (Table 1). Included are recipients of matched and mismatched related donor and unrelated donor transplants. Patients’ ages ranged from 1.2 months to 47 years with a median age of 1 year. The two commonest indications for transplantation for PIDD were SCID (47%) and WAS (16%). As a result, approximately 80% of patients were male.

Table 1
Patients with PIDD reported to CIBMTR (1968-2003)

Sixty-three patients were reported to have developed a new malignancy after HCT. Because of the inclusive dates of the analysis, and the fact that the CIBMTR does not maintain a tissue bank it was deemed impracticable to retrieve and review slides on biopsy/autopsy specimens to confirm the diagnosis of a malignancy. Therefore, post-HCT malignancy was confirmed in 52 patients using pathology reports and/or confirming with the transplant center. There was insufficient information to confirm the diagnosis of malignancy in 11 patients. To avoid reporting bias, patients transplanted at inactive centers or centers that did not respond to request to participate were excluded from the analysis (n=143 patients from 7 transplant centers).


Table 2 shows the characteristics of patients with PIDD who developed malignancy post-HCT as compared to those who did not. Fifty-two of 2266 patients were confirmed to have developed post-transplant malignancy. Patient-, disease- and transplant characteristics of these patients are shown in Table 3. The 5-year, 10-year and 15-year cumulative incidence of post-HCT malignancy was 2% (95% confidence interval 2-3%), 2% (2-3%) and 3% (2-5%), respectively. The corresponding cumulative incidence for patients with SCID was 2% (1-3%) at 5- and 10-years and 3% (1-6%) at 15-years; for WAS, 4% (2-6%) at all three time points and for other PIDD, 2% (1-3%) at 5-years and 2% (1-4%) at 10- and 15-years. With a median follow-up of 6 years (range 4–14), 12 patients were alive. Forty patients (77%) are dead; death was attributed to the post-transplant malignancy in 29 patients. Other causes of death include GVHD (n=3), infection without GVHD (n=4) and the cause of death was not reported for 4 patients.

Table 2
Characteristics of patients undergoing transplant for a primary immune deficiency and registered with the CIBMTR before 2003
Table 3
List of 52 patients with confirmed malignancy/lymphoproliferative disorder.

Lymphoproliferative disorders (LPD) ranging from post-transplant lymphoproliferative disease (PTLD) to a non-Hodgkin lymphoma was the most common malignancy and occurred in 45 patients. Epstein-Barr virus induced LPD was confirmed in 17 of these patients. GVHD prophylaxis or treatment for the 45 patients with PTLD consisted of TCD in 35 (78%) patients. Of these, 12 received TCD bone marrow graft, 13 received TCD bone marrow graft and in-vivo anti-thymocyte globulin (ATG), 1 patient received a TCD PBSC graft and in-vivo ATG and the remaining 9 patients received in-vivo ATG only. Only 5 patients received total body irradiation (TBI). The median time to development of the LPD was 3 months from transplant (range 1–41 months).

Three patients developed myelodysplastic syndrome (MDS) and one patient, acute myeloid leukemia (AML); these developed in patients with non-SCID PIDD. All three MDS patients had received TBI (1320–1400 cGy) as part of their conditioning regimen and a TCD bone marrow graft. The patient who developed AML received ATG as part of the conditioning regimen and one patient with MDS received ATG for treatment of acute GVHD. The median time to development of the MDS or AML was 34 months (range 9–55 months). Patient ID # 5 with WAS who underwent a sex-matched TCD unrelated donor HCT developed MDS 55 months post-HCT. Cytogenetics showed numerous structural abnormalities but was unable to resolve the source of the malignant clone. Patient ID # 16 with Chediak-Higashi syndrome developed MDS 44 months after a TCD unrelated donor transplant. Bone marrow showed multiple cytogenetic abnormalities (including del7q and del 20q) distributed among four independent clones whose origin could not be determined. Whether these were present pre-HCT could not be confirmed because the pre-transplant bone marrow failed to yield metaphases. The bone marrow did show rare mononuclear cells with abnormal Chediak granules suggesting residual host cells. Patient ID # 17 with WAS underwent a sex-mismatched TCD unrelated donor HCT. He developed MDS 23 months post-HCT and his bone marrow had 80% recipient and 20% donor cells with one of the recipient clones showing a del(7) abnormality.

Three patients developed a solid tumor. One patient with Omenn syndrome developed desmoplastic squamous cell carcinoma of the right foot 170 months after unrelated donor HCT, one patient with CID developed hepatocellular carcinoma 84 months after unrelated donor HCT and the remaining patient developed a brain tumor after HCT for SCID although the time to tumor development was not reported.


The etiology of cancer in childhood is multifactorial. An important factor that contributes to an increased incidence of cancer in children is the presence of underlying immunodeficiency, either inherited or acquired.1 Improved treatments and supportive care as well as allogeneic HCT for the PIDD have resulted in significant improvements in survival for these children. The Immunodeficiency-Cancer Registry was set up in 1973 to track the incidence of cancers in patients with PIDD. As of August 1986, 514 cases of malignancy had been registered in patients with PIDD. Of these, almost half were non-Hodgkin lymphoma, with leukemia or Hodgkin disease accounting for another 20% of cases. Nine percent of the cases were adenocarcinomas and other tumors accounted for the remainder. Although over half of these tumors occurred in patients with Ataxia-Telangiectasia (AT) (30%) and common variable immunodeficiency (24%), about 25% were seen in patients with the WAS and SCID.7-9 A recent analysis of data reported to the Australasian Society of Clinical Immunology and Allergy PID Registry showed that while there was a 1.6-fold excess relative risk of cancer observed for PID patients, the standardized incidence ratio (SIR) was 5.36-8.82 for non-Hodgkin lymphoma, leukemia and stomach cancer. The SIRs for all cancers were significantly increased in patients with CVID and AT.10

Patients with leukemia or aplastic anemia who have undergone bone marrow transplantation are at a significantly higher risk of developing a secondary cancer compared to age-matched healthy controls.11 In a recent analysis of over 18,000 BMT recipients by Curtis et al., the cumulative incidence of a PTLD was 1.0 ± 0.3% at 10 years after HCT with the highest incidence in the first 5 months post-HCT.12 Patients with non-Hodgkin lymphoma, Fanconi anemia and PIDD were excluded from this analysis.

Although our analysis can only serve to assess the risk factors that contribute to the development of a malignancy post-HCT for PIDD, the overall incidence of malignancies in transplanted PIDD patients (52/2266 or 2.3%) is lower than what has been reported in previous reports of patients with PIDD. LPD constitute the most frequent malignancy in patients with PIDD, especially those with WAS, common variable immune deficiency, AT and SCID. It has been estimated that the risk of malignancy in WAS, CVID and AT may be 100 times that of the general population. Since patients with SCID invariably die in infancy or early childhood without successful HCT, there is little data on long-term incidence of malignancies in non-transplanted patients. However, the median survival of patients with WAS who do not undergo HCT has been estimated to be in the late teens. Two large analyses of WAS patients by Perry et al. and Sullivan et al.13,14 reported development of a malignancy in 12 and 13% amongst 301 and 154 WAS patients respectively.

Of the 52 malignancies reported here, 45 (87%) were lymphoproliferative disorders. In the report by Curtis et al. discussed above, the risk of early PTLD was strongly associated with TCD of donor marrow (RR = 12.7), and use of ATG (RR = 6.4) or anti-CD3 monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute GVHD.12 In our analysis, TCD clearly contributed as a significant risk factor for the development of LPD. Since the most frequent malignancies/lymphoproliferative disorders reported in non-transplanted patients with PIDD are LPD,15,16 it is difficult to assess the relative contributions of the underlying immune deficiency, the preparative regimen and the TCD to LPD development. However, the median time of 3 months between the HCT and the LPD is very similar to the findings of Curtis et al.12 and suggests that the TCD was an important contributory risk factor. There was no correlation between incidence of PTLD and year of transplant (data not shown). EBV monitoring was not routinely available for the majority of patients transplanted during the period covered by this report. Of the 52 patients reported here, 40 died after developing a malignancy/ lymphoproliferative disorder with the majority of the deaths being attributed to the malignancy. With routine monitoring for EBV reactivation with EBV PCR and pre-emptive therapy, future analyses may allow us to assess the impact of these approaches on the incidence and survival of post-transplant lymphoproliferative disorders in these patients.

An analysis of 19,229 patients who had received allogeneic or syngeneic transplants for acute and chronic leukemias and a number of non-malignant diseases identified a cumulative incidence of new solid cancers of 2.2 % at 10 years and 6.7 % at 15 years. The use of TBI and the presence of chronic GVHD were associated with a higher risk of solid cancers and there was a trend toward an increased risk of solid cancers over time with younger patients having the greatest risk of developing solid cancers post-HCT.17 However, patients with Fanconi anemia and primary immune deficiencies were excluded from this analysis because of their inborn susceptibility to cancer. In a separate analysis of 700 patients with severe aplastic anemia including 79 with Fanconi anemia, Deeg et al. reported 23 malignancies post-HCT. There were 5 cases of lymphoid malignancies at a median of 3 months post-transplant and 18 cases of solid tumors at a median of 99 months post-HCT. In this analysis, the most significant risk factor for solid tumors was Fanconi anemia, consistent with the known risk of solid tumors in non-transplanted Fanconi anemia patients.18

There are a number of limitations to our analysis that need to be acknowledged. Centralized histopathologic examination of archived tissue or slides on each of the patients would have been the ideal way to confirm the occurrence of a malignancy. Since a large number of these patients had been diagnosed over 20 years earlier, it was considered impracticable to retrieve these specimens and we chose to review clinical and pathology reports to confirm the malignancy. Secondly, although data are available for the risk of malignancy in a cohort of age-matched healthy children, the true comparator for our cohort of patients with primary immune deficiencies would have been a similarly sized cohort of patients with PIDD who have not undergone transplantation. Unfortunately, reliable data on such a cohort are not available. For assessment of the impact of HCT on the risk of malignancy in PIDD, one has to thus rely on early data from the Immunodeficiency-Cancer Registry and data compiled through multi-institutional surveys of patients with Wiskott-Aldrich syndrome.

We conclude from this analysis that patients with primary immune deficiencies who undergo hematopoietic cell transplantation appear to be at a relatively low risk of developing malignancies compared to the historical risk of cancer in these patients. The most frequent malignancy/lymphoproliferative disorder seen in this cohort of patients is that of early-onset PTLD and as has been noted for other HCT recipients, the use of TCD appears to correlate with the development of PTLD post-transplantation.


The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Allos, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai, Inc.; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Vidacare Corporation; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.


Authorship Contributions Naynesh Kamani had full access to all of the data in the study and had final responsibility for the integrity of the data, the accuracy of the data analysis, and the responsibility for the decision to submit for publication.

Authors designed research (NK, ME, AHF), collected data (NK, JC, MC, JS, AF, PS, JW, EH, AHF), performed statistical analysis (NK, AH, JLR, ME), interpreted data (NK, SK, AH, JLR, ME, JC, MC, JSTC, AF, PS, JW, EH, AHF), drafted the manuscript (NK, ME, AHF), and critically revised the manuscript (All authors).

Conflict of Interest Disclosures The authors have no conflicts of interest to declare.

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