INTRODUCTION — The success of hematopoietic cell transplantation (HCT) has led to the unfortunate complication of secondary malignancies in patients who would otherwise be long-term survivors. Among the malignancies are solid tumors, acute leukemia, myelodysplastic syndromes, and post-transplant lymphoproliferative disease (PTLD). While the former occur late in the post-transplant course (>3 years post-transplant), PTLD usually occurs in the first year after transplantation [1]. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
The risk for development of secondary malignancies following HCT will be reviewed here. Other complications of HCT and the development of secondary malignancies following solid organ transplantation are discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor" and "Hematopoietic support after hematopoietic cell transplantation" and "Early complications of hematopoietic cell transplantation" and "Malignancy after solid organ transplantation".)
GENERAL OBSERVATIONS — Patients treated with chemotherapy and/or radiotherapy followed by HCT have an increased risk of developing myelodysplastic syndrome, acute leukemia, post-transplant lymphoproliferative disease, and solid tumors when compared with the general population [2-11]. These cancers are expected to have a significant impact on survival in this patient population. The relative risk of developing a malignancy following HCT has varied greatly among studies and is dependent on a number of patient and treatment factors, including:
●Radiation dose and fields
●Chemotherapy agents and doses administered
●Length and severity of immunodeficiency
●Chronic graft-versus-host disease (GVHD)
●Epstein-Barr virus infection
●Patient age at treatment
●Smoking history
There is an increased risk of second cancers when lenalidomide maintenance is used for multiple myeloma. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Standard-risk disease'.)
In addition to these factors, certain patients may have a genetic predisposition toward developing second malignancies after HCT. As an example, patients transplanted for Fanconi anemia or primary immunodeficiency diseases have an inborn susceptibility to cancer.
Solid tumors — Solid tumors are relatively uncommon among transplant survivors, but occur more frequently in this population when compared with the general population (ie, high relative risk). Large retrospective series have estimated the cumulative incidence rates of secondary solid tumors at 1 to 2 percent at 10 years and 3 to 5 percent at 20 years after allogeneic HCT [6-9,11]. Smaller retrospective studies of autologous HCT have estimated the cumulative incidence rates of secondary solid tumors at 4 percent at 10 years [10,12]. Solid tumors of practically every type have been described in the allogeneic and autologous HCT setting.
The largest experience comes from a review of 28,874 allogeneic transplant recipients by the International Bone Marrow Transplant Registry [6,7]. Patients transplanted for Fanconi anemia or primary immunodeficiency diseases were excluded because of their genetic susceptibility to cancer. The following findings were noted:
●HCT survivors developed new solid cancers at twice the expected rate in the general population (observed-to-expected ratio 2.1; 95% CI 1.8-2.5). The cumulative incidence of new solid cancers was 1 percent at 10 years, 2.2 percent at 15 years, and 3.3 percent at 20 years after transplantation.
●The observed-to-expected ratio increased with time since transplantation.
●The risk was significantly increased for malignant melanoma and cancers of the buccal cavity, liver, brain or other parts of the central nervous system, thyroid, bone, and connective tissue.
●Predisposing factors included younger age, higher doses of radiation therapy, and, for squamous cell cancers of the buccal cavity, chronic GVHD.
●For those irradiated at ages under 30 years, the risk of developing a nonsquamous cell carcinoma following conditioning radiation was nine times that of nonirradiated patients. The comparable risk for older patients was 1.1.
●Among patients under the age of 30, a significant excess risk of cancer was noted in patients transplanted for acute myeloid leukemia (excess risk 26.6 per 10,000 patients per year), acute lymphoblastic leukemia (17.5 per 10,000 patients per year), and chronic myeloid leukemia (9.7 per 10,000 patients per year). Among patients over the age of 30, a significant excess risk was noted only in those transplanted for acute myeloid leukemia (21 per 10,000 patients per year). (See 'Risk according to reason for HCT' below.)
●There was no significant increase in risk among patients transplanted for nonmalignant hematologic diseases other than aplastic anemia. (See 'HCT for nonmalignant hematologic disease' below.)
Similar results were noted in a report of 1036 consecutive patients who were transplanted because of malignancy, severe aplastic anemia, and inborn errors of the hematopoietic and immune systems [8]. The transplants were performed after 1985 and all analyzed patients survived for at least five years. At a median follow-up of 10.7 years, the actuarial incidence of second malignancy was 3.5 percent at 10 years and 12.8 percent at 15 years; the risk was 3.8 times higher than that in an age-matched control population. The most frequent sites of the 53 tumors were the skin (14 patients), oral cavity (seven), uterus or cervix (five), thyroid (five), breast (four), and glial tissue (three). The two major risk factors were older age and the administration of cyclosporine to prevent chronic GVHD.
A single-institution review of 4905 survivors of allogeneic HCT reported 581 secondary cancers in 499 individuals after median follow-up of >12 years, and described a strong effect of the dose of total body irradiation (TBI) on cancer incidence [13]. Compared with those who received chemotherapy conditioning, the risk was highest in those who received unfractionated TBI (hazard ratio [HR] 3.2; 95% CI 1.9-5.3) or high-dose fractionated TBI (HR 2.1; 95% CI 1.5-3.1); the risk with low-dose TBI (200 to 450 cGY) was comparable to that of chemotherapy.
The largest autologous experiences comes from a multicenter retrospective analysis that evaluated the incidence of secondary solid tumors in 1347 patients with lymphoma treated with high-dose sequential chemotherapy followed by autologous HCT rescue between 1985 and 2005 [10]. At a median follow-up of seven years, the estimated 5-, 10- and 15-year cumulative incidences of solid tumors were 2.54, 6.79, and 9.14 percent, respectively. Of the 65 secondary solid tumors identified, the most common were in the lung, gastrointestinal tract, skin, breast, head and neck, bladder, and thyroid. The risk of developing a secondary solid tumor was increased in patients age >45, in those receiving radiation after high-dose sequential chemotherapy (hazard ratio 0.89, 95% CI 0.64-1.25), and in patients whose treatment included rituximab (hazard ratio 0.59, 95% CI 0.47-0.74). Despite the association with an increased risk of developing secondary solid tumors, the addition of rituximab to the treatment program resulted in improved overall survival rates.
Nonmelanoma skin cancer — HCT survivors are at increased risk of developing nonmelanoma skin cancer. Risk factors include radiation exposure and GVHD. A report evaluated the incidence of, and risk factors for, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in 4810 patients who received allogeneic HCT and survived >100 days [14]. Twenty-year cumulative incidences of BCC and SCC were 6.5 and 3.4 percent, respectively.
●Factors significantly influencing development of BCC included total body irradiation, especially for those <18 years of age at the time of HCT, light-skinned patients, and chronic GVHD.
●Factors significantly influencing development of SCC included both acute and chronic GVHD.
All HCT survivors should be encouraged to avoid unnecessary sun exposure and to perform regular self-skin examinations. Physicians caring for transplant patients should be aware of these risks and perform appropriate screening examinations. The diagnosis of nonmelanoma skin cancer is presented separately. (See 'Screening and preventative measures' below and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma".)
Squamous cell cancers — HCT survivors are at increased risk for the development of squamous cell cancers (SCC) of the skin and oral cavity [6,15]. The risk of SCC is particularly high among patients with chronic GVHD, prior chronic lichenoid lesions of the oral mucosa, and/or a history of Fanconi’s anemia [5,7,16,17]. SCC of the oral cavity can involve the buccal mucosa, salivary glands, gingiva, lip, or tongue. The diagnosis should be suspected in patients with nonhealing oral lesions, leukoplakia, localized oral pain, or changes in the mucosal color or texture. SCC in this setting is often clinically aggressive and screening is recommended. (See 'Screening and preventative measures' below and "Overview of the diagnosis and staging of head and neck cancer", section on 'Clinical presentation'.)
In one study of oral SCCs arising in long-term survivors of allogeneic HCT, the source of the malignant cells was surprisingly found to be the HCT donor in four of the eight cases [18]. Of interest, none of these four hosts had personal risk factors for oral SCC (eg, smoking, alcohol abuse); all had a previous history of extensive chronic GVHD with oral mucosa involvement, requiring prolonged immunosuppressive therapy.
The relationship between SCC and GVHD was further explored in a study encompassing an international cohort of over 24,000 patients who underwent allogeneic or syngeneic HCT [16]. The predominant underlying primary diseases for patients in whom SCC developed were leukemia and severe aplastic anemia, with a median time from HCT to the diagnosis of a solid tumor of 7.0 years (range: 0.9 to 23 years), and a cumulative incidence of 1.1 percent at 20 years. Risk factors significantly associated with development of SCC included:
●Severe chronic GVHD – Relative risk (RR) 9.9
●Severe chronic GVHD treated with azathioprine – RR 16.2
●Severe chronic GVHD treated with azathioprine for ≥24 months – RR 28.8
Since azathioprine is now rarely, if ever, used for the treatment of chronic GVHD, this complication may be less of a problem for current and future patients. Until a decreased incidence is realized, serial oral examinations are indicated for all transplant survivors. (See 'Screening and preventative measures' below.)
Breast cancer — The three major risk factors for breast cancer in this population are younger age at HCT, exposure of the breast tissue to radiotherapy, and disruption of ovarian function by alkylating agents and/or other chemotherapy.
In a multicenter study of 3337 female survivors of allogeneic HCT, 52 developed breast cancer (1.6 percent) at a median of 12.5 years post-transplant, with a 25-year cumulative incidence of 11 percent [19]. The risk of developing breast cancer was significantly higher for those who received total body irradiation (hazard ratio 4.0) and those who were younger at the time of HCT (hazard ratio 9.5 for HCT at <18 years of age).
Female HCT survivors should be counseled about the need for regular breast cancer screening. (See 'Screening and preventative measures' below.)
Secondary myelodysplasia/acute leukemia — HCT survivors are at increased risk of developing acute leukemia and/or myelodysplastic syndrome (MDS) when compared with the general population [10,20]. Risk factors include the use of cytotoxic chemotherapy (eg, alkylating agents) and/or ionizing radiation therapy given as large fields that include the bone marrow. In addition, there are emerging data regarding donor-derived leukemia and/or myelodysplastic syndrome [21-26].
A multicenter retrospective analysis evaluated the incidence of secondary MDS/acute leukemia in 1347 patients with lymphoma treated with high-dose sequential chemotherapy followed by autologous HCT rescue between 1985 and 2005 [10]. At a median follow-up of seven years, the estimated 5-, 10- and 15-year cumulative incidences of MDS/acute leukemia were 3.1, 4.5, and 6.8 percent, respectively. The most secondary acute leukemias were most commonly of myeloid lineage, but there were two cases of acute lymphoblastic leukemia. The risk of developing secondary MDS/acute leukemia was higher among males (hazard ratio 3.1, 95% CI 1.52-6.28) and those who were infused with peripheral blood progenitor cells collected during a second harvest (hazard ratio 2.2, 95% CI 1.3-4.0).
Secondary MDS/acute leukemia should be suspected in patients who develop unexplained anemia, neutropenia, and/or thrombocytopenia. The diagnosis, treatment, and prognosis of therapy-associated AML are presented separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)
Post-transplant lymphoproliferative disease — Post-transplant lymphoproliferative disease (PTLD) occurs after solid organ and hematopoietic cell transplantation and is importantly related to the presence of Epstein-Barr virus (EBV) [27]. The cumulative incidence is 1 percent at 10 years, with 82 percent occurring in the first year. The risk of developing PTLD is highest at one to five months post-transplant followed by a steep decline in incidence after one year (120 versus 5 cases per 10,000 patients per year among survivors for more than one year). The risk of developing PTLD varies and is dependent on features of the donor, recipient, and preparative regimen in particular with the use of T cell depletion. This topic is discussed in more detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)
Donor-derived tumors — The vast majority of second malignancies following transplantation are host derived. The one exception is for EBV-associated PTLD which more frequently occurs in donor derived cells. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Pathogenesis'.)
RISK ACCORDING TO REASON FOR HCT
HCT for aplastic anemia — The risk of secondary malignancy is especially high in patients who undergo transplantation for severe aplastic anemia (SAA), which can be either acquired or congenital (Fanconi anemia). It is difficult to evaluate the role of HCT in the development of secondary malignancies in SAA because malignancy also occurs after use of immunosuppressive therapy alone in SAA, which often consists of antithymocyte globulin, corticosteroids, and cyclosporine. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Treatment of aplastic anemia in adults".)
The largest experience with malignancy in patients with SAA comes from the European Bone Marrow Transplantation Group and included 748 patients who underwent HCT and 860 treated with immunosuppressive therapy [28]. Hematologic malignancies occurring within six months or solid tumors developing within 12 months were excluded since they might have been due to the underlying disease rather than therapy. The 10-year cumulative risk of second malignancies was 3.1 percent with HCT and 18.8 percent with immunosuppressive therapy. The distribution of tumors was different: primarily solid tumors after HCT and primarily hematologic malignancies (acute leukemia and myelodysplastic syndrome) after immunosuppressive therapy. The risk of solid tumors was the same in the two groups. The major risk factors for malignancy after HCT were increasing age and the use of radiation therapy in the conditioning regimen.
In a second series, 700 patients with either SAA or Fanconi anemia underwent allogeneic HCT [29]. The actuarial risk of developing a secondary malignancy at 20 years was 14 percent overall but was 42 percent in the 79 patients with Fanconi anemia [29]. Among the tumors, there were 18 solid tumors (all but one squamous cell carcinoma) presenting at a median of 99 months after transplant and five hematologic malignancies (acute lymphoblastic leukemia and post-transplant lymphoproliferative disease) presenting at a median of three months post-transplant. Among the patients with SAA, the major risk factors for malignancy were the use of irradiation as part of the conditioning regimen and of azathioprine for chronic graft-versus-host disease. Since neither of these modalities is commonly used at present, it is likely that the current risk of secondary malignancy is lower. (See "Hematopoietic cell transplantation for aplastic anemia in adults" and "Treatment of chronic graft-versus-host disease".)
HCT for malignancy — Second malignancies, both hematologic and nonhematologic, have been observed following HCT for a variety of malignant conditions [30]. Among patients with non-Hodgkin lymphoma or Hodgkin lymphoma, autologous bone marrow or peripheral blood progenitor cell transplantation is associated with an estimated risk of second cancers, primarily myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), of 8 to 21 percent at 5 to 10 years, and as high as 29 percent at 15 years [31-36]. Among patients with Hodgkin lymphoma, solid tumors occur with increased frequency (relative risk 5.2) compared with matched nontransplanted controls [34]. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)
A central question is whether the increased risk of secondary MDS and leukemia is due to the chemotherapy and radiation therapy used during the transplant procedure or to the cumulative effect of all of the therapy that the patient has received [37]. A number of observations are compatible with a primary role for prior therapy in causing marrow damage leading to secondary MDS/AML, rather than the transplant procedure itself [34,38-40]:
●In one series of patients with Hodgkin lymphoma, the incidence of MDS and AML was similar in transplanted and matched nontransplanted patients [34].
●Some patients have cytogenetic abnormalities prior to HCT and are at particularly high risk for subsequent development of MDS or acute leukemia. In one report of seven such patients with Hodgkin lymphoma, MDS or acute leukemia occurred in all three who were transplanted, compared with an expected incidence of 9 to 18 percent in all transplants [38]. Every effort should be made to identify these patients prior to autologous HCT with screening bone marrow aspiration, biopsy, and cytogenetic studies. If a cytogenetic abnormality is found, altering the treatment approach to an allogeneic HCT is indicated.
●A third study evaluated 188 patients with multiple myeloma who underwent autologous transplantation [39]. The patients were divided into two groups: one exposed to prolonged therapy with alkylating agents prior to transplantation and one exposed to only one cycle of chemotherapy prior to transplantation. All seven patients who developed MDS, which occurred at a median of 24 months, were in the group with high pre-transplant exposure to chemotherapeutic agents. Due to these and other findings, it is recommended to avoid alkylating agents such as melphalan for the treatment of transplant-eligible multiple myeloma patients prior to collection of hematopoietic stem cells. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Initial chemotherapy'.)
A somewhat different conclusion was reached in a report that evaluated 612 patients who received autologous HCT for Hodgkin lymphoma or non-Hodgkin lymphoma [41]. The estimated cumulative probability of therapy-related MDS/AML was 8.6 percent at six years. The relative risk of this complication was 7.7 in patients who received stem cell priming with etoposide. Multivariate analysis revealed an association with pre-transplant radiation but not pre-transplant chemotherapy or the conditioning regimen. (See "Sources of hematopoietic stem cells".)
HCT for nonmalignant hematologic disease — Secondary malignancies have been described after allogeneic transplantation for nonmalignant hematologic diseases other than severe aplastic anemia and Fanconi anemia, such as hemoglobinopathies (eg, beta thalassemia) and inborn errors of metabolism. It is unclear, however, if the risk is increased. Data from the International Bone Marrow Transplant Registry suggested that patients undergoing HCT for nonmalignant diseases had an incidence of secondary malignancies that was not significantly increased when compared with the expected value in the normal population [6].
Similarly, although malignancy occurs after HCT for beta thalassemia, the rate does not appear to be higher than that seen in patients with this disorder who are not transplanted. In the Registry report described above, patients with congenital immune deficiencies were excluded because they may have an underlying increase in the risk for cancer.
SCREENING AND PREVENTATIVE MEASURES — While HCT survivors are at increased risk of developing secondary malignancies, the ideal screening program has not been defined. No prospective analyses have evaluated the benefit of screening in this population. However, extrapolation of data from other settings suggests that the ability to prevent and detect solid organ malignancies in the HCT survivor relies on periodic screening examinations and strict adherence to prophylactic measures. Our approach is similar to that proposed in the joint screening recommendations provided by the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation [42]:
●Risk awareness counseling annually – HCT survivors should be advised of their increased risk of developing a malignancy following HCT and encouraged to report any concerning symptoms to their physician. Smoking cessation should be recommended and patients should be counseled to limit unprotected sun exposure. (See "Overview of smoking cessation management in adults".)
●Screening clinical assessment annually – In addition to a routine physical examination, HCT survivors should undergo an at least annual complete skin examination and dental evaluation to monitor for the development of skin and oral cancers, respectively. More frequent oral examination (eg, every six months) should be considered for patients with chronic graft-versus-host disease, prior chronic lichenoid lesions of the oral mucosa, and/or a history of Fanconi anemia.
●HCT survivors should be encouraged to participate in routine age-appropriate cancer surveillance. (See "Overview of preventive care in adults", section on 'Cancer screening'.)
●Female HCT survivors should undergo screening for breast cancer beginning no later than age 40 years. For patients who have received total body or chest irradiation, breast cancer screening should begin eight years after radiation or at age 25 years, whichever occurs later.
The ideal test to use for breast cancer screening has not been determined and clinical practice varies. The international working group that proposed the guidelines described above suggest the use of mammography alone. In contrast, the American Cancer Society suggests the use of mammography for most patients, but also proposes that woman who received radiation to the chest between the age of 10 and 35 years undergo screening with both annual breast magnetic resonance imaging (MRI) and mammography [43,44]. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Post-treatment management'.)
SUMMARY
●Patients treated with chemotherapy and/or radiotherapy followed by hematopoietic cell transplantation (HCT) have an increased risk of developing myelodysplastic syndrome (MDS), acute leukemia, post-transplant lymphoproliferative disease (PTLD), and solid tumors when compared with the general population. These secondary malignancies are expected to have a significant impact on survival in this patient population. (See 'General observations' above.)
●HCT survivors develop new solid cancers at approximately twice the expected rate in the general population. Retrospective series have estimated the cumulative incidence rates at 1 to 2 percent at 10 years and 3 to 5 percent at 20 years after allogeneic HCT and at 4 percent 10 years following autologous HCT. Solid tumors of practically every type have been described in the allogeneic and autologous HCT setting. (See 'Solid tumors' above.)
●Radiation exposure and graft-versus host disease (GVHD) place HCT survivors at increased risk of developing nonmelanoma skin cancer. All HCT survivors should be encouraged to avoid unnecessary sun exposure and to perform regular self-skin examinations. (See 'Nonmelanoma skin cancer' above and 'Screening and preventative measures' above.)
●Squamous cell cancers (SCC) of the oral cavity are more common in HCT survivors, especially among those with chronic GVHD, prior chronic lichenoid lesions of the oral mucosa, and/or a history of Fanconi’s anemia. The diagnosis should be suspected in patients with nonhealing oral lesions, leukoplakia, localized oral pain, or changes in the mucosal color or texture. Oral screening should be performed at least annually in all HCT survivors. (See 'Squamous cell cancers' above and 'Screening and preventative measures' above.)
●The three major risk factors for breast cancer in this population are younger age at HCT, exposure of the breast tissue to radiotherapy, and disruption of ovarian function by alkylating agents and/or other chemotherapy. Female HCT survivors should undergo screening for breast cancer beginning no later than age 40 years. For patients who have received total body or chest irradiation, breast cancer screening should begin eight years after radiation or at age 25 years, whichever occurs later. (See 'Breast cancer' above and 'Screening and preventative measures' above.)
●HCT survivors are at increased risk of developing acute leukemia and/or MDS when compared with the general population. Risk factors include the use of cytotoxic chemotherapy (eg, alkylating agents), lenalidomide maintenance, and/or total body irradiation. (See 'Secondary myelodysplasia/acute leukemia' above.)
●PTLD is a rare complication of HCT that is related to the presence of Epstein-Barr virus and typically occurs within the first year post-HCT. The risk of developing PTLD varies and is dependent on features of the donor, recipient, graft manipulation, and preparative regimen. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Risk factors'.)
●The risk of secondary malignancy is increased among patients undergoing HCT for malignancy and is especially high in patients who undergo HCT for severe aplastic anemia. In contrast, the risk of malignancy after HCT does not appear to be increased among patients undergoing HCT for nonmalignant diseases other than severe aplastic anemia. (See 'Risk according to reason for HCT' above.)
●HCT survivors should be advised of their risk of developing a malignancy following HCT and encouraged to report any concerning symptoms to their physician. In addition to routine age-appropriate cancer surveillance, increased surveillance for oral and breast cancers is indicated. (See 'Screening and preventative measures' above.)
