Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood
Abstract
:1. Introduction
Characteristics of SMNs | Related to Previous and/or Conditioning Cytotoxic Treatment | PTLD | |
---|---|---|---|
Solid Tumours | t-AML/MDS | ||
Clinical presentation | Wide variety of sites including skin, thyroid, brain, gastrointestinal etc. | Cytopenias and associated clinical features of bone marrow failure, or overt AML with fever, lymphadenopathy, coagulopathy etc. | Spectrum from Glandular fever-like illness, lymphadenopathy, lymphomatous deposits, fever and organ dysfunction. Rarely primary CNS lymphoma |
Incidence | 7% at 20 years post-HSCT, but still rising by further 2% for every subsequent 5 years additional follow-up | 1%–2% following autologous transplant, but higher with intensive pre-transplant chemotherapies. Rarely described post allogeneic HSCT | Approximately 1% overall, up to 70% with multiple risk factors |
Latency | Variable but often long—Up to at least 20–30 years | Variable from 6 months for t-AML secondary to topoisomerase II inhibitors to 8–10 years for alkylating agent induced t-MDS | Short—Most cases present in first year post transplant |
Age at presentation | Any | Any | Any |
Associated features | Continued rise in cumulative incidence even after >20 years post-HSCT | Topoisomerase II inhibitors associated with an increased incidence of rearrangements of, classically, 11q32, but also rearrangement of 21q22, t(3;21)(q26.2;q22.1), t(15;17)(q22;q12) or inv(16)(p13.1q22). Alkylating agents associated with an increased incidence of unbalanced cytogenetic changes, especially del(7q) and del(5q) | EBV viraemia, fever, organ dysfunction |
Risk factors | Radiotherapy during previous treatment or conditioning regimen GvHD (especially chronic) | Epipodophyllotoxin/alkylating agent use PBSC (versus marrow) as stem cell source? | Specific T cell depletion > non-specific lymphocyte depletion. Intense immunosuppression (after RIC HSCT or for treatment of GvHD). Unrelated or mismatched related donor |
2. Epidemiology
2.1. Secondary Malignant Neoplasms in Childhood Cancer Survivors
2.2. Secondary Malignant Neoplasms in Survivors of HSCT
Author, Date | Study Characteristics | Secondary Malignancies | Risk Factors | Comments |
---|---|---|---|---|
Paediatric Studies | ||||
Socie, 2000 [35] | Multicentre international registry (IBMTR) and Seattle. Allogeneic HSCT for acute leukaemia. 3182 patients, HSCTs performed 1964–1992. Kaplan-Meier analysis of probability of SMN. Uni- and multivariate analysis of risk factors | 45 invasive SMNs (25 solid tumours, 20 PTLDs) compared with 1 expected case (p < 0.001). Solid tumours included brain (9), thyroid (5), melanoma (3), tongue SCC (3), salivary gland carcinoma (2), osteosarcoma (2) | Solid tumours associated with age <10 years at HSCT (RR 3.7) (especially for brain and thyroid SMNs, RR 12.2) and high dose TBI (>10 Gy single fraction, >13 Gy fractionated) (RR 3.1). NB Chronic GvHD or cGvHD lowered risk of solid tumours (RR 0.2). PTLD associated with moderate or severe cGvHD (RR 6.5), unrelated or HLA mismatched related donor (RR 7.5), T cell depletion (RR4.8) and use of ATG (RR 3.1) | Cumulative incidence of invasive solid SMN 0.9%, 4.3% and 11% at 5, 10 and 15 years post-HSCT respectively. Latency—median 6.0 (range 0.3–14.3) years |
Danner-Koptik, 2013 [30] | Multicentre international registry (CIBMTR). Autologous HSCT for lymphomas or solid tumours. 1487 patients, HSCTs performed 1987–2003. Competing risks (cumulative incidence function) analysis of probability of SMN. Multivariate analysis of risk factors | 35 SMNs (13 AML/MDS, 20 solid tumours). Solid tumours included bone (5), thyroid (5), breast (2), soft tissue (2). SIRs—overall 24, AML 266, MDS 6,603, bone 81, thyroid 53, breast 93, soft tissue 34 | No association between risk of SMN and age, gender, diagnosis, remission status at HSCT, time from diagnosis to HSCT, TBI, etoposide in conditioning, any radiotherapy, number of HSCTs, year of HSCT | Cumulative incidence of SMNs 1.0% and 2.6% at 5 and 10 years post-HSCT (0.6% and 1.1% AML/MDS, 0.4% and 1.3% solid tumours). Latency—6.3 (0.4–20.4) years (AML/MDS—2 years, solid tumours—7 years) |
De Latour, 2014 [44] | Multicentre international registry (EBMT). First HLA-matched allogeneic HSCT for Fanconi anaemia. 796 patients, HSCTs performed 1972–2009 (49% since 1999). Competing risks (cumulative incidence function) analysis of probability of SMN. Multivariate analysis of risk factors | 30 SMNs (only 2 since 2000). 89% were solid tumours, including 20 SCCs (13 were oral/oesophageal) | 10–20 or >20 years age at HSCT (HR 2.3 and 3.3 respectively). Clonal evolution as indication for HSCT (HR 4.6). PBSC as stem cell source (HR 3.3). Previous cGvHD (HR 3.3). Radiotherapy and donor type were not risk factors | Cumulative risk of SMNs 21% and 34% at 15 and 20 years post-HSCT respectively (in the 509 patients who survived >1 year post-HSCT) |
Martin 2014 [45] | Single centre retrospective analysis of 87 children undergoing autologous HSCT for high risk neuroblastoma. Competing risks analysis of probability of SMN. Univariate analysis of risk factors | 10 SMNs, including t-AML (1), t-MDS (5), papillary thyroid carcinomas (2), chondrosarcoma followed by hepatocellular carcinoma (1), biliary adenocarcinoma (1) | High risk of t-AML/MDS in this study likely to reflect the very high dose of cyclophosphamide and etoposide compounded by late harvesting of PBSCs | Cumulative incidence of SMN 7.2%, 16.5% and 34.2% at 5, 10 and 15 years respectively |
Bhatia, 1996 [27] | Single centre USA. Autologous and allogeneic HSCT for any diagnosis. 2150 patients, aged 20.0 (0.2–67) years at HSCT performed 1974–1995. Kaplan-Meier analysis of probability of SMN. Uni- and multivariate analysis of risk factors | 53 SMNs in 51 patients (22 PTLDs, 17 solid tumours, 11 AML/MDS, 3 lymphoma). Solid tumours included melanoma (3), BCC (3), brain (2). SIRs—overall 11.6, solid tumours 3.2, melanoma 10.3, brain 11.8, AML/MDS 286 | Solid tumours—TBI (RR 6.0) (cGvHD not risk factor for skin SMNs). AML/MDS—PBSC as stem cell source (RR 5.8), age >35 years at HSCT (RR 3.5). PTLD—in vitro T cell depletion (RR 11.9), ATG in conditioning (RR 5.9), mismatched donor (RR 8.9), PID (RR 2.5) | Cumulative risk of SMNs 9.9% at 13 years post-HSCT. Solid tumours 5.6% at 13 years. AML/MDS plateaued at 2.1% at 9 years, PTLD at 1.6% at 4 years. Latency—solid tumours 4.0 (0.2–13), AML/MDS 3.0 (0.3–9) years, PTLD 0.2 (0.1–3) |
Mixed Paediatric/Adult Studies | ||||
Kolb, 1999 [32] | Multicentre international registry (EBMT). Autologous and allogeneic HSCT for leukaemia, lymphoma, inborn errors or aplastic anaemia. 1,036 patients surviving >5 years post-HSCT, aged 21 (1–51.9) years at HSCT performed before 1985. Kaplan-Meier analysis of probability of SMN. Uni- and multivariate analysis of risk factors | 53 SMNs including skin (14), oral (7), gastrointestinal (5), thyroid (5), uterine/cervix (5), breast (4), brain (3), leukaemia (1) | Age at HSCT. Immunosuppressive treatment for cGvHD, specifically
| Cumulative incidence of SMNs 3.5% and 11.5% at 10 and 15 years post-HSCT respectively |
Curtis 1999 [46] | Multicentre international registry (CIBMTR) and Seattle. Allogeneic HSCT, excluding patients with primary immune deficiency, inherited cancer predisposition syndromes, initial diagnosis of NHL. 18,014 patients, aged 25 (<1–72) years at HSCT performed 1964–1992. Competing risks analysis for probability of PTLD. Multivariate analysis of risk factors for PTLD | 78 cases of PTLDs with 64 (82%) within the first year | Unrelated or HLA-mismatched related donor (RR 4.1). T-cell depletion of donor marrow (RR 12.7). Use of antithymocyte globulin (RR 6.4) or anti-CD3 monoclonal antibody (RR 43.2). Weaker association with grade II-IV aGvHD (RR 1.9) and radiation based conditioning (RR 2.9). Multiplicative effect of risk factors with 2 major risk factors (RR 8.0) and ≥3 factors (RR 22%) | Cumulative incidence of PTLDs 1.0% at 10 years post-HSCT. Latency—Most PTLDs early-onset (64/78 occurred within first year post-HSCT), minority late-onset (14/78 occurred 1–8.6 years post-HSCT) |
Bhatia, 2001 [26] | Single centre USA. Autologous and allogeneic HSCT for any diagnosis. 2129 patients, aged 33.9 (1.5–71.5) years at HSCT performed 1976–1998. Kaplan-Meier analysis of probability of SMN. Uni- and multivariate analysis of risk factors. Nested case control study of risk factors | 29 solids SMNs. Excluded PTLD and haematological malignancies. Included non-melanoma skin (9) (SCC 3, BCC 6), cervix (4), salivary gland (3), oral SCC (3), breast (2), liver (2), thyroid (2). Overall SIR (excluding skin SCC and BCC) 5.3 if <34 years age at HSCT, only 1.1 if older | Case control study revealed no association between risk of SMN and pre-HSCT or conditioning radiotherapy or chemotherapy, aGvHD or cGvHD, primary diagnosis, age at and type of HSCT However
| Cumulative incidence of SMNs 1.6% and 6.1% at 5 and 10 years post-HSCT respectively (allogeneic 6.4% and autologous 1.6% at 10 years). Latency—No data overall, but cervix 3.3 (1.6–9.7), oral 7.6 (4.7–11.7), breast 9.9 (2.6–17.1), thyroid 12.7 (7.5–18.0) |
Baker, 2003 [42] (NB Update of Bhatia 1996) [27] | Single centre USA. Autologous and allogeneic HSCT for any diagnosis. 3372 patients, aged 24 (0.1–67) years at HSCT performed 1974-2001. Competing risks analysis of probability of SMN. Multivariate analysis of risk factors | 147 invasive SMNs in 137 patients (44 PTLDs, 62 solid tumours, 36 AML/MDS, 5 other leukaemia/lymphoma. Solid tumours included skin BCC and SCC (19), melanoma (8), carcinoma-in-situ (5), oral (5), brain (4), breast (4), lung (3). SIRs—overall 8.1, solid tumours 2.8, AML/MDS 300; if <10 years age at HSCT, overall 60.4, solid tumours 33.3 | Solid tumours—Age ≥20 years at HSCT (RR 2.0). TBI not significant1. PTLDs—Mismatched related donors (RR 9.0), PID (RR 2.7), CML (RR 2.5), use of ATG (RR 3.7), in vitro T cell depletion (RR 4.0), grade 3–4 aGvHD (RR 2.4). AML/MDS—30 of 34 had undergone autologous HSCT. Risk highest for PBSC (RR 3.1) | Cumulative incidence of SMNs 6.9% at 20 years post-HSCT, increasing by ~2% in each successive 5 year follow-up period. Mostly solid tumours after 5 years (3.8% at 20 years). Latency—Very similar to Bhatia, 1996 |
Cohen, 2007 [40] | Multicentre international registry (EBMT). Autologous and allogeneic HSCT for any diagnosis. 70,859 patients, 27% aged 0–20 years age at HSCT, performed 1985–2003. Competing risks analysis of probability of SMN. Multivariate analysis of risk factors | 32 thyroid carcinomas (papillary cell 23, follicular 9). Presented with palpable nodule in 18 (56%). No symptoms/signs and diagnosed only on ultrasound surveillance in 9 (28%). SIRs—Overall 3.3, males 4.1, females 2.9, 0–10 years age at HSCT 61 | Age at HSCT (RR 24.6 for <10 years vs. >20 years). TBI or thoraco-abdominal radiotherapy (RR 3.4). Females (RR 2.8 vs. males). cGvHD (RR 2.9) | Cumulative incidence of thyroid SMNs ~0.05% at 20 years post-HSCT (0.2% in patients 0–10 year age at HSCT). Latency—8.5 (0.6–18.5) years |
Landgren 2009 [47]. (NB Update of Curtis 1999) [46] | Multicentre international registry (CIBMTR) and Seattle Allogeneic HSCT, excluding patients with primary immune deficiency, inherited cancer predisposition syndromes, initial diagnosis of NHL. 26,901 patients, aged 26.6 (0.1–68) years at HSCT performed 1964–1996. Competing risks analysis for probability of PTLD. Multivariate analysis of risk factors for PTLD | 127 PTLDs identified, 105 (83%) within the first year following transplant. | T cell depletion (RR 3.1–9.4), use of ATG (RR 3.8), HLA mismatching in presence of T-cell depletion/ATG use (RR 3.8), acute (RR1.7) and chronic (RR 2) GvHD. Less effect when T-cell depletion used agents which also remove B cell | Overall observed to expected (O/E) ratio 29.7 (4.2 at ≥5 years post-HSCT). Demonstrated a multiplicative effect of multiple major risk factors on incidence: 0 factors—cumulative risk 0.2% at 12 years post-HSCT; 1 factor—1.1%; 2 factors—3.6%; 3 factors—8.1%. Latency—most PTLDs early-onset (105/127 [83%] occurred within first year post-HSCT), minority late-onset (22/127 occurred 1–>10 years post-HSCT) |
Rizzo, 2009 [33] | Multicentre international registry (CIBMTR) and Seattle. Allogeneic HSCT for haematological malignancy, aplastic anaemia (except Fanconi anaemia) and haemoglobinopathy. 28,874 patients, aged 27 (0.08–72.4) years at HSCT performed 1964–1996. Competing risks analysis of probability of SMN (also performed Kaplan-Meier analysis for comparison with previous studies). Multivariate analysis of risk factors | 189 SMNs. Excluded BCC, PTLD and haematological malignancies. Included oral/pharyngeal (27), melanoma (18), brain (18), thyroid (16), breast (13), female genital (9), bronchus/lung (8), liver (7), soft tissue (7), bone/joint (6). SIRs—overall 2.1, bone/joint 8.5, oral 7.0, soft tissue 6.5, liver 6.3, brain 5.9, thyroid 5.8, melanoma 3.5 | Conditioning radiotherapy (TBI or limited field)—non-SCC tumours (RR 2.3 for TBI). Significant interaction with age at HSCT – RR 55.3 for <10 years, 6.2 if 10–19 years, 4.8 if 20-29 years; no excess risk if >30 years. cGvHD—SCCs (skin RR 11.0, oral RR 5.3). Patient gender (male)—SCCs (skin RR 11.9, oral RR 2.8). Most cases (27/40) of brain/CNS, thyroid, bone, soft-tissue SMNs occurred in patients who underwent HSCT at <17 years age | Cumulative incidence of solid SMNs 3.3% (competing risks analysis) and 8.8% (Kaplan-Meier analysis) at 20 years post-HSCT. Latency—65 SMNs occurred 1–4 years and 100 ≥5 years post-HSCT |
3. Pathogenesis, Clinical Features and Management
3.1. Solid Malignancies
3.2. Myeloid Malignancies—Acute Myeloid Leukaemia and Myelodysplasia
3.3. Post-Transplantation Lymphoproliferative Disorder
4. Risk Factors
4.1. Solid Malignancies
4.2. Myeloid Malignancies
4.3. Post-Transplantation Lymphoproliferative Disorder
4.4. Fanconi Anaemia
4.5. Other Cancer Predisposition Syndromes
5. Future Research Questions
Acknowledgements
Author Contributions
Conflicts of Interest
References
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Bomken, S.; Skinner, R. Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood. Children 2015, 2, 146-173. https://doi.org/10.3390/children2020146
Bomken S, Skinner R. Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood. Children. 2015; 2(2):146-173. https://doi.org/10.3390/children2020146
Chicago/Turabian StyleBomken, Simon, and Roderick Skinner. 2015. "Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood" Children 2, no. 2: 146-173. https://doi.org/10.3390/children2020146