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Reduced-Intensity Conditioning Regimens, Prior Chronic Lymphocytic Leukemia, and Graft-Versus-Host Disease Are Associated with Higher Rates of Skin Cancer after Allogeneic Hematopoietic Stem Cell Transplantation

Open ArchivePublished:October 11, 2018DOI:https://doi.org/10.1016/j.jid.2018.08.025
      To assess incidence and risk factors for skin cancer associated with allogeneic hematopoietic stem cell transplantation, we evaluated 1,974 adult allogeneic hematopoietic stem cell transplantation patients from Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute who received transplants between January 1995 and July 2013 for hematologic malignancy and survived at least 100 days. Median age was 51.1 years, and median follow-up time was 3 years. Overall, 119 patients had 221 skin cancers. The incidences of squamous cell carcinomas (incidence rate ratio = 9.8; 95% confidence interval = 7.7–12.3), basal cell carcinomas (incidence rate ratio = 2.5; 95% confidence interval = 1.9–3.2), and melanoma (standardized incidence ratio = 3.3; 95% confidence interval = 1.7–5.9) were elevated in our cohort. In multivariable models, risk factors for squamous cell carcinomas were increased age (P < 0.0001), chronic lymphocytic leukemia (P = 0.02), and chronic graft-versus-host disease (P = 0.0002). Risk factors for basal cell carcinomas were chronic lymphocytic leukemia (P = 0.003), reduced-intensity conditioning (P = 0.02), acute graft-versus-host disease (P = 0.03), and chronic graft-versus-host disease (P = 0.003). To our knowledge, previously unreported risk factors in this contemporary cohort include prior CLL for squamous cell carcinoma and basal cell carcinoma and reduced-intensity conditioning for basal cell carcinoma. This study also supports chronic graft-versus-host disease as a risk factor for nonmelanoma skin cancer, particularly squamous cell carcinoma.

      Abbreviations:

      BCC (basal cell carcinoma), CI (confidence interval), CLL (chronic lymphocytic leukemia), GVHD (graft-versus-host disease), HCT (hematopoietic stem cell transplantation), HR (hazard ratio), PY (patient-year), SCC (squamous cell carcinoma), TBI (total body irradiation)

      Introduction

      Hematopoietic stem cell transplantation (HCT) is increasingly used as treatment for malignant and nonmalignant conditions (

      D’Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR Summary Slides, 2017, http://www.cibmtr.org (accessed 6 February 2018).

      ). As the number and overall age of patients who receive HCT increases and patients survive longer, increased awareness of the long-term health risks associated with transplantation is increasingly important for optimal patient care. Secondary malignancies, especially skin cancers, are an important cause of morbidity among long-term survivors after HCT (
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      Solid cancers after allogeneic hematopoietic cell transplantation.
      ).
      Although an increased risk of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) in HCT patients has previously been reported (
      • Armstrong G.T.
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      Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation.
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      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
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      ), changing practices including shifting donor sources and use of reduced-intensity conditioning regimens are not reflected in these estimates. Hence, prior estimates may not reflect current risks.
      To assess the incidence and risk factors for secondary skin malignancy after HCT, we assessed skin cancers among a large, contemporary cohort of allogeneic HCT patients from the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center.

      Results

      In total, 1,974 patients (1,812 from the Dana-Farber Cancer Institute and 162 from Beth Israel Deaconess Medical Center) were included in the analysis, with a median follow-up time of 3.0 years (first to third quartile range = 1.1–6.0), totaling 7,795 years of follow-up after transplantation. Fifty-one percent (1,015/1,974) of patients survived for at least 3 years. The median age at transplantation was 51.1 years (first to third quartile range = 40.5–58.9). There were 119 patients who had one or more SCCs, BCCs, or melanomas, totaling 221 skin cancers (Table 1). Of these, 79 individuals had 127 SCCs, 54 individuals had 77 BCCs, and 11 individuals had 14 melanomas. More than 90% of patients in the cohort identified as Caucasian. This group represented nearly all (>98%) of the patients who developed skin cancer. Of the 119 patients who developed skin cancer, there were 44 (37%) with more than one SCC or BCC. Supplementary Table S1 online shows the cross-tabulation of patients with multiple SCCs and BCCs. Cumulative incidence estimates for SCC, BCC, and melanoma 10 years after HCT were 5.5%, 3.8%, and 0.7%, respectively (Figure 1, and see Supplementary Table S2 online).
      Table 1Characteristics of Allogeneic Hematopoietic Stem Cell Transplantation Patients
      CharacteristicAll Patients (n = 1,974)SCC Patients (n = 79)BCC Patients (n = 54)Melanoma Patients (n = 11)
      n%n%n%n%
      Age in years at transplantation, median (Q1, Q3)51.1 (40.5, 58.9)58.1 (51.0, 63.3)54.5 (46.1, 61.4)48.6 (42.4, 55.0)
      Age at transplantation, years
       <4045723.233.847.4218.2
       40–4943922.21316.51425.9436.4
       50–5963732.33443.02138.9327.3
       ≥6044122.32936.71527.8219.2
      Sex
       Female84242.72430.41731.5436.4
       Male1,13257.45569.63768.5763.6
      Race
       White1,81592.0791005398.211100
       Non-white944.80011.900
       Unknown653.3000000
      Primary disease
       AML69835.42227.91120.4218.2
       ALL1728.778.959.300
       CML1678.556.347.419.1
       CLL1799.11721.51629.6218.2
       Lymphoma39219.91721.51324.119.1
       Other (MDS, MM, etc.)36618.51113.959.3545.5
      Conditioning regimen
       Reduced intensity1,04152.74962.04074.1327.3
       Myeloablative93347.33038.01425.9872.7
      Radiation
       No TBI1,13257.45670.94175.9327.3
       TBI84242.72329.11324.1872.7
      Donor type
       Related78839.92734.21833.3436.4
       Unrelated1,18660.15265.83666.7763.6
      Graft source
       Cord blood1186.056.311.900
       BM1939.8810.159.3218.2
       BM and PB40.2000000
       PB1,65984.06683.54888.9981.8
      GVHD
       None48624.61012.7611.119.1
       Acute only31816.167.647.419.1
       Chronic only55127.92734.21425.9654.6
       Acute and chronic61931.43645.63055.6327.3
      Time from transplantation to last follow-up in years, median (Q1, Q3)3.0 (1.0–6.0)6.0 (4.1–8.2)5.3 (3.3–8.0)5.9 (3.6–8.0)
      Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BCC, basal cell carcinoma; BM, bone marrow; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; GVHD, graft-versus-host disease; MDS, myelodysplastic disease; MM, multiple myeloma; PB, peripheral blood; Q, quartile; SCC, squamous cell carcinoma; TBI, total-body irradiation.
      Figure thumbnail gr1
      Figure 1Cumulative incidence curves of SCCs, BCCs, and melanoma. Incidence of SCC, BCC, and melanoma increase over time from hematopoietic stem cell transplantation. Numbers of individuals at risk at each time point are shown. BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

       Risk factors for development of all skin cancers

      In separate Fine and Gray regression analyses, each adjusted for age at transplantation and sex, we examined potential risk factors for development of SCC, BCC, and any skin cancer. Hazards of all skin cancers significantly increased with age quartile at transplantation, male sex (hazard ratio [HR] = 1.6, 95% confidence interval [CI] = 1.1–2.3), prior disease with chronic lymphocytic leukemia (CLL) (HR = 2.6, 95% CI = 1.7–4.1), and chronic graft-versus-host disease (GVHD) (HR = 3.2, 95% CI = 2.0– 5.1) (Table 2). In multivariable analysis, age quartile at transplantation, male sex, prior CLL, and chronic GVHD remained significant factors for increased risk of all skin cancers (Table 3).
      Table 2Univariable Analysis of All Skin Cancers, SCCs, and BCCs
      CharacteristicAll Skin Cancers (n = 119)SCCs (n = 79)BCCs (n = 54)
      HR (95% CI)PHR (95% CI)PHR (95% CI)P
      Age at transplantation, years
       <40refrefref
       40–492.94 (1.38–6.26)0.00034.55 (1.30–15.88)0.00023.69 (1.22–11.20)0.07
       50–594.10 (2.02–8.31)8.48 (2.61–27.57)3.88 (1.34–11.23)
       ≥604.51 (2.19–9.31)10.84 (3.30–35.58)4.14 (1.39–12.31)
      Sex
       Femalerefrefref
       Male1.58 (1.07–2.34)0.021.56 (0.96–2.53)0.071.57 (0.88–2.82)0.13
      Prior disease
       No CLLrefrefref
       CLL2.64 (1.71–4.07)<0.00012.16 (1.25–3.74)0.0063.53 (1.95–6.37)<0.0001
      Conditioning regimen
       Reduced intensityrefrefref
       Myeloablative0.99 (0.63–1.54)0.961.29 (0.74–2.26)0.370.41 (0.20–0.82)0.01
      Radiation
       No TBIrefrefref
       TBI0.89 (0.58–1.36)0.590.89 (0.52–1.51)0.660.45 (0.22–0.91)0.03
      Donor type
       Relatedrefrefref
       Unrelated1.31 (0.90–1.91)0.161.27 (0.80–2.02)0.311.42 (0.80–2.50)0.23
      Graft source
       Bone marrow or cord bloodrefrefref
       Peripheral blood0.83 (0.52–1.34)0.450.78 (0.43–1.41)0.411.42 (0.62–3.27)0.41
      Acute GVHD
       Norefrefref
       Yes1.36 (0.95–1.96)0.091.32 (0.85–2.06)0.221.90 (1.08–3.31)0.03
      Chronic GVHD
       Norefrefref
       Yes3.18 (1.99–5.07)<0.00013.06 (1.74–5.37)<0.00013.21 (1.59–6.48).001
      Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; HR, hazard ratio; ref, reference group; SCC, squamous cell carcinoma; TBI, total-body irradiation.
      Table 3Multivariable Analysis, Final Models of All Skin Cancers, SCCs, and BCCs
      Factors without results reported were not included in the final multivariable model for the indicated outcome.
      CharacteristicAll Skin Cancers (n = 119)SCCs (n = 79)BCCs (n = 54)
      HRP95% CIHRP95% CIHRP95% CI
      Age at transplantation, years
       <40refrefref
       40–492.600.0003(1.22–5.56)4.19<0.0001(1.20–14.60)2.830.35(0.90–8.90)
       50–593.77(1.86–7.64)8.01(2.47–25.99)2.52(0.79–8.01)
       ≥604.62(2.22–9.60)12.45(3.47–37.31)2.45(0.65–9.16)
      Sex
       Femalerefrefref
       Male1.430.08(0.96–2.13)1.450.14(0.88–2.39)1.390.27(0.78–2.50)
      Prior disease
       No CLLrefrefref
       CLL2.43<0.0001(1.56–3.78)1.980.02(1.14–3.44)2.560.003(1.38–4.74)
      Conditioning regimen
       Reduced intensityref
       Myeloablative0.430.02(0.20–0.90)
      Acute GVHD9
       Noref
       Yes1.900.03(1.08–3.34)
      Chronic GVHD
       Norefrefref
       Yes3.04<0.0001(1.90–4.86)2.950.0002(1.68–5.19)2.910.003(1.45–5.84)
      Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; HR, hazard ratio; ref, reference group; SCC, squamous cell carcinoma.
      1 Factors without results reported were not included in the final multivariable model for the indicated outcome.
      Clinically, the morbidity of multiple skin cancers can be substantial. We performed Poisson analysis of total numbers of skin cancers, BCCs, and SCCs using time as an offset variable. In the univariable analysis, older age at transplantation, male sex, CLL, unrelated donor, acute GVHD, and chronic GVHD increased the risk of any skin cancer (Table 4). In the multivariable Poisson analysis of all skin cancers, age quartile at transplantation, male sex, prior CLL, and chronic GVHD were significantly associated with increased skin cancer incidence (Table 5).
      Table 4Univariable Poisson Models of All Skin Cancers, SCCs, and BCCs
      CharacteristicAll Skin Cancers (n = 221)SCCs (n = 127)BCCs (n = 77)
      IRR (95% CI)PIRR (95% CI)PIRR (95% CI)P
      Age at transplantation, years
       <40111
       40–496.20 (3.06–12.58)<0.00017.16 (2.13–24.10)<0.00016.96 (2.43–19.95)<0.0001
       50–598.78 (4.42–17.46)17.26 (5.40–55.15)5.91 (2.06–16.95)
       ≥6013.59 (6.79–27.20)27.91 (8.69–89.64)8.85 (3.04–25.80)
      Sex
       Female111
       Male1.57 (1.18–2.09)0.0021.34 (0.93–1.93)0.112.13 (1.28–3.55)0.002
      Prior disease
       No CLL111
       CLL2.12 (1.55–2.91)<0.00011.68 (1.09–2.61)0.023.15 (1.93–5.13)<0.0001
      Conditioning regimen
       Reduced intensity111
       Myeloablative0.88 (0.64–1.22)0.451.47 (0.96–2.25)0.080.29 (0.16–0.52)<0.0001
      Radiation
       No TBI111
       TBI0.71 (0.51–0.99)0.040.90 (0.58–1.39)0.640.33 (0.19–0.60)0.0001
      Donor type
       Related111
       Unrelated1.57 (1.17–2.09)0.0011.47 (1.01–2.14)0.041.65 (1.02–2.67)0.04
      Transplant source
       Bone marrow or cord blood111
       Peripheral blood1.48 (0.98–2.23)0.051.19 (0.71–2.00)0.502.03 (0.97–4.26)0.04
      Acute GVHD
       No111
       Yes1.65 (1.26–2.16)0.00021.64 (1.15–2.33)0.0061.93 (1.21–3.06)0.005
      Chronic GVHD
       No111
       Yes2.24 (1.55–3.22)<0.00012.47 (1.50–4.07)<0.00011.88 (1.05–3.36)0.02
      Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; IRR, incidence rate ratio; SCC, squamous cell carcinoma; TBI, total body irradiation.
      Table 5Multivariable Analysis of Total Numbers of Skin Cancers, SCCs, BCCs, and Final Models
      CharacteristicAll Skin Cancers (n = 221)SCCs (n = 127)BCCs (n = 77)
      IRR(95% CI)PIRR(95% CI)PIRR(95% CI)P
      Age at transplantation, years
       <40111
       40–495.67(2.79–11.54)<0.00016.85(2.03–23.10)<0.00015.00(1.72–14.50)0.02
       50–597.65(3.84–15.26)16.27(5.08–52.13)2.94(0.99–8.76)
       ≥6012.25(6.10–24.59)28.06(8.70–90.49)3.52(1.14–10.88)
      Sex
       Male111
       Female1.44(1.08–1.92)0.011.23(0.85–1.79)0.281.65(0.98–2.77)0.06
      Prior disease
       No CLL111
       CLL2.03(1.48–2.79)<0.00011.58(1.02–2.45)0.042.23(1.34–3.70)0.002
      Conditioning regimen
       Reduced intensity1
       Myeloablative0.29(0.16–0.54)<0.0001
      Acute GVHD
       No11
       Yes1.50(1.05–2.13)0.032.11(1.31–3.38)0.002
      Chronic GVHD
       No111
       Yes2.16(1.50–3.12)<0.00012.27(1.37–3.75)0.0011.58(0.88–2.85)0.13
      BCC, basal cell carcinoma; CI, confidence interval; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; IRR, incidence rate ratio; SCC, squamous cell carcinoma.

       Risk factors for development of SCC

      In univariable Fine and Gray regression analyses adjusted for age at transplantation and sex, hazards of SCC significantly increased with age quartile at transplantation (HR = 10.8, 95% CI = 3.3–35.6) in patients older than 60 years. CLL (HR = 2.2, 95% CI = 1.3–3.7) and chronic GVHD (HR = 3.1, 95% CI = 1.7–5.4) were associated with increased hazard of SCCs in univariable models (Table 2). Multivariable analysis substantiated the significantly increased hazards of SCC in patients with older age at transplantation, with prior CLL, and who developed chronic GVHD.
      In the univariable Poisson analysis of total SCCs, significant risk factors were age at transplantation, prior CLL, unrelated donor, acute GVHD, and chronic GVHD (Table 4). In multivariable Poisson analysis, increased age, prior CLL, acute GVHD, and chronic GVHD were significant risk factors for multiple SCCs (Table 5).
      The incidences per 100,000 patient-years (PY) of SCC for age groups younger than 40, 40–49, 50–59, and 60 years or older were 136, 638, 1,408, and 2,365, respectively.

       Risk factors for development of BCC

      In univariable Fine and Gray regression analyses of BCCs adjusted for age at transplantation and sex, we found that a myeloablative conditioning regimen (HR = 0.4, 95% CI = 0.2–0.8) and total body irradiation (TBI) were protective (HR = 0.5, 95% CI = 0.2–0.9), whereas prior CLL (HR = 3.5, 95% CI = 2.0–6.4), acute GVHD (HR = 1.9, 95% CI = 1.1–3.3), and chronic GVHD (HR = 3.2, 95% CI = 1.6–6.5) increased hazards of BCCs (Table 2). In the multivariable model for BCCs, adjusted for age and sex, a myeloablative conditioning regimen remained significantly protective (HR = 0.4, 95% CI = 0.2–0.9) (Table 3). Because there was a sizable overlap between those patients who received TBI and those who had myeloablative conditioning (more than 86% of patients received TBI as part of their myeloablative conditioning, and more than 96% of patients who received TBI had myeloablative transplants), a myeloablative regimen but not TBI was used in the final multivariable model to avoid collinearity. Prior disease with CLL, acute GVHD, and chronic GVHD also increased hazards of BCCs in the multivariable model.
      In the cohort of patients who received a myeloablative transplant and did not develop acute or chronic GVHD (n = 194), the risk for developing BCC during follow-up was extremely low, with no events in that group (P < 0.0001). These “favorable” risk factors were unique to BCC development; in the same cohort, the HRs for SCC development were not significantly different from those who received a reduced-intensity transplant and developed GVHD.
      In univariable Poisson analysis, older age quartile at transplantation, male sex, unknown donor, no TBI, reduced-intensity conditioning, peripheral blood source, acute GVHD, and chronic GVHD individually increased risk of multiple BCCs (Table 4). Similar to the Fine and Gray regression analysis, myeloablative conditioning regimen and TBI were protective against BCC development. In the multivariable Poisson model, older age quartile, male sex, prior CLL, acute GVHD, and chronic GVHD significantly increased outcome of BCC formation (Table 5). Additionally, a myeloablative conditioning regimen was significantly protective.
      The incidences per 100,000 PY of BCC for age groups younger than 40, 40–49, 50–59, and 60 years or older were 182, 687, 896, and 1,223, respectively.

       Incidence of melanoma

      Given the limited number of melanoma cases (11 individuals, 14 cases), we did not perform additional analyses for risk factors. In our cohort, incidences of melanoma per 100,000 PY were 91, 196, 128, and 163, in the younger than 40, 40–49, 50–59, and 60 years or older age groups. Within our cohort, the incidence of melanoma is 5 times greater (incidence rate ratio = 5.3, 95% CI = 1.2–24.6) after 3 years of follow-up compared with the period of initial follow-up.
      The incidence of melanoma was also examined relative to rates from the Surveillance Epidemiology and End Results (i.e., SEER) program. Per 100,000 PY, the incidence of melanoma was 115 and 161 in age groups younger than 50 years and 50 years and older with a standardized incidence ratio of 3.3 (95% CI = 1.7–5.9).

      Discussion

      The results from our cohort refine and update assessments of increased incidence rates of SCC, BCC, and melanoma in the HCT population and reflect trends toward reduced-intensity regimens in older patients and peripheral blood and cord blood sources of stem cells. Reflecting advances that allow older patients to be eligible for HCT, the median age at transplantation of our cohort was one of the oldest (51.1 years) in the literature (
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      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ,
      • Majhail N.S.
      • Brazauskas R.
      • Rizzo J.D.
      • Sobecks R.M.
      • Wang Z.
      • Horowitz M.M.
      • et al.
      Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning.
      ,
      • Omland S.H.
      • Gniadecki R.
      • Haedersdal M.
      • Helweg-Larsen J.
      • Omland L.H.
      Skin cancer risk in hematopoietic stem-cell transplant recipients compared with background population and renal transplant recipients: a population-based cohort study.
      ,
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ,
      • Schwartz J.L.
      • Kopecky K.J.
      • Mathes R.W.
      • Leisenring W.M.
      • Friedman D.L.
      • Deeg H.J.
      Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation.
      ,
      • Shimoni A.
      • Shem-Tov N.
      • Chetrit A.
      • Volchek Y.
      • Tallis E.
      • Avigdor A.
      • et al.
      Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.
      ,
      • Yokota A.
      • Ozawa S.
      • Masanori T.
      • Akiyama H.
      • Ohshima K.
      • Kanda Y.
      • et al.
      Secondary solid tumors after allogeneic hematopoietic SCT in Japan.
      ). As a manifestation of therapies, altered biology, or immune status, total SCCs outnumbered BCCs in our cohort in a ratio of 1.5:1, unlike in the general population. Our data support the observation of increased risk of SCCs in association with chronic GVHD and older age. Chronic and acute GVHD were additionally associated with increased risk of BCC. We also identified prior CLL as a risk factor for any skin cancer and found that a myeloablative regimen, TBI, was protective against BCC development.
      Patients with CLL who have not received HCT have an increased incidence of melanoma and nonmelanoma skin cancers and a greater risk of advanced disease, metastases, and recurrence (
      • Brewer J.D.
      • Christenson L.J.
      • Weenig R.H.
      • Weaver A.L.
      Effects of chronic lymphocytic leukemia on the development and progression of malignant melanoma.
      ,
      • Brewer J.D.
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      • Roenigk R.K.
      • Cerhan J.R.
      • Kay N.E.
      • et al.
      Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study.
      ,
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      ,
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      • et al.
      Increased incidence and recurrence rates of nonmelanoma skin cancer in patients with non-Hodgkin lymphoma: a Rochester Epidemiology Project population-based study in Minnesota.
      ,
      • Famenini S.
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      ,
      • Mehrany K.
      • Weenig R.H.
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      High recurrence rates of basal cell carcinoma after Mohs surgery in patients with chronic lymphocytic leukemia.
      ,
      • Mehrany K.
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      ,
      • Velez N.F.
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      ). We identified CLL as an independent additional significant risk factor for increased incidence of all skin cancers, SCCs, and BCCs in our cohort of HCT patients. Patients with CLL before HCT could be at higher risk for secondary malignancy because of a greater likelihood of prolonged intrinsic and iatrogenic immunosuppression before HCT.
      Greater risk of BCCs has been associated with ionizing radiation exposure, particularly in Caucasians (
      • Ehrhardt M.J.
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      • Liu Q.
      • Yasui Y.
      • Krasin M.J.
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      • et al.
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      ,
      • Karagas M.R.
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      • Stukel T.A.
      • Weiss J.E.
      • Baron J.A.
      • et al.
      Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For The Skin Cancer Prevention Study Group.
      ,
      • Lichter M.D.
      • Karagas M.R.
      • Mott L.A.
      • Spencer S.K.
      • Stukel T.A.
      • Greenberg E.R.
      Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group.
      ,
      • Watt T.C.
      • Inskip P.D.
      • Stratton K.
      • Smith S.A.
      • Kry S.F.
      • Sigurdson A.J.
      • et al.
      Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study.
      ). Within the HCT literature, an increased risk of BCCs has been reported in patients receiving TBI, particularly with radiation exposure at a younger age (
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ,
      • Omland S.H.
      • Gniadecki R.
      • Haedersdal M.
      • Helweg-Larsen J.
      • Omland L.H.
      Skin cancer risk in hematopoietic stem-cell transplant recipients compared with background population and renal transplant recipients: a population-based cohort study.
      ,
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ,
      • Schwartz J.L.
      • Kopecky K.J.
      • Mathes R.W.
      • Leisenring W.M.
      • Friedman D.L.
      • Deeg H.J.
      Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation.
      ). In contrast to other single cohort studies and meta-analyses, we found that having received TBI or a myeloablative therapy for conditioning before transplantation was protective against occurrence of BCCs. Additional examination of this phenomenon confirmed a “favorable” cohort of patients who received myeloablative conditioning and did not experience GVHD and were protected from BCCs. Relative to previously published studies, our study has a higher percentage of patients who had reduced-intensity conditioning (
      • Baker K.S.
      • DeFor T.E.
      • Burns L.J.
      • Ramsay N.K.
      • Neglia J.P.
      • Robison L.L.
      New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors.
      ,
      • Curtis R.E.
      • Rowlings P.A.
      • Deeg H.J.
      • Shriner D.A.
      • Socie G.
      • Travis L.B.
      • et al.
      Solid cancers after bone marrow transplantation.
      ,
      • Curtis R.E.
      • Metayer C.
      • Rizzo J.D.
      • Socie G.
      • Sobocinski K.A.
      • Flowers M.E.
      • et al.
      Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.
      ,
      • Gallagher G.
      • Forrest D.L.
      Second solid cancers after allogeneic hematopoietic stem cell transplantation.
      ,
      • Hasegawa W.
      • Pond G.R.
      • Rifkind J.T.
      • Messner H.A.
      • Lau A.
      • Daly A.S.
      • et al.
      Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation.
      ,
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ,
      • Majhail N.S.
      • Brazauskas R.
      • Rizzo J.D.
      • Sobecks R.M.
      • Wang Z.
      • Horowitz M.M.
      • et al.
      Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning.
      ,
      • Omland S.H.
      • Gniadecki R.
      • Haedersdal M.
      • Helweg-Larsen J.
      • Omland L.H.
      Skin cancer risk in hematopoietic stem-cell transplant recipients compared with background population and renal transplant recipients: a population-based cohort study.
      ,
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ,
      • Schwartz J.L.
      • Kopecky K.J.
      • Mathes R.W.
      • Leisenring W.M.
      • Friedman D.L.
      • Deeg H.J.
      Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation.
      ,
      • Yokota A.
      • Ozawa S.
      • Masanori T.
      • Akiyama H.
      • Ohshima K.
      • Kanda Y.
      • et al.
      Secondary solid tumors after allogeneic hematopoietic SCT in Japan.
      ). Additionally, to better define risk of skin malignancy in the adult transplantation population, we excluded HCT recipients younger than 18 years, and our median age at transplantation was 51.1 years, one of the oldest in the literature. Previous studies noted that the increased risk of BCC in patients receiving TBI was most pronounced in younger age groups (
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ,
      • Schwartz J.L.
      • Kopecky K.J.
      • Mathes R.W.
      • Leisenring W.M.
      • Friedman D.L.
      • Deeg H.J.
      Basal cell skin cancer after total-body irradiation and hematopoietic cell transplantation.
      ). Other studies have suggested that there is an interaction between TBI and age at transplantation for BCC risk, with radiation posing a greater risk if given at a younger age (
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ,
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ). In another cohort of patients, researchers found that beyond the age of 30 years, the effect of TBI on BCC development was not significant (
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ). Our data extend the observation that myeloablative therapy including TBI does not hold the same increased risk for BCC development when administered at a later age, including in the adult population.
      Even when other factors were controlled for, the increased risk of BCC was associated with reduced-intensity HCTs, which are now increasingly used (

      D’Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR Summary Slides, 2017, http://www.cibmtr.org (accessed 6 February 2018).

      ). This risk may be due to factors related to the reduced-intensity conditioning regimen itself. One potential contributor is fludarabine, a purine analog that affects DNA synthesis and repair, which was used in more than 90% of our patients who received reduced-intensity conditioning. Patients treated with fludarabine chemotherapy for lymphoma and CLL experience greater rates of secondary solid tumors than acute myelogenous leukemia/myelodysplastic syndrome (
      • Shimoni A.
      • Shem-Tov N.
      • Chetrit A.
      • Volchek Y.
      • Tallis E.
      • Avigdor A.
      • et al.
      Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.
      ). The majority of CLL patients in this study also received reduced-intensity conditioning with fludarabine. Because of concern for collinearity with reduced-intensity conditioning, CLL, and the limited number of events in our cohort, we were not able to examine prior chemotherapy or specific conditioning agents, including fludarabine, in our model.
      Chronic GVHD was an independent significant risk factor for development of cutaneous SCCs. The magnitude of increased risk we observed was consistent with published values (
      • Curtis R.E.
      • Rowlings P.A.
      • Deeg H.J.
      • Shriner D.A.
      • Socie G.
      • Travis L.B.
      • et al.
      Solid cancers after bone marrow transplantation.
      ,
      • Curtis R.E.
      • Metayer C.
      • Rizzo J.D.
      • Socie G.
      • Sobocinski K.A.
      • Flowers M.E.
      • et al.
      Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.
      ,
      • DePry J.L.
      • Vyas R.
      • Lazarus H.M.
      • Caimi P.F.
      • Gerstenblith M.R.
      • Bordeaux J.S.
      Cutaneous malignant neoplasms in hematopoietic cell transplant recipients: a systematic review.
      ,
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ,
      • Majhail N.S.
      • Brazauskas R.
      • Rizzo J.D.
      • Sobecks R.M.
      • Wang Z.
      • Horowitz M.M.
      • et al.
      Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning.
      ,
      • Rambhia P.H.
      • Conic R.Z.
      • Atanaskova-Mesinkovska N.
      • Piliang M.
      • Bergfeld W.F.
      Role of graft-versus-host disease in the development of secondary skin cancers in hematopoietic stem cell transplant recipients: a meta-analysis.
      ,
      • Rizzo J.D.
      • Curtis R.E.
      • Socie G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ,
      • Shimoni A.
      • Shem-Tov N.
      • Chetrit A.
      • Volchek Y.
      • Tallis E.
      • Avigdor A.
      • et al.
      Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.
      ,
      • Yokota A.
      • Ozawa S.
      • Masanori T.
      • Akiyama H.
      • Ohshima K.
      • Kanda Y.
      • et al.
      Secondary solid tumors after allogeneic hematopoietic SCT in Japan.
      ). History of chronic GVHD also increased risk of multiple SCCs in univariable and multivariable analyses. We found chronic GVHD to be a risk factor for BCC development and for multiple BCCs in univariable and multivariable analyses. For BCCs, the patients who experienced acute GVHD were at additional risk.
      The mechanisms by which GVHD might increase nonmelanoma skin cancer risk include alloreactivity and immunodeficiency (
      • Rambhia P.H.
      • Conic R.Z.
      • Atanaskova-Mesinkovska N.
      • Piliang M.
      • Bergfeld W.F.
      Role of graft-versus-host disease in the development of secondary skin cancers in hematopoietic stem cell transplant recipients: a meta-analysis.
      ). Chronic GVHD, as it manifests in the skin, eyes, mucosal surfaces, liver, and lungs, has features of autoimmunity. Patients with autoimmune disorders have an associated increased risk of malignancy, which has been attributed to immune dysregulation (
      • Grivennikov S.I.
      • Greten F.R.
      • Karin M.
      Immunity, inflammation, and cancer.
      ). Inflammation can also be directly pro-carcinogenic. Chronic inflammation and scarring have been associated with higher risk of cancer in certain organ systems, including the gastrointestinal tract, liver, and skin (
      • Balkwill F.
      • Mantovani A.
      Inflammation and cancer: back to Virchow?.
      ,
      • Coussens L.M.
      • Werb Z.
      Inflammation and cancer.
      ,
      • Fujiki H.
      Gist of Dr. Katsusaburo Yamagiwa’s papers entitled “Experimental study on the pathogenesis of epithelial tumors” (I to VI reports).
      ,
      • Hensler S.
      • Mueller M.M.
      Inflammation and skin cancer: old pals telling new stories.
      ,
      • Taniguchi K.
      • Karin M.
      NF-κB, inflammation, immunity and cancer: coming of age.
      ). In particular, cutaneous SCC has been associated with chronic wounds and chronic contact dermatitis (
      • Curtis R.E.
      • Metayer C.
      • Rizzo J.D.
      • Socie G.
      • Sobocinski K.A.
      • Flowers M.E.
      • et al.
      Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.
      ,
      • Demehri S.
      • Cunningham T.J.
      • Hurst E.A.
      • Schaffer A.
      • Sheinbein D.M.
      • Yokoyama W.M.
      Chronic allergic contact dermatitis promotes skin cancer.
      ,
      • Taniguchi K.
      • Karin M.
      NF-κB, inflammation, immunity and cancer: coming of age.
      ). In addition, patients with active GVHD are also more likely to be immunosuppressed as part of its treatment. In a large case-controlled study, prolonged immunosuppression over 24 months for treatment of chronic GVHD with azathioprine-based regimens has been shown to be a risk factor for SCC after HCT (
      • Curtis R.E.
      • Metayer C.
      • Rizzo J.D.
      • Socie G.
      • Sobocinski K.A.
      • Flowers M.E.
      • et al.
      Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.
      ). In solid organ transplantation patients, immunosuppression is associated with an increased risk of nonmelanoma skin cancer, particularly SCC (
      • Garrett G.L.
      • Blanc P.D.
      • Boscardin J.
      • Lloyd A.A.
      • Ahmed R.L.
      • Anthony T.
      • et al.
      Incidence of and risk factors for skin cancer in organ transplant recipients in the United States.
      ).
      The age-adjusted incidences of SCCs, BCCs, and melanoma in our cohort were 1,000, 692, and 141, respectively, per 100,000 PY. Compared with the white population in the SEER program, our standardized incidence rate of melanoma was 3.3 (95% CI = 1.7–5.9). The incidence of melanoma in our cohort is elevated relative to melanoma rates in survivors of non-Hodgkin lymphoma (81/100,000 PY) (
      • Lam C.J.
      • Curtis R.E.
      • Dores G.M.
      • Engels E.A.
      • Caporaso N.E.
      • Polliack A.
      • et al.
      Risk factors for melanoma among survivors of non-Hodgkin lymphoma.
      ) and higher in patients followed up for 3 or more years. This upsurge in melanoma cases after the initial years after HCT suggests a real rise in incidence rather than a result of increased surveillance. When adjusted for age stratum and sex, the incidence of SCCs (incidence rate ratio = 9.8, 95% CI = 7.7–12.3) and BCCs (incidence rate ratio = 2.5, 95% CI = 1.9–3.2) is elevated relative to a population at similar latitude in Olmsted County, Minnesota (
      • Muzic J.G.
      • Schmitt A.R.
      • Wright A.C.
      • Alniemi D.T.
      • Zubair A.S.
      • Olazagasti Lourido J.M.
      • et al.
      Incidence and trends of basal cell carcinoma and cutaneous squamous cell carcinoma: a population-based study in Olmsted County, Minnesota, 2000 to 2010.
      ). The relatively small increase in BCCs may reflect the protective effects of myeloablative therapy. For patients receiving HCT before age 60 years, these estimates represent a rate of SCCs of approximately 1 per 100 per year. This clinically notable increase in observed melanoma and SCCs related to the age-adjusted population should be considered when determining the timing and nature of follow-up.
      Development of SCCs has been associated with inherited or iatrogenic immunodeficiency (
      • Euvrard S.
      • Kanitakis J.
      • Claudy A.
      Skin cancers after organ transplantation.
      ,
      • Przybyszewska J.
      • Zlotogorski A.
      • Ramot Y.
      Re-evaluation of epidermodysplasia verruciformis: reconciling more than 90 years of debate.
      ), and HCT patients are thought to be at risk for secondary malignancies because of the prolonged immune suppression after the procedure, especially in the presence of GVHD. An additional manifestation of an immunosuppressed population is the reversal in the ratio of SCCs to BCCs, which is typically at least 1 to 3 in the general population (
      • Karagas M.R.
      • Greenberg E.R.
      • Spencer S.K.
      • Stukel T.A.
      • Mott L.A.
      Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group.
      ,
      • Madan V.
      • Lear J.T.
      • Szeimies R.M.
      Non-melanoma skin cancer.
      ,
      • Muzic J.G.
      • Schmitt A.R.
      • Wright A.C.
      • Alniemi D.T.
      • Zubair A.S.
      • Olazagasti Lourido J.M.
      • et al.
      Incidence and trends of basal cell carcinoma and cutaneous squamous cell carcinoma: a population-based study in Olmsted County, Minnesota, 2000 to 2010.
      ,
      • Stern R.S.
      The mysteries of geographic variability in nonmelanoma skin cancer incidence.
      ). In our cohort this ratio was reversed, and the number of SCCs exceeded BCCs in each age category, with the greatest increase in SCCs among the youngest patients.
      Limitations to our retrospective cohort study include underreporting of cutaneous carcinomas, which were likely less in patients without posttransplantation complications (e.g., in those without GVHD). Because of the limited number of events, the number of risk factors that could be fitted into a model was restricted. We did not examine specific conditioning regimens, indication for transplantation except CLL, GVHD prophylaxis, or treatments as risk factors. We did not have complete data for body location of skin cancer, skin type, sun exposure history, history of skin cancer before transplantation, or use of voriconazole, an antifungal medication associated with increased photoaging and development of nonmelanoma and melanoma skin cancers (
      • Kuklinski L.F.
      • Li S.
      • Karagas M.R.
      • Weng W.K.
      • Kwong B.Y.
      Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation.
      ). Finally, the latency period for skin cancers can be long, and our median follow-up time was 3 years. For melanoma, the incidence was higher among patients followed up for 3 or more years compared with the first few years of follow-up. Longer follow-up would likely yield more cases of skin cancer.
      HCT patients should be closely monitored for development of secondary skin cancers. This study examined individuals in the stem cell transplant population who developed SCC, BCC, and melanoma as secondary skin cancers and the total numbers of cancers in these patients, as well as associated risk factors. We confirmed GVHD as a risk factor, identified CLL as an additional risk factor, and found that patients who received myeloablative transplants in adulthood had fewer BCCs than their counterparts. Given the nature of reporting secondary malignancies, including skin cancer, to oncologists, the number of skin cancers is likely underreported in this population, and these estimates of risk are conservative. We hope that this information reflecting new trends in the transplantation population will help direct future studies and guidelines regarding the surveillance and counseling of patients.

      Materials and Methods

       Patients

      This study was a two-center, cross-sectional cohort study of adult patients who underwent transplantation with an allogeneic donor from January 1, 1995, until July 1, 2013, at the Dana-Farber Cancer Institute or Beth Israel Deaconess Medical Center. The study excluded patients who received transplantation for primary immunodeficiencies or Fanconi anemia and those who did not survive at least 100 days after transplantation. Follow-up information was obtained until March 25, 2015. Institutional review board approval was obtained through the Dana-Farber Cancer Institute/Harvard Cancer Center. Patients signed written informed consent for collection of long-term outcome data from their transplantations.

       Ascertainment of cases

      Cases of secondary malignancy were identified from the stem cell transplant data repositories at the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. All charts of patients with skin cancer and 100 randomly selected charts of patients without reported skin cancer were reviewed to verify case status by KXL, CAC, and PAW. Cases were considered verified if there was a pathology report or mention of skin malignancy in the physician notes. Counts for SCC, BCC, and melanoma included only cutaneous carcinomas; mucosal lesions were not counted. In situ SCCs were counted toward the total number of SCCs.

       Statistical analysis

      Cumulative incidence estimates of SCC, BCC, and melanoma were calculated by treating death as a competing risk event and censoring on the date of last contact. For the cumulative incidence of each type of skin cancer, time at risk was counted from the time of first transplantation to the time of first skin cancer—SCC, BCC, or melanoma.
      Fine and Gray regression models were used to evaluate potential risk factors for any skin cancer, SCC, and BCC, accounting for death as a competing risk (
      • Fine J.P.
      • Gray R.J.
      A proportional hazards model for the subdistribution of a competing risk.
      ). Based on the literature and clinical experience, the risk factors we examined for their association with outcome included age at HCT, sex, number of HCTs, prior disease with CLL, TBI, conditioning regimen, HCT source, donor relation to patient, presence of acute GVHD, and presence of chronic GVHD. Because of its association with prolonged immune dysfunction before transplantation (
      • Krackhardt A.M.
      • Harig S.
      • Witzens M.
      • Broderick R.
      • Barrett P.
      • Gribben J.G.
      T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy.
      ), we also examined CLL, to our knowledge, a previously unreported independent risk factor. Poisson models with time as an offset variable were used to evaluate total numbers of all skin cancers, SCC, and BCC, as well as prognostic factors for total number of skin cancers. The multivariable models included sex and age, as well as factors that were clinically or statistically significant in stepwise selection modeling. Statistical analyses were performed with SAS software, version 9.4 (SAS Institute Inc., Cary, NC) and STATA, version 12.1 (StataCorp, College Station, TX).

       ORCID

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      The authors would like to acknowledge Gail Howrigan for her assistance in editing the manuscript. This work was conducted with support from the Skin Cancer Foundation (to PAW); Women’s Dermatologic Society (to PAW); Harvard Catalyst , The Harvard Clinical and Translational Science Center ( National Center for Research Resources and the National Center for Advancing Translational Sciences , National Institutes of Health Award UL1 TR001102 ); and financial contributions from Harvard University and its affiliated academic health care centers (to RBD).

      Supplementary Material

      References

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