Risk Factors for the Development of Cutaneous Melanoma after Allogeneic Hematopoietic Cell Transplantation

Abstract Introduction Advances in clinical practice for allogeneic hematopoietic cell transplantation (HCT), a potentially curative treatment most frequently indicated for hematologic malignancies, have led to substantial improvements in prognosis. HCT survivors are at risk for a number of post-transplant complications, including the development of new malignancies. Although cutaneous melanoma risk is known to be increased after HCT, no previous study has comprehensively investigated risk factors in order to identify patients at highest risk for melanoma development. The purpose of this study was to identify risk factors for developing melanoma after allogeneic HCT, specifically evaluating the relationship between melanoma and conditioning regimens as well as factors associated with immunosuppression and immune dysfunction. Methods We conducted a nested case-control study of melanoma within a cohort of 21,590 patients receiving a first allogeneic HCT during 1985-2012, as reported to the Center for International Blood and Marrow Transplant Research. Data on patient and transplant characteristics derived from standardized reports pre-HCT, 100 days and 6 months post-HCT, and annually thereafter or until death. The cohort was restricted to non-Hispanic Caucasians because melanoma is rare among other racial/ethnic groups. Among cases with a melanoma diagnosis reported by transplant centers (N=140), 82 (59%) were confirmed by pathology report review. Four controls were matched to each case on age at HCT (±3 years), sex, primary disease, and time since HCT (without a melanoma diagnosis). Conditional logistic regression was utilized to assess risk factors associated with melanoma development after allogeneic HCT. Multivariable models were adjusted for ambient ultraviolet radiation (UVR), estimated based on residence at the time of HCT, because of the known association between UVR and melanoma. Exploratory analyses were conducted to assess melanoma risk by age and time to melanoma development. Results Among the 140 melanoma cases, the median age at HCT was 46 years (range, 1-73 years), 56% were male, and median time from HCT to melanoma was 4 years (range <1-24 years). Patients were most frequently transplanted for chronic myeloid leukemia (24%) followed by acute myeloid leukemia (18%), acute lymphoblastic leukemia (18%), and non-Hodgkin lymphoma (12%). Multivariable analysis showed that melanoma risk was statistically significantly increased among HCT survivors who received myeloablative conditioning regimens with total body irradiation [odds ratio (OR), 95% confidence interval (95%CI): 1.8, 1.0-3.2] or reduced intensity conditioning regimens containing melphalan (OR, 95%CI: 2.6, 1.1-6.0) or fludarabine (OR, 95%CI: 2.7, 1.0-7.3) compared with those receiving a busulfan-containing myeloablative conditioning regimen; acute graft-versus-host disease (GvHD) with stage 2+ skin involvement (OR, 95%CI: 1.9, 1.2-3.1) versus no acute GvHD; chronic GvHD without skin involvement (OR, 95%CI: 1.9, 1.0-3.6) versus no chronic GvHD; and occurrence of keratinocytic carcinoma (OR, 95%CI: 2.4, 1.2-4.8; median time from keratinocyte carcinoma to melanoma: cases=3.5 years, controls=2.8 years). In exploratory analyses of these factors by patient subgroup, melanoma risks associated with acute GvHD stage 2+ skin involvement were especially increased among individuals of younger age at HCT (age<40 years: OR, 95%CI: 3.2, 1.4-7.4) but not among those of older age at HCT. In the multivariable model, no significant associations were observed with other patient and transplant characteristics, including graft source and ex-vivo or in-vivo T-cell depletion. Conclusion In the largest study to date of melanoma risk factors following allogeneic HCT, we report novel associations with specific conditioning regimens, occurrence of acute and chronic GvHD, and occurrence of keratinocyte carcinoma. Our results emphasize the importance of adherence to current surveillance guidelines for HCT recipients, specifically routine skin examination, heightened skin cancer awareness, and photoprotection recommendations, particularly for those survivors at highest risk. Disclosures No relevant conflicts of interest to declare.

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Long-Term Survival and Late Deaths in 2-Year Survivors of Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Hematologic Disorders.

Blood ◽

10.1182/blood.v114.22.520.520 ◽

2009 ◽

Vol 114 (22) ◽

pp. 520-520

Author(s):

John R. Wingard ◽

Navneet S. Majhail ◽

Ruta Bajorunaite ◽

Zhiwei Wang ◽

Kathleen A. Sobocinski ◽

...

Keyword(s):

Risk Factors ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Term Survival ◽

Long Term Survival ◽

Hematologic Disorders ◽

Allogeneic Hct ◽

Conditioning Regimens ◽

All Diseases

Abstract Abstract 520 Allogeneic hematopoietic-cell transplantation (HCT) is potentially curative therapy for a variety of hematologic disorders. Most deaths after HCT occur within the first 2-years, due to relapse, acute or chronic graft-versus-host disease (GVHD) or regimen-related toxicities. Among allogeneic HCT recipients who had survived in complete remission (CR) for at least 2-years following transplantation, we (1) investigated their long-term survival, (2) evaluated risk factors for late mortality, and (3) compared their long-term survival to that of the general population. Our study cohort consisted of 10,632 patients who received a myeloablative allogeneic HCT through 2003, surviving in CR for 2-years after transplant reported to the CIBMTR. The median followup of our cohort was 9 (range, 2-31) years; 37% of survivors were followed for ≥10-years and 12% for ≥15-years. Diagnoses included acute myeloid leukemia (AML, N=4,017), acute lymphoblastic leukemia (ALL, N=2,895), myelodysplastic syndrome (MDS, N=930), lymphoma (N=619) and severe aplastic anemia (SAA, N=2,171). Donors were HLA-identical siblings (72%), unrelated donors (22%) or other related donors (6%). Patients <20 years of age comprised 45% of our cohort and 17% were >40 years at HCT. Total body irradiation (TBI) based conditioning regimens were given to 60% of patients. Most frequent conditioning regimens were cyclophosphamide + TBI for AML, ALL and lymphoma, busulfan + cyclophosphamide for MDS and cyclophosphamide alone for SAA. Acute grade 2-4 GVHD had occurred in 39% and 43% patients experienced chronic GVHD by 2-years after HCT. Probability of overall survival at 10-years after HCT was 84% (95% CI, 82-85%) for AML, 84% (82-85%) for ALL, 80% (77-83%) for MDS, 84% (81-87%) for lymphoma and 92% (91-93%) for SAA. Disease relapse was the most common cause of death for AML, ALL, MDS, and lymphoma while GVHD was the most common cause of death for SAA. The cumulative incidence of relapse at 10-years post-HCT was 10% (9-11%) for AML, 9% (8-10%) for ALL, 10% (8-12%) for MDS and 6% (4-8%) for lymphoma. Older age at HCT and chronic GVHD were both associated with greater late mortality for all diseases in Cox-regression analyses that accounted for important patient, disease and transplant related factors (Table). Furthermore, some risk factors were associated with increased mortality for specific diseases only, including: more advanced disease (AML, ALL), peripheral blood as graft source (ALL), acute GVHD (MDS and SAA), unrelated donor (lymphoma) and longer time from diagnosis (SAA). Overall survival rates at 10-years post-HCT for patients with and without chronic GVHD were 79% and 89% for AML, 80% and 87% for ALL, 75% and 87% for MDS, 80% and 90% for lymphoma and 87% and 95% for SAA. At 15-years after HCT, the relative mortality of patients who had received HCT for AML, ALL, MDS and SAA remained significantly higher than in age-, race- and gender-matched normal populations. Mortality rates for lymphoma patients were not significantly different than those of the matched general population after 8-years post-HCT. Recipients of myeloablative allogeneic HCT for AML, ALL, MDS, lymphoma and SAA who remain in remission for at least 2-years have favorable subsequent long-term survival. Older age at HCT and chronic GVHD are important risk factors for late deaths in all diseases evaluated. Disclosures: No relevant conflicts of interest to declare.

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Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽

10.1182/blood-2010-08-302109 ◽

2011 ◽

Vol 117 (11) ◽

pp. 3214-3219 ◽

Cited By ~ 320

Author(s):

Mary E. D. Flowers ◽

Yoshihiro Inamoto ◽

Paul A. Carpenter ◽

Stephanie J. Lee ◽

Hans-Peter Kiem ◽

...

Keyword(s):

Risk Factors ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Human Leukocyte ◽

National Institutes Of Health ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

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Risk Factors and Outcomes of Klebsiella Pneumoniae Infection before and after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-125320 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4502-4502

Author(s):

Eleni Gavriilaki ◽

Ioanna Sakellari ◽

Thomas Chatziconstantinou ◽

Despina Mallouri ◽

Ioannis Batsis ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Klebsiella Pneumoniae ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Secondary Prophylaxis ◽

Post Transplant ◽

Before And After

Introduction: Carbapenemase-producing (KPC) Klebsiella pneumoniae (Kp) infections have emerged as a major healthcare concern worldwide. Although infections are recognized as a major contributor of morbidity and mortality before and after allogeneic hematopoietic cell transplantation (HCT), the burden of Kp infections has not been extensively evaluated. Therefore, we aimed to determine risk factors and outcomes of these infections in HCT recipients. Methods: We retrospectively studied consecutive patients with Kp colonization and/or infection before and/or after HCT performed in 2008-2018. Patients were transplanted according to standard operating procedures of our JACIE-accredited center. Colonization was defined as the isolation of the microorganism from any non-sterile body site in the absence of clinical signs or symptoms of disease. Patients with colonization or infection pre-transplant received secondary prophylaxis pre and during transplant. Nurses, visitors and staff were carefully trained on infection control measures such as contact precautions and intensified hygienic measures in patients with pre-transplant isolation. Statistical analysis included the following factors: age, gender, disease phase at transplant (early, intermediate or advanced), donor, pre-transplant and post-transplant Kp infections and colonizations, KPC-Kp, severe acute and extensive chronic GVHD, relapse, treatment-related mortality (TRM) and overall survival (OS). Results: We studied 52 patients with a median age of 42 (range 17-42). Colonizations were detected in 9 patients pre-transplant (17%) and 29 post-transplant (56%); whereas infections in 23 pre- and 28 post-transplant (44% and 54%, respectively). KPC-Kp was isolated in 12 patients (29%). With a median follow-up of 23.5 months (range 1-99), cumulative incidence (CI) of severe acute GVHD was 44.5% and severe chronic GVHD 56.7%. Two-year CI of TRM was 14.3% and was independently predicted by the isolation of KPC-Kp (p=0.040, Figure 1A) and chronic GVHD (p<0.001). Among pre-transplant and transplant factors, acute GVHD was associated only with pre-transplant Kp infections (p=0.049). Pre-transplant infections were also associated with post-transplant infections (p=0.010), despite secondary prophylaxis. Overall survival was associated with disease phase at transplant (p=0.017), post-transplant infections (p=0.034) and acute GVHD (p=0.013). In the multivariate model, only post-transplant Kp infections independently predicted OS (beta=9.042, p=0.008, Figure 1B). Conclusions: Our study highlights the significant impact of Kp infections on TRM and OS of HCT recipients. In our population of patients with Kp colonization and/or infection, the burden of GVHD was high. Acute GVHD was linked with pre-transplant Kp infections, suggesting that disruption of intestinal microbiota may be an underlying predisposing condition. Secondary prophylaxis did not improve rates of post-transplant infections, but allowed the performance of HCT with an acceptable TRM rate. Our data suggest that additional interventions need to be further investigated to address the major problem of Kp infections in HCT. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Nephrotic Syndrome After Allogeneic Hematopoietic Cell Transplantation: Incidence and Outcomes.

Blood ◽

10.1182/blood.v114.22.3324.3324 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3324-3324

Author(s):

Yasser Khaled ◽

Sung Choi ◽

David A Hanauer ◽

Pavan Reddy

Keyword(s):

Nephrotic Syndrome ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Minimal Change ◽

Unrelated Donor ◽

Allogeneic Hct ◽

History Of ◽

Conditioning Regimens ◽

Related Donor ◽

Membranous Gn

Abstract Abstract 3324 Poster Board III-212 The NIH Consensus recognizes nephrotic syndrome (NS) as part of the chronic GVHD symptomatology, but this manifestation is rare and the incidence and outcomes have not been well-defined. To characterize this complication, we conducted an IRB-approved retrospective review of 626 consecutive patients (age > 16 yrs: related donor [RD], n=352; unrelated donor [URD], n=274) who underwent allogeneic hematopoietic cell transplantation (HCT) between October 2000 and December 2007 at the University of Michigan. Data abstraction was facilitated by the use of an electronic medical record search engine (EMERSE) that allowed for efficient identification of key concepts based on a specified set of key words and phrases (e.g. “GVHD,” “proteinuria,” and “nephrotic syndrome”). Conditioning regimens included full intensity (FIC) in 470 patients and reduced intensity (RIC) in 156 patients. Nephrotic range proteinuria was identified in 17 of the patients, which is the largest cohort reported to date following allogeneic HCT. Renal biopsy confirmed the diagnosis in seven of these patients. The median time to onset of NS was 7.3 months (range 1.4 – 40.6 months) following allogeneic HCT. Clinical manifestations included hypoalbuminemia (100%), hypercholesterolemia (82%), edema (76%), renal impairment (65%), and thrombosis (29%). The overall cumulative incidence of NS was 2.9%: 2.4% in FIC and 4.6% in RIC HCT recipients; and 2.3% in RD and 3.7% URD HCT recipients. Of note, in patients who received irradiation-based conditioning regimens, there was an increased cumulative incidence of NS compared to those who did not, 4.8% versus 2.1%, respectively. Diagnostic symptoms of chronic GVHD based upon the NIH Consensus was seen in 65% (n=11) of the patients, all of whom were on immunosuppressive therapy at the time of diagnosis of NS. Prior history of acute GVHD was seen in 65% (n=11) of the patients. Interestingly, history of symptomatic cystitis was seen in 53% (n=9) of the patients, eight of whom had BK virus detected in the urine. The management and treatment for NS was variable. All of the patients received systemic steroids (0.25 mg/kg – 2 mg/kg), with or without mycophenolate mofetil and a calcineurin inhibitor. Additional therapy with rituximab was administered in nine patients. Durable remission with no further recurrence of proteinuria was observed in 47% of the patients (n=8). The median time to response was 4.8 months (range 0.3 – 13.5 months). Recurrence of proteinuria was seen in 29% of the patients (n=5), and primary refractory proteinuria was observed in 23% of the patients (n=4). Overall survival for the cohort was 49.5% at 4 years (confidence interval 24% - 75%) with median follow up of 5.1 years. The median survival from diagnosis of NS was 2.5 years. As of May 2009, eight patients are alive and nine have died. The causes of death include GVHD (n=6), relapse (n=2) and unknown (n=1). NS is a rare but important complication following allogeneic HCT. Early recognition of the clinical presentations and identification of high-risk groups may limit the potential morbidity and mortality associated with NS. Patient MUD/MRD PB vs BM Age at TP Conditioning Regimen DX Proteinuria estimate (g/24h) Gender GVHD Regimen Kidney Biopsy 1 MUD PB 53 FluBuTLI MPD 5.5 F Tacro/MTX Minimal change GN 2 MUD PB 56 FluBuTLI MM 14 M Tacro/MTX Membranous GN 3 MRD PB 57 BuCy MDS 14 M Tacro/MTX Membranous GN 4 MUD PB 55 BAC AML 3.4 M Tacro/MTX N/A 5 MRD PB 30 CVB NHL 3.74 M Tacro/MTX Membranous GN 6 MRD PB 47 BAC AML 10 M Tacro/MTX Membranous GN 7 MUD PB 49 FluBuTLI NHL 6.9 M Tacro/MMF N/A 8 MUD PB 38 BuCy AML 8.7 F Tacro/MMF N/A 9 MUD BM 18 CyATG Aplastic Anemia 4.22 F Tacro/MTX N/A 10 MRD PB 34 BAC AML 5.96 F Tacro/MTX N/A 11 MUD PB 61 FluBuTLI MDS 13.27 M Tacro/MTX N/A 12 MRD PB 26 BuCy CMML 3.58 F Tacro/MMF N/A 13 MRD PB 63 FluBuTLI NHL 4.54 F Tacro/MMF/MTX N/A 14 MUD PB 55 BuCy AML 22.57 M Tacro/MTX/Etanercept Minimal change GN 15 MRD PB 59 CVB-R NHL 3.37 M Tacro/MMF N/A 16 MRD PB 62 FluBuTLI AML 5.47 F Tacro/MMF/MTX Membranous GN 17 MUD PB 46 CyTBI AML 7.96 F Tacro/MTX/Etanercept N/A MUD = matched unrelated donor; MRD = matched related donor; PB = peripheral blood; BM = bone marrow; GN = glomerulonephritis; N/A = non applicable; MTX = methotrexate; MMF = mycophenolate mofetil; FluBuTLI = Fludarabine, Busulfan, Total Lymphoid Irradiation; BuCy = Busulfan, Cytoxan; BAC = Busulfan, Ara-C, Cytoxan; CVB = Cytoxan, Etoposide, BCNU; CyATG = Cytoxan, ATG Disclosures Hanauer: UMERSE, LLC: Consultancy, Patents & Royalties.

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A Retrospective Comparison of Tacrolimus Vs. Cyclosporine for Immunosuppression After Allogeneic Hematopoietic Cell Transplantation with G-CSF-Mobilized Blood Cells

Blood ◽

10.1182/blood.v116.21.2319.2319 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2319-2319

Author(s):

Yoshihiro Inamoto ◽

Mary E.D. Flowers ◽

Frederick R. Appelbaum ◽

Paul A. Carpenter ◽

H. Joachim Deeg ◽

...

Keyword(s):

Cell Transplantation ◽

Blood Cells ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Unrelated Donors ◽

Total Body

Abstract Abstract 2319 Background: Graft-versus-host disease (GVHD) is a common immunologic complication after allogeneic hematopoietic cell transplantation (HCT). Cyclosporine or tacrolimus in combination with other agents represent widely accepted standards of care as immunosuppressive regimens after HCT. Results of open-label randomized prospective phase III studies have indicated that the risk of grades II-IV acute GVHD after bone marrow transplantation with related or unrelated donors is lower with the use of tacrolimus as compared to cyclosporine, in combination with methotrexate. The current study was carried out to compare results with tacrolimus versus cyclosporine after HCT with G-CSF-mobilized blood cells. Patients and methods: The study cohort included 510 consecutive patients who received a first G-CSF-mobilized blood cell graft from related or unrelated donors after high-intensity conditioning for treatment of hematological malignancies between 7/1/2003 and 2009 at our center. All patients received ursodeoxycholic acid from 2 weeks before conditioning until 90 days after HCT to prevent hepatic complications, and all patients received immunosuppression with either tacrolimus or cyclosporine in combination with methotrexate after HCT. Endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, end of treatment for chronic GVHD, overall survival, disease-free survival, recurrent malignancy and nonrelapse mortality. Multivariate Cox regression models were used to evaluate hazard ratios for these endpoints with tacrolimus as compared to cyclosporine. The models were adjusted for patient age, donor type, recipient and donor gender combination, disease type, disease risk category, use of total body irradiation in the conditioning regimen, and year of HCT. The analysis was carried out as of July, 2010. Results: The median age of patients was 47 (range, 1 to 66) years. Diagnosis at HCT was acute myeloid leukemia in 200 (39%) patients, acute lymphoblastic leukemia in 73 (14%), chronic myeloid leukemia in 49 (10%), myelodysplastic syndrome or myeloproliferative disorders in 160 (31%) and other lymphoid malignancies in 28 (5%). Total body irradiation was used for conditioning in 168 (33%) patients. Of the 510 patients, 277 (54%) had HLA-matched related donors, 203 (40%) had HLA-matched unrelated donors, and 30 (6%) had HLA-mismatched related or unrelated donors. Outcomes according to immunosuppression with tacrolimus or cyclosporine are shown in Table 1. Multivariate analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested (Table 2), although the results showed a trend suggesting that the risk of non-relapse mortality might be lower with tacrolimus as compared to cyclosporine. Conclusion: In this retrospective analysis, tacrolimus offered no statistically significant advantage over cyclosporine for preventing grades II-IV acute GVHD after HCT with G-CSF-mobilized blood cells, and results for other outcomes also showed no statistically significant differences. Although our data support the hypothesis that either regimen could be an acceptable standard of care for immunosuppression, the number of patients analyzed in this study is not sufficient to completely exclude clinically meaningful differences in outcomes with the two regimens. Disclosures: Off Label Use: Tacrolimus and cyclosporine for immunosuppression after allogeneic hematopoietic cell transplantation.

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Association of Graft-Versus-Host Disease and Immunosuppressive Treatment with Risks of Recurrent Malignancy and Mortality After Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v116.21.218.218 ◽

2010 ◽

Vol 116 (21) ◽

pp. 218-218

Author(s):

Yoshihiro Inamoto ◽

Mary E.D. Flowers ◽

Stephanie J. Lee ◽

Paul A. Carpenter ◽

Edus H. Warren ◽

...

Keyword(s):

Myeloid Leukemia ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Immunosuppressive Treatment ◽

Time Varying ◽

Graft Versus Host ◽

Recurrent Malignancy ◽

Time Varying Covariates

Abstract Abstract 218 Background: Graft-versus-leukemia (GVL) effects are closely associated with graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). In a reexamination of GVL effects, we evaluated acute and chronic GVHD defined by NIH consensus criteria and immunosuppressive treatment (IST) as risk factors for recurrent malignancy after HCT. Patients and methods: We analyzed a cohort of 2656 consecutive patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) who received allogeneic HCT after high-intensity conditioning between 1992 and 2005. The onset of NIH chronic GVHD was ascertained by retrospective chart review using follow-up information obtained by our Long Term Follow Up clinic. Rates and hazards of recurrent malignancy and mortality were analyzed according to GVHD and IST as time-varying covariates. To illustrate the effect of time-varying covariates, we calculated the rate of recurrent malignancy per patient-year according to prior GVHD within sequential 90-day intervals after HCT. Cox proportional hazard models were adjusted for potential factors affecting outcomes. Results: The median patient age at HCT was 39 years (range, 0 to 71 years). Donors were HLA-identical relatives (n=1088), HLA-matched unrelated volunteers (n=912), HLA-mismatched relatives (n=243), and HLA-mismatched unrelated volunteers (n=413). GVHD prophylaxis was mostly cyclosporine and methotrexate (n=1885, 71%). Relapse rates per patient-year declined from 3 months until at least 36 months after HCT for patients with prior acute GVHD or NIH chronic GVHD (Figure). Patients without prior GVHD showed a much less pronounced decline between 12 and 30 months after HCT. Adjusted Cox analysis showed that acute GVHD and NIH chronic GVHD were associated with statistically similar reductions in risk of late recurrent malignancy beyond 18 months after HCT, with no incremental effect of chronic GVHD in patients with prior acute GVHD (Table 1). GVL effects were demonstrable in patients with CML or AML but not in those with ALL or MDS/MPN. Discontinuation of IST was associated with a decreased risk of recurrent malignancy among patients without prior GVHD but not among those with prior GVHD (Table 2). Grades III–IV acute GVHD and NIH chronic GVHD with prior acute GVHD were associated with a statistically significant increase in risk of early mortality between 3 and 18 months, but grade II acute GVHD and NIH chronic GVHD without prior acute GVHD were not. Conclusion: Both acute and NIH chronic GVHD are associated with potent GVL effects, but NIH chronic GVHD does not confer any incremental benefit after acute GVHD. Withdrawal of IST was associated with a reduction in risk of recurrent malignancy in patients without prior GVHD. Analyses of GVL effects should account for time from HCT, the history of GVHD, type of malignancy and IST. Immune manipulations such as prophylactic donor lymphocyte infusion or early withdrawal of IST may represent reasonable approaches to decrease the risk of recurrent malignancy in patients without prior GVHD, if the risk of GVHD could be minimized. Disclosures: No relevant conflicts of interest to declare.

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Incidence, Risk Factors and Outcomes of Sclerotic Chronic Graft-Versus-Host Disease (GVHD) Phenotype After Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v118.21.322.322 ◽

2011 ◽

Vol 118 (21) ◽

pp. 322-322

Author(s):

Yoshihiro Inamoto ◽

Barry Storer ◽

Effie W. Petersdorf ◽

Paul A. Carpenter ◽

Stephanie J. Lee ◽

...

Keyword(s):

Risk Factors ◽

Malignant Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Factors Associated ◽

Increased Risk ◽

Unrelated Donors ◽

Recurrent Malignancy

Abstract Abstract 322 Background: A sclerotic GVHD phenotype represents one of the most severe late complications of allogeneic hematopoietic cell transplantation (HCT), sharing some clinical similarities with systemic sclerosis. The incidence and risk factors of sclerotic chronic GVHD and its association with major transplant outcomes are not well established. Patients and methods: We analyzed 986 consecutive patients who received systemic therapy for chronic GVHD after a first allogeneic HCT performed between 2000 – 2008 in Seattle for malignant and nonmalignant diseases. Chronic GVHD was diagnosed by the NIH consensus criteria. Sclerotic GVHD was defined when manifestations of cutaneous sclerosis, fasciitis or joint contracture were first documented in the medical record. Multivariate Cox regression analyses accounted for patient and donor age per decade, donor type, HLA matching, ABO matching, diagnosis and disease risk, stem cell source, patient gender, intensity of conditioning regimen, use of total body irradiation (TBI) or rabbit antithymocyte globulin in the conditioning regimen, and GVHD prophylaxis. Risk factors considered at the onset of chronic GVHD were prior acute GVHD, prior severe (stage 3 and 4) skin acute GVHD, eosinophilia, thrombocytopenia, progressive onset, extent of skin involvement, and bronchiolitis obliterans. Overall mortality (OM), nonrelapse mortality (NRM; malignant disease only) and recurrent malignancy (malignant disease only) were compared between patients with and without sclerotic features using time-dependent Cox models. Results: Of the 986 patients, median age was 47 (0–78) years, 776 (79%) were Caucasian, 950 (96%) had malignant diseases, 407 (41%) had HLA-matched related donors, 356 (36%) had HLA-matched unrelated donors, and 223 (23%) had HLA-mismatched related or unrelated donors. The median time from HCT to chronic GVHD was 5.3 (2.5–46) months; 73 patients (7%) presented with sclerotic features at initial diagnosis and 142 patients (14%) developed sclerosis after the onset of chronic GVHD. The cumulative incidence of sclerotic GVHD was 20% (95%CI, 18–23) at 36 months after onset of chronic GVHD, and median onset of sclerosis was 7.9 months after onset of chronic GVHD (Figure). In multivariate models (Table), factors associated with an increased risk of sclerotic GVHD were mobilized blood cell graft, female recipient, TBI >450cGy, and prior severe skin acute GVHD. Factors associated with a decreased risk of sclerotic GVHD were HLA-mismatched donors and ABO major mismatch. Risks of OM, NRM and recurrent malignancy in patients with sclerotic features did not differ statistically from patients without sclerotic features (hazard ratio (HR) 0.97, 95% CI 0.7–1.3, p=0.83; HR 0.94, 95% CI 0.6–1.4, p=0.78; HR 0.73, 95% CI 0.5–1.2, p=0.17, respectively). Conclusion: Sclerotic GVHD is an underestimated phenotype of chronic GVHD. Female predominance in sclerotic chronic GVHD is similar to that in systemic sclerosis. Risks of major transplant outcomes do not differ statistically between patients with and without sclerotic chronic GVHD phenotype. Mechanisms that account for the decreased risk of sclerosis associated with HLA and ABO mismatching and for the increased risk associated with prior severe skin acute GVHD warrant future investigation. Disclosures: No relevant conflicts of interest to declare.

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Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.1460 ◽

2010 ◽

Vol 28 (17) ◽

pp. 2859-2867 ◽

Cited By ~ 135

Author(s):

Boglarka Gyurkocza ◽

Rainer Storb ◽

Barry E. Storer ◽

Thomas R. Chauncey ◽

Thoralf Lange ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Allogeneic Hct ◽

Unrelated Donors ◽

Acute Myeloid

PurposeAllogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients.Patients and MethodsTwo hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression.ResultsWith a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk.ConclusionAllogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML.

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Nonmelanoma Skin and Mucosal Cancers After Hematopoietic Cell Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.7052 ◽

2006 ◽

Vol 24 (7) ◽

pp. 1119-1126 ◽

Cited By ~ 116

Author(s):

Wendy Leisenring ◽

Debra L. Friedman ◽

Mary E.D. Flowers ◽

Jeffrey L. Schwartz ◽

H. Joachim Deeg

Keyword(s):

Risk Factors ◽

Cell Carcinoma ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Significant Risk ◽

Hematopoietic Cell ◽

Allogeneic Hct ◽

Increased Risk ◽

The Impact

Purpose To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT). Patients and Methods The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days. Results Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC (P = .003), most strongly among patients younger than 18 years old at HCT (P = .02, interaction). Light-skinned patients had an increased risk of BCC (P = .01). Acute graft-versus-host disease (GVHD) increased the risk of SCC (P = .02), whereas chronic GVHD increased the risk of both BCC (P = .01) and SCC (P < .001). Conclusion This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.

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Incidence and Risk Factors of De Novo Skin Cancer in a Contemporary Cohort of Hematopoietic Cell Transplantation Survivors

Blood ◽

10.1182/blood-2019-124993 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2011-2011

Author(s):

Jennifer Berano Teh ◽

Farah Abdulla ◽

Kelly Peng ◽

Liezl Atencio ◽

Alicia Gonzales ◽

...

Keyword(s):

Risk Factors ◽

Skin Cancer ◽

Cell Carcinoma ◽

Cumulative Incidence ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Chronic Gvhd ◽

Allogeneic Hct ◽

Skin Cancers

Introduction: Hematopoietic cell transplantation (HCT)-related factors, such as total body irradiation (TBI) used for conditioning, graft-versus-host disease (GvHD), and prolonged exposure to calcineurin-inhibitors, can result in high risk for subsequent skin cancers in long-term survivors. Previous studies examining skin cancers after HCT have largely focused on patients transplanted in earlier eras (<2000), which may not be as informative for providers caring for survivors treated with contemporary conditioning (e.g. less myeloablative) approaches or GvHD treatment regimens, and do not account for newer stem cell sources (e.g. cord, haploidentical) with their evolving immunosuppression risk. Additionally, due to registry reporting, past studies have largely focused on melanoma, which underestimates the burden due to more common skin cancers such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The current study describes the incidence and risk factors of melanoma and non-melanoma skin cancer in a large contemporary cohort of HCT survivors. Methods: 2338 consecutive patients who underwent a first HCT between 2005 and 2014 at City of Hope (COH) and survived ≥1 year, were included in the study. Patients with a history of skin cancer prior to HCT were excluded from the cohort. All skin cancers were validated using pathology reports, and physician notes (20%) whenever the former was not available. Skin cancers included SCC, BCC, melanoma, atypical fibroxanthoma, and merkel cell carcinoma. Patients were followed from HCT to death, second HCT, last known alive date, or December 31, 2018, whichever occurred first. Cumulative incidence of skin cancer was estimated taking into consideration competing risk of death. Fine-Gray sub-distributional hazard regression was used to calculate hazard ratio (HR) estimates, adjusted for relevant covariates. Results: Median age at HCT was 51.8y (range: 0.7-78.7); 57.6% were male; 56.5% were non-Hispanic white (NHW); 4.4% had a history of Pre-HCT cancer (antecedent to primary diagnosis); 47.7% underwent allogeneic HCT; 22.0% received myeloablative TBI (≥1200 cGy)-based conditioning. Among survivors of allogeneic HCT, 57.2% developed ≥moderate chronic GvHD (84% involving the skin); the most common immunosuppressive agents used for the management of ≥moderate chronic GvHD were tacrolimus (84.6%), followed by sirolimus (76.5%), and cyclosporine (28.4%). Burden of skin cancer over time: 179 survivors developed a total of 450 skin cancers after HCT; median time from HCT to first skin cancer was 2.8 years (range: 0.2-13.6). SCC was the most common subtype (59.1%), followed by BCC (31.3%), melanoma (5.1%), and other (4.4%); 43.4% of patients with SCC had invasive or high grade disease at presentation. The cumulative incidence of de novo skin cancer after HCT was 8.3% at 5 years, and 14.8% at 10 years (figure). Eighty-nine patients with skin cancer had a second skin cancer at a median of 0.5 years (range: 0.2 to 7.2) from the first; 55.1% were of a different histology. The cumulative incidence of a second skin cancer was 41.9% at 5-years (figure). Risk factors: Multivariate analysis revealed male sex (HR=1.7, p=0.0008), NHW race/ethnicity (HR=9.0, p<0.0001), older age HCT (≥50years at HCT, HR=2.4, p<0.0001), allogeneic HCT (HR=2.2, p<0.0001), and a history non-skin cancer prior to HCT (HR=1.7, p=0.04) to be significant and independent predictors of post-HCT skin cancer risk. Among allogeneic HCT patients, neither severity of chronic GvHD, location (e.g. skin), nor duration of post-HCT immunosuppression were associated with risk of de novo skin cancer, irrespective of skin cancer histology. Conclusions: This study confirms the higher risk of skin cancer by sex, race/ethnicity, and age at HCT, and highlights the greater than two-fold risk of skin cancer among allogeneic HCT survivors compared to autologous patients, a finding that is not entirely explained by GvHD and its treatment. Further, we identified a previously unreported association between pre-HCT (non-skin) cancer and post-HCT cancer risk, and describe the very high burden of multiple histologically distinct skin cancers over time. Taken together, these data set form the basis for implementation of updated risk-based screening and prevention practices in survivors at highest risk of skin cancer after HCT. Disclosures Abdulla: Johnson & Johnson: Research Funding; Elorac: Research Funding; Trillium: Research Funding; Stemline: Research Funding; MiRagen: Research Funding; Bionz: Research Funding; Mallinckrodt: Research Funding; Mallinckrodt: Consultancy; Mallinckrodt: Speakers Bureau. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

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