Cumulative Incidence Of Second Primary Malignancies Research Articles

Incidence of Second Primary Malignancies in Medicare-Insured Patients in the US with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

Background As therapeutic advances have increased life expectancy for patients (pts) with relapsed/refractory (RR) multiple myeloma (MM), second primary malignancies (SPMs) have become an increasingly important safety consideration. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation, and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased risk of SPM. Pts who are triple-class exposed (TCE), defined as prior exposure to an IMiD, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb), represent an increasingly large subgroup of RRMM pts. The objective of this study was to describe the incidence and characteristics of SPMs in Medicare-insured pts with TCE RRMM initiating a new line of therapy (LOT). Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient Dx 30-365 days apart OR ≥1 inpatient Dx AND 6 months of continuous eligibility prior to initial Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE (≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb) were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse (TCE pts were assumed to have RRMM based on exposure). The first LOT after TCE was defined as the index LOT and the associated date of initiation was defined as the index date. Pts with SPMs prior to the index date were excluded. SPMs were identified based on having ≥2 outpatient Dx of SPM (of the same cancer type) 30-365 days apart OR ≥1 inpatient Dx of SPM. Dx of SPM included Dx of invasive malignancies or myelodysplastic syndromes (MDS), excluding MM, Waldenström macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a Dx of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each pt. Cumulative incidence of SPM (with death as a competing risk) was also calculated. For pts who experienced SPM, overall survival (OS) and measures of healthcare resource utilization (HRU) and costs (in 2021 USD, on a per patient per month [PPPM] basis) were calculated. Results A total of 3,088 TCE RRMM pts were identified, of whom 989 had no evidence of SPM prior to the index date (Table). These 989 pts had a mean age of 75.2 years, a mean of 2.9 prior LOTs and a mean of 3.1 years since MM Dx. Over a median follow-up of 7.1 months, 166 pts (19.3 per 100 PY) experienced an SPM, including 93 (10.8 per 100 PY) with a solid tumor and 73 (8.5 per 100 PY) with a hematologic malignancy. The latter included 27 (3.1 per 100 PY) with acute myeloid leukemia (AML) and 18 (2.1 per 100 PY) with MDS. The cumulative incidence of SPM (95% confidence interval [CI]) at 12, 24, and 36 months was 15.2% (12.8-17.9%), 19.7% (16.8-22.8%), and 23.8% (20.2-27.6%), respectively (Figure). Median (95% CI) OS from SPM Dx was 7.9 months (5.4-10.9). Kaplan-Meier estimated probability of survival (95% CI) at 12, 24, and 36 months following SPM Dx was 40.3% (31.6-48.9%), 27.6% (18.6-37.4%), and 9.5% (2.1-23.8%), respectively. Mean (95% CI) total costs after SPM were $22,514 ($19,105-$26,404) PPPM. Conclusions The incidence of SPM in Medicare-insured TCE RRMM pts is high. Many SPMs in these pts, such as AML, are life-threatening and may interfere with or prevent MM treatment. Pts with SPMs have poor survival and high HRU and costs. With increasing OS for RRMM pts due to therapeutic advancements, there is a need for effective treatments that are not associated with increased risk of SPMs.

Correlation between lymphoma and second primary malignant tumor.

Although studies have investigated the risk of second primary malignancies (SPMs) associated with lymphoma of various sites, limited studies have investigated risk of lymphoma with different SPMs and risk factors related to different SPMs. We conducted a retrospective cohort study to evaluate the cumulative incidence and risk factors of different secondary SPMs in patients previously diagnosed as lymphoma, and to compare the survival rates of SPMs and primary malignant tumors. Retrospective analysis was performed on data obtained from Surveillance, Epidemiology, and End Results database. Patients with an initial primary malignancy diagnosis of lymphoma between 2000 and 2019 were included in the study. The statistical analysis was conducted from March 2022 to January 2023. The development of an SPM defined as any type of malignant tumor 292,210 patients remained in final cohort, including 35,220 patients with secondary primary malignant tumor. The cumulative incidence of SPMs during 20 years of follow-up is 1.95% in combined respiratory system, 0.14% in central nervous system, is 0.82% hepatobiliary pancreatic system, is 1.31% in urinary system, is 1.92% digestive tract. Multivariate competitive risk model analysis showed that Different characteristics of lymphoma patients were associated with secondary different types of SPMS. The risk of secondary SPMs in lymphoma patients after radiotherapy and chemotherapy varies with the change of diagnosis time, diagnosis age and incubation period. Propensity score matching and Kaplan-Meier analysis showed that the survival rate of secondary tumor was significantly lower than that of matched primary malignant tumor. This study reminds us to consider the possibility of SPMs in the initial treatment of lymphoma patients, and develop a follow-up plan according to the characteristics of patients to reduce the risk of SPMs. Occurring more than 6 months after the diagnosis of lymphoma. The cumulative incidence of SPMs was estimated by Fine-Gray competing risk regression. Poisson regression was used to evaluate the therapeutic factors associated risk for SPMs in patients undergoing radiotherapy or chemotherapy. The Kaplan-Meier method was used to assess the survival outcomes of patients with SPMs.

Association between radiotherapy and risk of second primary malignancies in patients with resectable lung cancer: a population-based study

BackgroundThe most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer.MethodsWe screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis.ResultsAmong the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer.ConclusionAfter receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.

Incidence of Second Primary Malignancies in Lymphoma Survivors: A Prospective Cohort Study in the Modern Treatment Era

Background: Improved treatments for Hodgkin and non-Hodgkin lymphoma has resulted in a growing population of long-term survivors, many of whom are cured. A focus of long-term care of these patients (pts) has in turn moved toward optimizing survivorship, including identification and management of second primary malignancies (SPM). In this prospective cohort study initiated in the modern treatment era, we describe the incidence and factors associated with risk of SPM. Methods: Pts were identified from the Molecular Epidemiology Resource (MER) cohort of the University of Iowa/Mayo Clinic Lymphoma SPORE, which offers enrollment to all consecutive patients with newly diagnosed lymphoma aged 18+ years. Clinical and treatment data are abstracted from medical records using a standard protocol. Pts are prospectively contacted regularly to assess disease status and development of SPM. All reported SPM through 2021 were validated against medical records. For this analysis, SPM were defined as any cancer other than lymphoma diagnosed >90 days from lymphoma diagnosis. Cumulative incidence of SPM and 95% confidence intervals (CI) were calculated with death as a competing risk, and associations with patient and treatment characteristics were estimated with Cox models. To evaluate the incidence of SPM in the MER against expected population rates, we calculated the standardized incidence ratio (SIR) using the Iowa component of the Surveillance, Epidemiology and End Results (SEER) database, accounting for age, sex, calendar year and person-time. Results: Of 6929 pts enrolled into the MER from 9/2002 - 6/2015, 59% were male; median age at enrollment was 61 yrs (IQR: 51-70). 763 pts developed SPM through 2021, including 37 acute myeloid leukemia and myelodysplastic syndrome (AML/MDS), 341 non-melanoma skin, 133 genitourinary (GU), 57 gastrointestinal (GI), 49 breast, and 52 lung cancers. The 10-year cumulative incidence of SPM was 12% (CI: 11-13), and 31% (CI: 30-32) for the competing risk of death (Fig 1A). Skin cancers had highest 10-year cumulative incidence of 6.6% (CI: 5.9 -7.4), followed by GU 2.4% (CI: 2.0-2.9), breast 1.0% (CI: 0.8-1.4), lung 1.0% (CI: 0.8-1.3), GI 0.9% (CI: 0.7-1.3), and AML/MDS 0.7% (CI: 0.5-1.0)(Fig 1B). The MER cohort had a lower than expected rate of any SPM (excluding non-melanoma skin cancer, which SEER does not collect) compared to the general Iowa population (SIR=0.61, CI: 0.5-0.7), as well as lower than expected rates of GU (SIR=0.60, CI: 0.5-0.7), GI (SIR=0.45, CI: 0.3-0.6), breast (SIR=0.69, CI: 0.5-0.9), and lung (SIR=0.47, CI: 0.4-0.6) cancer. In contrast, the MER showed a 5-fold higher than expected rate of AML/MDS (SIR=5.2, CI: 3.6-7.1). Risk of SPM increased with age: compared to pts age 18-40 years, those 41-60 yrs had a 3-fold (CI: 1.9-4.5) and >60 yrs had a 6.3-fold (CI: 4.2-9.6) elevated risk of SPM. Females were at lower risk of SPM (HR=0.7, CI: 0.6-0.9). After adjustment for age and sex, there was no association with lymphoma subtype. For initial treatment class (adjusted for age, sex and subtype), risk of a SPM was associated with use of a systemic chemotherapy (HR=1.3, CI: 1.1-1.6); was inversely associated with initial observation (HR=0.8, CI: 0.6-0.9); and was not associated with use of local radiation (HR=0.9, CI: 0.7-1.2), an anthracycline (HR=1.0, CI: 0.8-1.3), alkylator (HR=1.2, CI: 1.0-1.4) or R-monotherapy (HR=1.0, CI: 0.7-1.3). In joint modeling of initial treatment adjusted for age, sex and subtype, compared to pts not receiving systemic chemotherapy, pts with systemic therapy including an alkylator but no anthracycline (HR=1.4, CI: 1.1-1.7) or systemic therapy without an alkylator or anthracycline (HR=1.3, CI:1.1-1.7) had increased risks of SPM, while those receiving both an alkylator/anthracycline were not at significantly elevated risk (HR=1.2, CI: 0.9-1.5). Conclusions: In the rituximab era, the cumulative incidence of any SPM increased over time and at 10 years after diagnosis was 12%, with about half of these due to non-melanoma skin cancers. While the cumulative incidence of AML/MDS at 10 years was low (0.7%), this represented a 5-fold excess risk over expected population rates, consistent with prior eras. In contrast, solid tumors were below expected population rates. Older age, male sex and systemic chemotherapy were associated with higher risk of SPM. Prevention and management of SPM continues to remain an important need for lymphoma survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of Second Primary Malignancies (SPMs) in Patients in the US with Triple-Class-Exposed (TCE) Relapsed or Refractory Multiple Myeloma (RRMM)

Background Therapeutic advances have increased life expectancy for patients with RRMM. As survival has improved, SPMs have become an increasingly important safety consideration for RRMM patients. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation (ASCT), and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased SPM risk. Patients who are TCE (exposure to ≥1 IMiD, ≥1 proteasome inhibitor [PI], and ≥1 anti-CD38 monoclonal antibody [mAb]) represent an increasingly large subgroup of RRMM patients. The objective of this study was to describe the incidence of SPMs in patients with TCE RRMM. These data may inform development and selection of novel treatments for these patients. Methods Data were from two large US health-insurance claims databases: the Optum Clinformatics® Data Mart and the IQVIA PharMetrics® Plus Health Insurance Claims database. TCE RRMM patients were selected if they had ≥1 confirmed diagnosis of multiple myeloma (MM) on or after December 1, 2015 (date of approval by the US Food and Drug Administration of 1st anti-CD38 mAb for RRMM) and evidence of being TCE. The first line of therapy (LOT) after becoming TCE was identified ("index LOT") and the date of initiation of this LOT was defined as the "index date". Patients who experienced SPMs prior to the index date were excluded. SPMs were identified based on having at least one inpatient or two outpatient diagnoses (of the same cancer type) of invasive malignancies or myelodysplastic syndromes (MDS) other than MM, Waldenstrom macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a diagnosis of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each patient. Cumulative incidence of SPM with death as competing risk was calculated for patients in Optum database (data on mortality was unavailable in the PharMetrics database). Results A total of 1,110 TCE RRMM patients were identified in the two databases, of whom 726 had no evidence of SPM prior the index date (Table). These 726 patients had a mean age of 66.6 y; 45% were female, with a mean of 3 prior LOTs and 3.2 years since diagnosis. Over a mean (SD) follow-up of 11.7 (10.4) months, 96 patients (14.8 per 100 PY) experienced a new SPM, including 47 (7.2 per 100 PY) with solid tumor and 51 (7.9 per 100 PY) with a hematologic malignancy. The latter included 22 (3.4 per 100 PY) with acute myeloid leukemia (AML) and 17 (2.6 per 100 PY) with myelodysplastic syndrome. Among patients in the Optum database (N=416), the cumulative incidence of SPM (95%CI) was estimated to be 10.3% (7.4% , 13.7%), 14.9% (10.8% , 19.6%), and 20.1% (13.9% , 27.2%) at 12, 24, and 36 months, respectively (Figure). Conclusions The incidence of SPM in TCE RRMM patients is clinically significant. Many SPMs in these patients are potentially serious malignancies, including AML and MDS. There is a need for effective treatments for TCE RRMM that are not associated with increased risks of SPMs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancy Risk in Multiple Myeloma from 1975 to 2018.

Simple SummaryMultiple myeloma (MM) is the second most common hematological malignancy with median age of diagnosis between 65–70 years. Since the introduction of multiple novel agents in MM management, survival times of MM patients continue to improve. Longer survival in patients with MM may be associated with increased risks of developing second primary malignancies (SPM). In this study, we investigated the risk factors associated with SPM and survival among MM survivors from 1975 to 2018. Age, race, and sex were important factors for the risk of SPM. Moreover, after SPM development, MM patients had a statistically significant 1.4-fold increased risk of death than MM patients without SPM. Site- and time-specific surveillance strategies surveillance strategies should be recommended to monitor SPM in high-risk MM patients.As the survival times for multiple myeloma (MM) patients continue to extend, the risk of a second primary malignancy (SPM) among MM survivors has become a topic of increasing concern within the medical community. The Surveillance, Epidemiology, and End Results (SEER) 9 Registry Database was used to evaluate the risk and survival of SPM among MM survivors from 1975 to 2018. The standardized incidence ratio (SIR), absolute excess risk (AER), and cumulative incidence (CMI) of SPM for MM risk were calculated. Survival and the CMI were estimated by using hazard ratios (HRs). Subgroup analyses were performed according to race, sex, age, time of myeloma diagnosis, and the SPM site. A total of 43,825 cases were recorded with the initial diagnosis of MM from 1975 to 2018. A total of 3101 (7.1%) patients developed 3407 SPMs. Solid tumors were decreased in patients with MM (SIR = 0.93; 95% CI = 0.90–0.97) compared to the general population, whereas the risk of hematological malignancy was increased (SIR = 1.90; 95% CI = 1.72–2.10). Taking death as a competing event, the CMI of SPM in the whole population was 7.38% at 10 years (6.11% solid and 1.27% hematologic). Factors associated with SPM occurrence were age, sex, race, and time of MM diagnosis. The survival of SPM patients from MM diagnosis was longer than that of patients without SPM (HR = 0.67, 95% CI = 0.58–0.63). The median survival time was 17 months from SPM diagnosis and 34 months from MM diagnosis (HR = 1.4, 95% CI = 1.35–1.46). Age, race, and sex were important factors for the risk of SPM. Site- and time-specific surveillance strategies should be recommended to monitor SPM in high-risk MM patients.

Impact of second primary malignancy post-autologous hematopoietic stem cell transplantation on outcomes of multiple myeloma: A CIBMTR analysis.

8057 Background: Following autologous hematopoietic stem cell transplant (auto HCT), maintenance therapies improve survival, reduce relapse risk in multiple myeloma (MM), and are the de facto standard-of-care. However, clinical trials have shown an increased risk of second primary malignancies (SPM) with maintenance therapy, including second hematological malignancies (SHM). We examined data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to evaluate the impact of SPM on progression-free (PFS) and overall survival (OS) and the utilization of allogeneic HCT in patients with therapy-related myeloid neoplasms (t-MN). Methods: Adult patients (pts) with MM who underwent first auto HCT in the United States with a melphalan conditioning regimen from 2011-2018 and subsequently received maintenance therapy were included (N=3948). The primary endpoint of interest was the impact of SPM and SHM on OS. Multivariate analytic (MVA) modelling was applied, accounting for competing risks while integrating significant covariates to determine the impact of SPM on PFS and OS. Finally, we studied the utilization and survival following allogeneic HCT for SHM. Results: Baseline characteristics were similar between the two groups. Maintenance regimens used were lenalidomide (2836, 72%), bortezomib (370,9 %) or lenalidomide + bortezomib (372, 9%) based combinations. At a median follow up of 37 months, 175 (5%) pts developed SPM, including 112 (64%) solid 36 (21%) myeloid, and 27 (15%) lymphoid cancers. In MVA, the development of SPM and SHM was associated with an inferior PFS (HR 2.62, P<0.001 and HR 5.01, P<0.001, respectively) and OS (HR 3.85, P<0.001 and 8.13, P<0.001, respectively). The two commonest causes of death were MM (42%) and SPM (30%) for those developing SPM. Similarly, MM (53%) and SHM (18%) were the two commonest causes of death for those developing SHM. Nine (14%,5 t-MDS and 4 t-AML) of 63 patients with SHM underwent an allogeneic HCT. Patients undergoing allogeneic HCT were more likely to have Karnofsky score ≥90 (100% vs. 50%, P=0.02) compared to those who did not. One year survival from allo SCT was 66.7% (CI 34.6-92%). Conclusions: The three-year cumulative incidence of SPM was 3.3 (2.6-4)% in this large contemporaneous CIBMTR cohort. Disease relapse remains the primary cause of death in MM patients who develop SPM or SHM. Given the median OS for MM is now > 10 years, longer follow-up is needed to assess the SPM and SHM risks with maintenance therapy post-auto HCT.

Risk Prediction of Second Primary Malignancies in Primary Early-Stage Ovarian Cancer Survivors: A SEER-Based National Population-Based Cohort Study.

PurposeThis study aimed to characterize the clinical features of early-stage ovarian cancer (OC) survivors with second primary malignancies (SPMs) and provided a prediction tool for individualized risk of developing SPMs.MethodsData were obtained from the Surveillance, Epidemiology and End Results (SEER) database during 1998–2013. Considering non-SPM death as a competing event, the Fine and Gray model and the corresponding nomogram were used to identify the risk factors for SPMs and predict the SPM probabilities after the initial OC diagnosis. The decision curve analysis (DCA) was performed to evaluate the clinical utility of our proposed model.ResultsA total of 14,314 qualified patients were enrolled. The diagnosis rate and the cumulative incidence of SPMs were 7.9% and 13.6% [95% confidence interval (CI) = 13.5% to 13.6%], respectively, during the median follow-up of 8.6 years. The multivariable competing risk analysis suggested that older age at initial cancer diagnosis, white race, epithelial histologic subtypes of OC (serous, endometrioid, mucinous, and Brenner tumor), number of lymph nodes examined (<12), and radiotherapy were significantly associated with an elevated SPM risk. The DCA revealed that the net benefit obtained by our proposed model was higher than the all-screening or no-screening scenarios within a wide range of risk thresholds (1% to 23%).ConclusionThe competing risk nomogram can be potentially helpful for assisting physicians in identifying patients with different risks of SPMs and scheduling risk-adapted clinical management. More comprehensive data on treatment regimens and patient characteristics may help improve the predictability of the risk model for SPMs.

Changes in Second Primary Malignancies (SPM) after Hodgkin Lymphoma over Time in the United States

Background Improved treatments for Hodgkin lymphoma (HL) have prolonged survival. However, the increased risk of second primary malignancies (SPMs) among HL survivors compared to the general population remains the leading cause of death among long-term HL survivors. Treatment has evolved to include improved radiation techniques and response adapted chemotherapy regimens with the goal of improving HL cure rates, limiting treatment-associated morbidity, and improving long-term overall survival. Few population-based studies in the United States have examined whether the incidence of SPMs has decreased over time with these attempts to limit treatment-related toxicities.Methods Data for 20,530 patients of all ages diagnosed with a first primary HL during 1992-2013 were obtained from 13 Surveillance, Epidemiology and End Results (SEER13) regions in the United States. The incidences of SPM that developed >1 year after the initial HL diagnosis were determined for two treatment eras (1992-2002 and 2003-2013). To balance follow up time, HL patients diagnosed in 1992-2002 were followed through 2002 and patients diagnosed in 2003-2013 were followed through 2013. In each treatment era, we calculated standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (CIs) comparing HL patient's subsequent cancer incidence with the expected number of first primary cancer incidence, based on the age (at 5-year intervals), sex, calendar year (at 5-year intervals), cancer site, and race/ethnicity, derived from the general SEER13 population. SIRs were calculated for all invasive cancers and by cancer categories (solid and hematologic tumors) as well as by HL stage at diagnosis (stage I/II vs stage III/IV) and initial treatment with radiation. The cumulative incidence of SPMs, accounting for the competing risk of death, were estimated, with Gray's K-sample test statistic used to determine whether the difference in cumulative incidence of SPMs by treatment era was statistically significant (P -values that were <0.05).Results The mean follow-up time was 4.9 (±3.3) years for 9,989 patients (n=275 SPMs) diagnosed in 1992-2002 and 4.8 (±3.3) years for 10,541 patients (n=285 SPMs) diagnosed in 2003-2013. The mean age was similar for patients in the two treatment eras (38.4 years, 1992-2002; 39.4 years, 2003-2013). There was a statistically significant increase in SPMs of all sites in both time-periods compared to the expected number of first primary tumors in the general population. More specifically, there was a considerably elevated risk of lymphatic and hematopoietic SPMs amongst all patients with primary HL (1992-2002 SIR: 6.53 (5.24-8.03); 2003-2013 SIR: 5.85 (4.77-7.11)) and a suggestion of elevated risk of solid tumors (1992-2002 SIR: 1.37 (1.17-1.58); 2003-2013 SIR: 1.11 (0.95-1.29)). For all those diagnosed with HL, there was an increased rate of acute myeloid leukemia compared to the general population (1992-2002 SIR: 15.43 (9.14-24.39); 2003-2013 SIR: 17.23 (11.35-25.06)). At 5-years, the cumulative incidence of all SPMs (1992-2002: 1.93%; 2003-2013: 2.12%; p=0.84), lymphatic and hematopoietic SPMs (1992-2002: 1.23%; 2003-2013: 1.25%; p=0.94) and solid SPMs (1992-2002 0.69%, 2003-2013 0.85%, p=0.59) were similar in the two treatment eras (Figure). Further, the cumulative incidence of SPMs did not differ by stage at diagnosis or initial treatment with radiation therapy.Conclusions Despite changes in radiation techniques and chemotherapy regimens for the treatment of HL, there continues to be increased risk of SPMs, specifically those of the lymphatic and hematopoietic systems, in survivors of HL compared to the general population. Additionally, there is no change in the cumulative incidences of SPMs in HL survivors over time. Other studies have shown that SPMs do not begin to peak until 10-15 years after cancer diagnosis. Therefore, it is important to continue to monitor whether changes in treatment regimens will result in fewer SPMs as additional follow-up time becomes available.Figure. Cumulative incidence of all subsequent primary malignancies 1 to 10 years after a first diagnosis of Hodgkin lymphoma, by treatment era. [Display omitted] DisclosuresWun:Janssen: Other: Steering Committee for Cassini Study and Callisto Program, Research Funding; Pfizer: Other: Steering Committee: RESET study, Research Funding.

Analysis of chemotherapy effect on the second primary malignancy for head and neck cancer patients by a nomogram based on SEER database

Second primary malignancy (SPM) ranks the second leading cause of death in patients with head and neck cancer (HNC), while studies exploring the risk factors for SPM are limited. To clarify this, we investigated the relationship between the chemotherapy and SPM using the Surveillance, Epidemiology, and End Results (SEER) database. 11 345 patients initially diagnosed with HNC between 1998 and 2016 were selected from the SEER database. First, these patients were divided into two groups according to chemotherapy or not. With Fine and Gray model, the subdistribution hazard ratio (sHR) of chemotherapy was calculated based on Propensity Score Matching (PSM). Second, the 11 345 cases were randomized into a training set and a validation set. Based on the training set, the different cumulative incidence of SPMs between the patients with and without chemotherapy was estimated respectively in the high‐ and low‐risk group according to the scores derived from a nomogram. Chemotherapy was negatively correlated to the SPMs (sHR: 0.847, 95% CI: 0.733‐0.977, P = .023) by conducting competing risk analysis. With chemotherapy, forest plots showed subgroups of squamous cell carcinoma (SCC, sHR: 0.815, 95% CI: 0.7‐0.948, P = .008), 50‐64 years old (sHR:0.794, 95% CI: 0.655‐0.962, P = .019), male (sHR:0.828, 95% CI: 0.703‐0.974, P = .023), and well/moderate histological grade (sHR:0.828, 95% CI: 0.688‐0.996, P = .045) were negatively correlated to SPMs; the nomogram showed the high‐risk population characterized as SCC, elder age, male, and well/moderate histological grade also tended to have lower incidence of SPMs (sHR: 0.805, 95% CI: 0.669‐0.969, P = .022). Despite HNC patients with characteristics of SCC, increased age, male, and well/moderate histological grade had higher risk of a SPM, they were also more likely to be benefitted from chemotherapy to avoid it.

Second primary malignancy after rituximab-containing immunochemotherapy for diffuse large B cell lymphoma

Extended post-therapy long-term survival of patients with diffuse large B cell lymphoma (DLBCL) may also lead to an increase of late adverse events. We retrospectively investigated the frequency and clinical manifestation of second primary malignancy (SPM) after rituximab-containing immunochemotherapy in patients with DLBCL treated at seven institutes belonging to the Kyoto Clinical Hematology Study Group (KOTOSG) from the perspective of the existence of past or synchronous cancer history. In a median follow-up period of 899 days, 69 SPMs were observed in 58 of 809 patients. The most frequent SPM was gastric cancer, followed by lung cancer and colorectal cancer. The cumulative incidence of SPM increased steadily over time and was not significantly influenced by the presence or absence of past or synchronous cancer history. Our study suggests the need for careful attention to SPM in patients with DLBCL in daily practice.

PS1462 SECOND PRIMARY MALIGNANCIES IN MYELOFIBROSIS PATIENTS TREATED WITH RUXOLITINIB: REAL WORLD EVIDENCE FROM 215 CONSECUTIVELY TREATED PATIENTS IN LOMBARDY

Background:Patients with myeloproliferative neoplasms (MPNs) have a higher risk than the general population of developing a lymphoid neoplasm (Rumi et al, Haematologica 2011). It is still unclear whether this holds true for non‐hematological second primary malignancies (SPMs) (Frederiksen et al, Blood 2011; Susini et al, Blood 2012). However, among 20,250 MPN patients included in the Surveillance, Epidemiology, and End Results Program (SEER) database, the 10‐year cumulative incidence of SPMs was 12.7%, significantly higher than that expected in the general U.S. population (Brunner et al, Leuk Lymphoma 2016). Ruxolitinib (RUX) is an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF). Recently, Porpaczy et al (Blood 2018) alerted on the possible risk of aggressive lymphomas developing in MPN patients treated with JAK inhibitors including RUX, even though patient selection bias complicates interpretation.Aims:To assess SPM occurrence in RUX‐treated MF patients on the basis of real world data (RWD) provided by the health authority of Regione Lombardia, complemented with institutional data.Methods:Lombardy, a region of roughly 10 million individuals, has a well‐established network for hematology (Rete Ematologica Lombarda, REL), with a specific commission for MPNs. Within the REL we conducted an ambispective observational study (RUXOREL‐MF) including all MF patients treated with RUX, i.e. 215 subjects regularly followed at 17 centers. The study was approved by the Review Board of each Institution and conducted in accordance with the Declaration of Helsinki. Incidence rates were computed from the number of events versus the time at risk after RUX start. Time‐to‐event analyses used Kaplan‐Meier estimators, log‐rank tests and cause‐specific Cox models based on time elapsed after RUX start.Results:Main patient characteristics according to SPM (excluding non‐melanoma skin cancer, NMSC) occurrence are summarized in Table 1. Median follow up from diagnosis of MF was 61.5 months (interquartile range, IQR, 34.1–97.3). Median follow up from RUX start was 24.2 months (IQR 12.6–40.4). Forty‐nine (22.8%) patients died, two due to the SPM. Median overall survival from RUX start was 78.7 months. 27 cases of SPMs were reported prior to RUX start, with no case of lymphoma. 24 cases of SPMs occurred after RUX start (lung, 1; breast, 3; prostate, 2; bladder, 1; melanoma, 1; multiple myeloma, 1; NMSC, 13; other, 2). The incidence rate of SPMs post‐RUX was 4.3 per 100 pt‐years (95% CI 2.7–6.5), whereas it was 1.7 per 100 pt‐years (95% CI 0.8–3.2), when excluding NMSCs from the analysis. Median time to SPM diagnosis after RUX start was 16.9 months (IQR 6.9–21.5) and 19.8 months (IQR 16.3–36.7) when excluding NMSCs. Cumulative incidence of SPMs (excluding NMSCs) after RUX start is reported in Fig. 1. Patients with a SPM pre‐RUX were at higher risk of developing a SPM post‐RUX (HR 3.6, 95% CI 1.1–11.0, p = 0.02). Significance was lost if the analysis excluded NMSC (HR 3.8, 95% CI 0.8–18.7, p = 0.08).Summary/Conclusion:Our RWD offer a unique opportunity to provide real world evidence on the incidence of SPMs in MF patients receiving RUX. In our cohort no case of lymphoma was registered with a median follow up after RUX start matching the median time to lymphoma occurrence reported in the aforementioned publication. Incidence of SPMs after RUX start was 4.3 per 100 pt‐years and 1.7 per 100 pt‐years when excluding NMSC. A matched control study including MF patients not receiving RUX is ongoing and will be presented at the EHA meeting.image

Second primary malignancy after multiple myeloma-population trends and cause-specific mortality.

The management of multiple myeloma (MM) has evolved with the increased use of autologous haematopoietic cell transplantation (AHCT) and the introduction of new agents. AHCT and lenalidomide maintenance have been associated with increased risk of second primary malignancy (SPM). We iseutilised the Surveillance, Epidemiology and End Results 13 registries to analyse 9833 patients diagnosed at age <65 years for three eras: 1995-99 (pre-thalidomide, limited use of AHCT), 2000-04 (post-thalidomide, pre-lenalidomide and bortezomib, increased isautilisation of AHCT) and 2005-09 (post-lenalidomide and bortezomib, higher isautilisation of AHCT). Changes in risk of SPM were assessed by utilising standardised incidence ratio (SIR) and cause-specific risk of death. Cumulative incidence of SPM at 90months was 4·7%, 6·0% and 6·3% respectively, P=0·0008. SIR for haematological malignancies in years 1-5 increased, from 1·28 (95% confidence interval [CI] 0·47-2·78) in 1995-99 to 2·17 (95% CI: 1·27-3·48) in 2005-09, due to increased risk of acute leukaemias and lymphomas. A similar trend was observed in years 6-10. Overall mortality in patients with MM declined sharply over time due to declines in MM-associated and cardiovascular mortality with no increase in risk of death from SPM. The evolution of MM therapy is linked to population-level increase in risk with no discernible effect in death from SPM.

Increased risk of second primary malignancies following uterine cancer: a population-based study in Taiwan over a 30-year period.

BackgroundPrevious studies assessing second primary malignancies (SPMs) after uterine cancer have been conducted in Western populations with conflicting results. This study aimed to define the incidence and risk of SPMs in Taiwanese patients with an initial diagnosis of uterine cancer.MethodsUsing population-based data from the Taiwan Cancer Registry for the period 1979–2008, we quantified standardized incidence ratios (SIRs) among 11,571 women with an initial diagnosis of uterine cancer.ResultsAmong the 11,571 women, 555 (4.80 %) developed at least one SPM during 69,987 person-years of follow-up. There was a 71 % increased risk of SPM following uterine cancer (SIR = 1.71, 95 % CI, 1.57–1.86), with higher risks in the vagina/vulva (SIR = 9.06), small intestine (SIR = 8.45), ovary (SIR = 4.15), urinary bladder (SIR = 2.31), kidney (SIR = 2.24), colorectum (SIR = 2.24), lung (SIR = 1.96), and breast (SIR = 1.43). The risk of SPM was found to be the highest within the first 5 years after diagnosis of uterine cancer, with surveillance bias possibly contributing to the extremely high risk observed in the first follow-up year. The overall risk and pattern of SPM development observed in this study differed from those previously reported in Western populations, possibly because of the methodology and shorter follow-up period employed in this study. The cumulative incidence of SPMs was significantly higher in older patients (≥50 years) than in younger patients (P < 0.001).ConclusionsTo our knowledge, this is the first study in an Asian population to report 71 % increased risk in SPMs in women previously diagnosed with uterine cancer. A younger age at diagnosis of uterine cancer conferred an increased risk of second malignancies, and SPMs worsened survivorship in patients who survived uterine cancer.

Second primary malignancies following thyroid cancer: a population-based study in Taiwan

Most studies on second primary malignancies (SPMs) after primary thyroid cancer were conducted in USA or Europe. The discrepancy between SPMs in these studies could be attributed to geographical and ethnic heterogeneity. Thus, there is a clear need for another large-scale epidemiological study, particularly in Asian countries, to define the incidence and risk of SPMs in thyroid cancer survivors. A population-based study was conducted using the nation-wide database from Taiwan Cancer Registry between 1979 and 2006. We quantified standardized incidence ratios (SIRs) and cumulative incidence of SPMs among 19,068 individuals (4205 males and 14,863 females) with primary thyroid cancer. A total of 644 cases (3.38%) developed at least a SPM during 134,678 person-years of follow-up. The risk for subsequent SPMs was significantly greater than that of the general population (SIR=1.33, 95% CI 1.23-1.44). There was a greater risk of developing major salivary glands, nasopharyngeal, lung, thymus, breast (females), bladder, and brain cancers, and leukemia and lymphoma. We observed that the risk was highest within the first 5 years of diagnosis of thyroid cancer (SIR=5.29, 1.68, and 0.68 for ≤ 5, 5-10, and >10 respectively) and in the younger patients (SIR=1.81 vs 1.61 for <50 and ≥ 50 respectively). The median overall survival for primary thyroid cancer patients was 23.28 years, but it was only 4.73 years for those who developed SPMs. Thyroid cancer is associated with a 33% risk increment of SPMs, which had a negative impact on survival. There are sites of SPMs in the Asian population that are distinctive from those in the Western population, suggesting that other genetic predisposition or environmental factors may play a role.

Second Cancer Incidence, Risk Factor, and Specific Mortality in Head and Neck Squamous Cell Carcinoma

Second primary malignancies (SPMs) are common in patients with head and neck squamous cell carcinoma (HNSCC) and have a negative impact on their survival. This study aimed to evaluate risk factors for SPM occurrence and cause-specific mortality in Asian HNSCC patients. A retrospective cohort study. University teaching hospital. Nine hundred and thirty-seven patients without previous cancer history who were treated between 2000 and 2009 and followed for at least 2 years. Confirmation of SPMs was performed by histopathology. The cumulative probability of a SPM among survivors of index HNSCC was calculated using a competing risk model. Univariate and multivariate analyses were utilized to determine factors predictive of SPM occurrence and cause-specific mortality. Of 937 patients, cumulative incidence of SPMs was 7.2% at 0 to 6 months (synchronous), 17.9% at 5 years, and 23.1% at 10 years after index tumor diagnosis. In multivariate analyses, old age (>60 years) (P = .002), hypopharyngeal index tumor site (P = .001), and heavy drinker (P = .001) were independently associated with the development of SPMs, and hypopharyngeal index tumor site were independent variables for SPM-specific survival (P < .001). Cumulative incidence function of SPM-specific mortality according to index tumor sites was significantly higher in the hypopharynx than other sites (P = .011). Elderly patients, hypopharyngeal index cancer patients, or heavy drinkers may require careful surveillance for the development of SPMs. Our results may help identify and properly manage Asian patients at high risk of SPMs.

Second Primary Malignancies after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Recent studies demonstrate an increased risk of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving maintenance lenalidomide after autologous stem cell transplantation (ASCT). We explored the possibility of other risk factors driving post-ASCT SPMs in patients with MM through analysis of our large transplantation database in conjunction with our Long-Term Follow-Up Program. We conducted a retrospective cohort study of 841 consecutive patients with MM who underwent ASCT at City of Hope between 1989 and 2009, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during, and after ASCT. Median duration of follow-up for the entire cohort was 3.4 years (range, 0.3-19.9 years). Sixty cases with a total of 70 SPMs were identified. The overall cumulative incidence of SPMs was 7.4% at 5 years and 15.9% at 10 years when nonmelanoma skin cancers (NMSCs) were included and 5.3% at 5 years and 11.2% at 10 years when NMSCs were excluded. Multivariate analysis of the entire cohort revealed associations of both older age (≥55 years; relative risk, 2.3; P < .004) and race (non-Hispanic white; relative risk, 2.4; P = .01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend toward increased risk (odds ratio, 3.5; P = .15); however, an insufficient number of patients were treated with lenalidomide to allow us to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables but was accompanied by loss of statistical significance. This large single-institution analysis identified associations between race and older age and increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that might not be restricted to lenalidomide.

Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance

AbstractThalidomide and lenalidomide constitute an important part of effective myeloma therapy. Recent data from the Intergroup Francophone du Myélome, Cancer and Leukemia Group B, and Gruppo Italiano Malattie Ematologiche dell Adulto MM-015 trials suggest that lenalidomide maintenance therapy is associated with a higher incidence of second primary malignancies (SPMs), including both hematologic and solid malignancies. In the present study, we analyzed data from the Total Therapy 2 (TT2) trial, along with the 2 Total Therapy 3 (TT3) trials. TT2 patients were assigned randomly to either a control group (no thalidomide) or to the experimental group (thalidomide during induction, between transplantations, and during consolidation and maintenance). The 2 TT3 trials used thalidomide and bortezomib during induction, before and in consolidation after tandem melphalan-based transplantation; TT3A applied VTD (bortezomib, thalidomide, dexamethasone) in the first year of maintenance and TD for 2 more years, whereas TT3B used VRD (bortezomib, lenalidomide, dexamethasone) maintenance for 3 years. The cumulative incidence of SPMs did not differ significantly among the TT trial components when measured from enrollment (P = .78) or from initiation of maintenance (P = .82). However, a pairwise comparison of the TT2 arms suggested a lower incidence of hematologic SPMs in the thalidomide maintenance arm (hazard ratio = 0.38; P = .09). These trials are registered at www.clinicaltrials.gov as NCT00573391 (TT2), NCT00081939 (TT3A), and NCT00572169 (TT3B).

Risk factors for development of second primary malignancies (SPM) after autologous stem cell transplant (ASCT) for multiple myeloma.

8038 Background: Studies from the CALGB and IFM have suggested an increased incidence of SPM post ASCT in patients on lenalidomide maintenance. Patients with MM as well as patients post ASCT are inherently at higher risk of SPM. Therefore, assessment of risk factors associated with SPM would be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. Methods: We conducted a retrospective cohort study of 841 consecutive MM patients who underwent at least one ASCT at City of Hope from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested case-control study was also conducted to understand the role of therapeutic exposures associated with SPMs. Controls were MM patients post ASCT matched by year of HCT (±5 years). Results: The median length of follow up was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 18-77). 62% had received a single autologous HCT, 27% tandem autologous HCT, 11% had received multiple HCTs (72 had a second allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for patients &gt;55 years approached 21.9% at 10 years. The cumulative incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors examined included age, race, sex, number and individual therapeutic exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites (RR=2.4, 95% CI, 1.2-4.6, p=0.01) and older age (&gt;55) at diagnosis of MM (RR=2.3, 95% CI, 1.3-4.1, p=0.004) to be associated with an increased risk of developing SPMs. Only cumulative thalidomide exposure (both pre-ASCT and post-ASCT) demonstrated a trend toward a positive association (OR=3.5, 95% CI, 0.6-19.4, p=0.15). Six patients (3 cases and 3 controls) were exposed to lenalidomide prior to development of SPM (OR=1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis identified non-hispanic whites and older age to be associated with increased risk of developing SPM in pts post ASCT for MM. The trend towards increased risk with thalidomide exposure may be suggestive of a class effect from IMIDs that is not restricted to lenalidomide alone.