Female Hodgkin Lymphoma Patients Research Articles

Fertility Rates in Young Hodgkin Lymphoma Survivors: A Danish Nationwide Cohort Study of 769 Patients

Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls. Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately. Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value < 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1). Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (<30 years), limited stage disease, and for patients without children at the time of diagnosis. No clinical subgroup did significantly decrease the fertility rates. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding. Frederiksen:Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Glimelius:Janssen Pharmaceuticals: Honoraria. Ekstroem Smedby:Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

Family History of Breast Cancer Associated with Breast Cancer in Survivors of Hodgkin Lymphoma.

Advances in treatments for Hodgkin Lymphoma (HL) have significantly increased survival of childhood and adult patients; however, the leading cause of death in HL survivors is due to secondary malignancy following HL treatment [1,2]. Among women treated for HL, breast cancer (BC) is the most common secondary malignancy [3]. We explored if an association exists between HL and BC exists within families. Utilizing the Utah Population Database and the Utah Cancer Registry, we identified 988 women with HL, and no history of BC prior to HL, diagnosed in Utah from 1966-2014. We examined if women with HL were at greater risk of developing BC based on the presence or absence of family history of BC. We also examined the familial recurrence risk of BC among female FDRs of women with HL and BC using Cox regression methods. Among 988 female HL patients, 42 (4.3%) were diagnosed with subsequent BC while among 9,876 matched controls, 280 controls (2.8%) were diagnosed with BC from 1966-2014 (P < 0.05). We observed a significant 3-fold increased risk of BC in the first-degree relatives (parent, full sibling, or child of patient) of female HL patients with subsequent BC, compared to FDR in controls (HR = 2.8, 95%CI 1.4-5.6; P = 0.005). Female HL patients who had a family history of BC were significantly more likely to develop BC, compared to HL patients with no history of BC among relatives (HR = 3.3, 95%CI 1.6-7.1; P = 0.002). Women with HL and a family history of BC are at even higher than anticipated risk of BC, as are their female relatives. Obtaining a thorough family history for a woman preparing to undergo therapy for HL is important for treatment decisions for HL and maintaining an up to date family history over time is also important for the management of a woman's ongoing cancer risks and her surveillance strategy following survival of HL.

UK: NATIONAL COHORT STUDY INVESTIGATING MAJOR LATE EFFECTS OF HODGKIN LYMPHOMA TREATMENTS ON BEHALF OF THE ENGLAND &amp; WALES HODGKIN LYMPHOMA FOLLOW‐UP GROUP

Background: Dramatic improvement in Hodgkin Lymphoma (HL) survival rates over recent decades is one of the greatest success stories in modern Oncology. However it has come at a significant cost: treatment-related toxicity. These issues are epitomised in female HL patients treated at young ages, who have many decades to accumulate late effect burden, and are additionally susceptible to sex-specific outcomes such as breast cancer and premature menopause. In 2003, a national cohort comprising all young women (under <36 years) treated for HL with radiotherapy above the diaphragm in England and Wales since 1960 was established (5,000 women). This quantified the significantly raised risks of breast cancer, particularly those treated with high dose radiotherapy to the breast around menarche. Increased risk of other second malignancies and mortality are also known to be serious consequences of HL treatments. It is hoped de-intensification of treatments will attenuate risk of these long-term effects but this has not yet been definitively demonstrated. These outcomes have been studied in relation to treatment largely in those treated in childhood or in smaller populations than our UK cohort. We have expanded this cohort to include women treated more recently, until 2010, and to encompass all treatment types, to investigate risk factors for the most severe long term effects of HL treatments, and whether risks have diminished over time. Methods: 10,000 women diagnosed with HL under 36 years have been identified from English and Welsh Cancer Registries from the 1960-2010 with >99% complete follow up for mortality until 2018 and are in the process of linking to causes of death. We are currently obtaining treatment and second cancer information for each patient from NHS hospital records across the country. We have achieved this for 7,000 patients so far. We have also obtained linked second cancers from national cancer registrations. Once complete, this will be the much the largest cohort of its kind worldwide, to enable high power analyses of risk factors for a range of serious late effects in Hodgkin Lymphoma. Keywords: Hodgkin lymphoma (HL).

Suicide in European Hodgkin Lymphoma Patients.

The purpose of this study was to determine whether there is an increased risk of suicide in European Hodgkin Lymphoma (HL) patients compared to the general European population.European HL patients enrolled in the German Hodgkin Study Group (GHSG) HD7 through HD15 studies were analyzed and standardized mortality ratio (SMR) was calculated using suicide mortality rates for the general European population. Case-control analysis was performed to identify characteristics associated with risk of death by suicide. Among 12,202 European HL patients observed for 94,972 person-years, 19 suicides (17 males and 2 females) were identified resulting in a SMR 1.63 (95% CI: 1.01–2.50, p = 0.046). The only characteristic associated with a statistically significant increased risk of suicide was male sex with an odds ratio (OR) 8.42 (95% CI = 1.04–67.85; p = 0.046) on multivariate analysis. These findings were confirmed in an independently analyzed Surveillance, Epidemiology, and End Results Program (SEER) validation dataset. European HL patients have a significantly increased incidence of suicide compared to the general European population. Male HL patients have a greater than 8-fold increased risk of suicide compared to female HL patients. Further study of social risk factors associated with an increased risk of suicide in HL patients is needed.

SU-E-T-278: Risk of Developing a Second Cancer in the Breast for Hodgkin Lymphoma Patients Receiving Carbon Ion Therapy Versus Proton Therapy

Purpose: Although radiation therapy is frequently used to cure Hodgkin lymphoma (HL), young patients treated with radiation have an increased risk to develop secondary malignant neoplasms. The purpose of this study was to determine whether using carbon ion therapy instead of proton therapy would show a difference in the predicted risk of radiation‐induced second cancers in the breast for female HL patients. Methods: We retrospectively selected 6 female HL patients who were previously treated with proton therapy and limited our study to patients with supradiaphragmatic disease. We designed scanned proton and scanned carbon ion treatment plans to deliver 36 Gy (RBE) to the HL target using a single anterior‐posterior beam for each patient. We calculated relative predicted risks of second cancer in the breast using a linear‐no‐threshold tumor induction model and a linear‐quadratic breast cell inactivation model, and we explicitly modeled RBE values for both of these competing processes. Results: For all patients, we found that the predicted risk for second cancer incidence in the breast was slightly lower using carbon ions instead of protons. For individual patients, we observed large variations in predicted risk given the plausible range of RBE for cancer induction for protons and carbon ions. Conclusion: Our findings are indicative that a higher or lower risk of second cancer in the breast might be expected for some patients using carbon therapy instead of proton therapy, depending on RBE for tumor induction, which implicitly depends on the α/β ratio of breast tissue, as well as on the physical dose distribution. UT MD Anderson Rosalie B. Hite Fellowship

Knowledge of and adherence to breast cancer screening guidelines in Hodgkin lymphoma survivors treated with mantle radiation.

e19509 Background: Female Hodgkin Lymphoma (HL) survivors treated with mantle radiation have 3-10 times the risk of the general population for developing breast cancer. Forty percent are unaware of their increased risk and receive follow-up (f/u) care solely with a primary care provider (PCP) and may not receive the National Comprehensive Cancer Network (NCCN) recommended f/u. We aimed to assess the knowledge and practice of PCPs within the Gundersen Lutheran Health System (GLHS) toward breast cancer screening recommendations in this population. Methods: A review of medical records (MR) of female HL patients treated with mantle radiation from 1980-2005 was completed. Cancer and survival rates were calculated using Kaplan-Meier statistics. An email survey assessing knowledge on care for HL survivors was distributed to GLHS PCPs. Results: MR review of 61 patients found a mean age of diagnosis for HL of 34± 18 years (range, 6 to 82 years) and a mean f/u period of 11 years (range, 0.2-29.7years). Only 2 patients (3%) had received a breast MRI in follow-up care. Of those eligible for screening mammography per NCCN with 10 years f/u (n=23), 83% had one in the previous 2 years. Of those with >5 years of f/u, 5 (23.5%) were diagnosed with breast cancer. A survey of 87 PCPs found that 61% were aware that HL survivors had an increased risk of breast cancer, but only 36% were aware of complete recommended f/u care; 59% were aware of all but breast MRI recommendations and 66% stated they were “uncomfortable” treating female patients with a history of HL. Fewer than 50% of PCPs who care for female patients with HL inform these patients of increased breast cancer risk. Reasons for this included lack of awareness of the risk or assumption the risk was explained by an oncologist. Conclusions: We confirmed a high rate of breast cancer in female survivors of HL and lack of compliance with breast cancer screening guidelines. GLHS PCPs had average knowledge of the increased breast cancer risk and limited knowledge of the NCCN breast cancer screening guidelines in HL survivors. These results emphasize the need for cancer survivorship care that provides information for patients and PCPs in this and likely other aspects of long-term survivor f/u.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL).Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up.Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%).Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

High incidence of late effects found in Hodgkin's lymphoma survivors, following recall for breast cancer screening

Assessment of late effects in a cohort of female Hodgkin's lymphoma patients treated with mantle radiotherapy, identified from the DoH breast cancer screening recall showed high mortality and frequent undiagnosed abnormalities in tissues affected by radiotherapy. With increasing age, this patient group may suffer premature cardiac and respiratory morbidity.

Leucopenia during Treatment Is a Good Prognostic Risk Factor for Patients Undergoing Chemotherapy for Hodgkin's Lymphoma: An Analysis of the German Hodgkin Study Group (GHSG).

Purpose: A systematic analysis of gender-specific factors in Hodgkin's lymphoma (HL) studies previously revealed a better outcome for female HL patients. Factors contributing to better prognosis among female patients not only included more favorable risk factors at diagnosis, but also more treatment-induced severe leuopenia (WHO grade III/IV). The purpose of the current analysis was to characterize and investigate the protective role of severe leucopenia for both, male and female HL patients.Patients and Methods: 4626 HL patients including 2050 females (f) and 2576 males (m) of all prognostic risk groups who were enrolled into the multicenter studies HD4-HD9 of the GHSG were evaluated. The median follow-up after treatment was 5.5 years.Results: Female patients had a significantly better freedom from treatment failure (FFTF) with 81% at 66 months (95% confidence interval 79% – 82%), when compared with male patients (74%; 72% – 76%; p<.0001). This was in part related to the occurrence of more acute chemotherapy-related leucopenia (WHO grade III/IV): 69.9% in female patients and 55.2% in male patients (p<.0001). Furthermore, severe leucopenia during chemotherapy was strongly associated with better FFTF for both, male and female patients. Separate multivariate analyses showed that severe leucopenia remained significant when only male patients were included (0.011).In addition, patients who developed severe leucopenia within the first two cycles of chemotherapy also had a significantly better FFTF (p=.0002) compared with all other patients (Klimm et al, JCO in press). When considering patients with advanced HL undergoing BEACOPP in baseline or escalated dose, the presence of severe leucopenia during chemotherapy (p=.0074) was associated with a better outcome. This finding was also confirmed when only the first two cycles of treatment were analyzed (p =.0205).Conclusion: The protective role of severe leucopenia suggests evaluating of a more individualized therapy in future trials, that may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.