Incidence of Second Malignancies in the History of Chronic Lymphocytic Leukemia

Introduction The occurrence of other neoplasms in patients diagnosed with chronic lymphocytic leukemia (CLL) is a known but insufficiently studied complication, highlighting the need for further research. Our study aims to analyze the incidence of other malignancies in CLL. Methods We performed a retrospective observational study of patients diagnosed with CLL between 2000-2016 at our center. Variables collected included: demographics, stage at diagnosis, treatment, response to treatment, death, other neoplasm (type, date of diagnosis, outcome), biomarker profiles studied by karyotyping, FISH, immunoglobulin heavy chain gene variable region mutational status, and TP53 mutational status. A descriptive study was performed. Quantitative variables are described as medians with their range, and qualitative variables as percentages. The relationship between qualitative variables and the development of second malignancies was performed using Chi-square and Fisher's exact test. Survival analyses were performed using the Kaplan-Meier method and the difference between groups was analyzed using the log-rank test. Results A total of 182 patients were evaluated, 104 men (57%) and 78 women (43%); median age: 74 years (39 - 97). Most patients were diagnosed at early stages (74% at Rai stage 0 and 84% at Binet stage A) and the median CIRS scale score at diagnosis was 4 (0 - 15). With a median follow-up of 76 months (20-212), 77/182 (42%) patients had received ≥1 line(s) of treatment: 1: 53%, 2: 26%, 3: 8%, ≥4: 13%. Forty-nine cases (27%) were reported with other malignancies in addition to CLL; cases with Richter transformation (n=5, 2.7%) were excluded. The diagnosis of CLL preceded the other neoplasm in 33/182 cases (18%): 8 hematologic and 27 non-hematologic neoplasms. Half of the hematologic malignancies involved MGUS (n=4), 1 mutated JAK2 (V617F) cMPN, 1 AML and 1 MALT lymphoma. As for non-hematologic tumors, non-melanoma skin cancer accounted for 30% of cases (n=8), followed by breast cancer (n=5, 18.5%). Neoplasms of the stomach, colon, liver, bladder and prostate together accounted for 37%, in the same proportion each (n=2, 7.4%). The remaining neoplasms corresponded to lung and bronchus, kidney, melanoma and pancreas. Five of the 27 patients had a third solid organ neoplasm, with non-melanoma skin cancer again being the most frequent (n=2). The other neoplasms were lung, small bowel and thyroid. The incidence of second neoplasms was higher in treated patients (26% vs. 12.4%, p=0.019). The incidence of a second hematologic malignancy was related to treatment administration (9%) compared to 1% in untreated patients (p=0.011), especially in those with ≥ 3 lines (37.5% vs. 3%), p=0.024. We could not find any association between the variables analyzed and the development of second non-hematologic malignancies. The development of second neoplasms after the diagnosis of CLL did not have a negative impact on the overall survival of these patients. Conclusions The incidence of second malignancies is high in patients with CLL, being higher in those patients who have received treatment, and especially in those with a greater number of lines received. In contrast, the development of solid tumors did not seem to be affected by treatment administration, which should motivate further investigation in specific subgroups of patients. In our series, the development of second neoplasms after the diagnosis of CLL did not have a negative impact on the overall survival of these patients. Disclosures Gonzalez-Lopez: Novartis: Other: Advisoryboard and speakers honoraria, Research Funding; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Sobi: Other: Advisory board honoraria; Grifols: Other: Advisory board honoraria.

Type of recurrence, cause of death and second neoplasms among 737 patients with ductal carcinoma in situ of the breast: 15-year follow-up.

e12592 Background: The aim of the study is to assess the results of the treatment of 737 consecutive patients with DCIS with particular attention to the character of recurrences, other neoplasms and causes of deaths. Methods: A retrospective analysis was carried out of 737 consecutive DCIS patients treated in one institution in the years 1996-2011. The percentage of failures, causes of death, cumulated recurrence risk, DFS, OS depending on the method of treatment (mastectomy, breast conserving treatment BCT, breast conserving surgery BCS), was calculated. Results: 66 recurrences (42% DCIS, 58% invasive) were reported: 61 recurrences in the breast, 5 outside the breast. The comparison of mammography images before the initial treatment and after local recurrence revealed the true recurrence in the breast in 48/61 (79%) of cases. The cumulated recurrence risk after 15-year observation, after mastectomy, BCT and BCS was 3.2%, 19.5% and 31.2 %, respectively (p < 0.001). 15-year DFS after mastectomy, BCT and BCS was 72%, 65% and 48%, respectively (p < 0.001). 15-year OS after mastectomy, BCT and BCS was 75%, 83% and 70%, respectively, p = 0.329. In the course of the whole observation period 124 other neoplastic lesions in 121 patients (16%) were reported including 58 (8%) contralateral breast cancers. Deaths due to DCIS progression were reported in 4 (0.5%) of patients. An overwhelming majority (74/86) of deaths was linked to the age of the patients or other diseases, including other neoplasms. Conclusions: The highest recurrence risk reported in patients after BCS was unacceptable and, moreover, it kept growing over the fifteen years of observation. 79% of recurrences in the treated breast were true recurrences. Local recurrences were effectively treated without influence on OS. The percentage of deaths due to DCIS was low.

RARE-41. SECOND MALIGNANCIES FOLLOWING TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM TUMORS IN PEDIATRIC PATIENTS: A SINGLE-INSTITUTIONAL RETROSPECTIVE REVIEW

Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.

Increase in Mortality and Second Neoplasms in Chronic Lymphocytic Leukemia with Pro/Pro Genotype of TP53 Codon 72

Chronic Lymphocytic Lymphoma (CLL) is a heterogeneous disease in which many important factors for its prognosis have been identified. The normal functioning of p53 is one of the most critical barriers against cancer; therefore, if it has a deletion and/or mutation, it is a robust biomarker for the therapeutic response in CLL. The possibility was raised that some germline single - nucleotide polymorphisms of TP53 in healthy populations may also affect p53 function. One of the most studied polymorphisms of the TP53 gene is codon 72 in exon 4, a CGC to CCC transition (R72P), due to its potential effect on cancer risk. As with many types of cancer, its association with a worse prognosis in CLL is unclear. We analyzed the relationship of the genotypes of the TP53 codon 72 polymorphism in a large cohort of patients with CLL, to demonstrate the association of codon 72 with the evolution of the disease. Using the IDIPHIM patient database, 558 patients with a diagnosis of CLL were included, with clinical data, immunophenotype studies, FISH, IgHV, and karyotype, at the time of diagnosis and during follow-up. The TP53 codon 72 Arg/Arg, Arg/Pro, and Pro/Pro genotypes were analyzed using RT-PCR and Sanger sequencing techniques. After analyzing the sample of patients, 321 patients with the Arg/Arg genotype, 202 with the Arg/Pro genotype, and 35 with the Pro/Pro genotype were found. In the comparative analysis of the three groups, the patients with the Pro/Pro genotype had a higher number of patients in advanced stages B and C. The latter had a significant association with Binet staging (p = 0.002) compared to the other groups. Likewise, patients with the Pro/Pro genotype had a higher incidence of Richter transformation, whose association was significant (p = 0.013). Also, the patients who were within the Pro/Pro genotype group showed a significant association (p = 0.030) with the Time to the first treatment (TFT), also observing that the group of patients with the Arg/Pro genotype had a more considerable time until your first treatment. 19.7% (110/558) had a second neoplasm, having a significantly higher association with the homozygous groups (Arg/Arg and Pro/Pro) than with the Arg/Pro group, which on the contrary, had fewer second neoplasms (p = 0.016) (see Table 1). Regarding the type of tumors, we found 14.5% of the bladder, 14.5% of the skin, 14.5% of the colon, 13.6% of the prostate, and 12.7% of the lung. No associations were found between Codon 72 and CD38+, ZAP70+, complex karyotype, IgHV, NOTCH-1, del 11q, 12+, p53, del 13q, TP53 mutation. Still, when forming a group between the p53 deletion and TP53 mutation, if significant differences were found (p = 0.023), Pro / Pro group had the highest percentage. The overall survival was 156.32 months (139.92 - 172.72), showing that patients with the Arg/Pro genotype live 40 months more significantly than the other groups (p = 0.028) (see Figure 1). Finally, in the multivariate analysis, age, complex karyotype, 11q deletion, p53 deletion, unmutated IgHV, and Pro/Pro genotype at codon 72 were identified as independent variables associated with an increased risk of death (see Table 2). In conclusion, the Pro/Pro genotype of TP53 Codon 72 has a potential role in the progression and the higher mortality of patients with CLL. Conversely, the Arg / Pro genotype was associated with a lower incidence of second malignancies and higher overall survival. Disclosures No relevant conflicts of interest to declare.

NCMP-22. SECOND MALIGNANCIES FOLLOWING TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM TUMORS IN PEDIATRIC PATIENTS: A SINGLE-INSTITUTIONAL RETROSPECTIVE REVIEW

Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.

Late Effects in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia

Background Knowledge regarding late effects (medical conditions and subsequent neoplasms) in survivors of adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) is lacking. Methods Using the population-based California Cancer Registry linked with California hospitalization data, we evaluated late effects in 1069 AYAs (aged 15–39 years) diagnosed with ALL in California between 1995 and 2012 and surviving a minimum of 3 years from diagnosis. Results The estimated 10-year cumulative incidence of subsequent endocrine disease (28.7%, 95% confidence interval [CI] = 25.8% to 31.6%) and cardiac disease (17.0%, 95% CI = 14.6% to 19.5%) were strikingly high; avascular necrosis (9.6%, 95% CI = 7.8% to 11.6%), liver disease (6.5%, 95% CI = 5.0% to 8.3%), respiratory disease (6.2%, 95% CI = 4.8% to 8.0%), seizure and/or stroke (4.3%, 95% CI = 3.1% to 5.8%), renal disease (3.1%, 95% CI = 2.1% to 4.4%), and second neoplasms (1.4%, 95% CI = 0.7% to 2.4%) were estimated to occur at 10 years with the reported frequencies. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private and/or military insurance) and receipt of hematopoietic cell transplantation were independently associated with the occurrence of all late effects considered. In multivariable analyses limited to the 766 AYAs who were not transplanted, we continued to find a statistically significant association between public and no insurance and the occurrence of all late effects. Frontline regimen type (pediatric vs adult) was not statistically significantly associated with any of the late effect categories. Conclusions This large population-based analysis is among the first to describe late effects in survivors of AYA ALL. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy.