Cumulative Incidence Of Secondary Malignancies Research Articles

Long-term efficacy and safety of dose-dense and dose-intense ABVD without consolidation radiotherapy in patients with advanced Hodgkin lymphoma: A 15-year follow-up of the ABVDDD-DI phase II study.

We demonstrated that dose-densified and dose-intensified ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; ABVDDD-DI) was safe and effective. Here, we present a post hoc long-term analysis of the 82 patients enrolled in the original study. The median observation time was 175 months (IQR 159-197). At 15 years, progression-free and overall survival rates were 81.2% (95% CI, 69.9%-88.7%) and 92.7% (95% CI, 82.6%-97.0%), respectively. Four patients with multiple cardiovascular risk factors experienced delayed G3 cardiac events. The cumulative incidence of second malignancies at 20 years was 6.1%. Fertility and childbearing potential were unaffected. Data support an ongoing benefit for ABVDDD-DI without uneven late toxicities.

Secondary myeloid malignancy after CAR T cell therapy for non-Hodgkin lymphoma (NHL).

7033 Background: Prior studies have described toxicities associated with chimeric antigen receptor T cell therapy (CART). Recently, myeloid malignancies were identified in myeloma patients (pt) after receipt of cilta-cel. In this study, we sought to describe the cumulative incidence and characteristics of secondary myeloid malignancies in pt treated with CART for NHL. Methods: We conducted a single institution retrospective study among pt ages ≥18 years (yr) who received commercial CART for NHL at Ohio State between December 2017 to April 2022. Descriptive statistics were used to summarize pt/disease characteristics. Cumulative incidence was calculated from date of infusion with death/relapse as competing risks. Results: For 190 pt treated with CART, median age was 63 yr (23-85 yr). Disease subtypes included diffuse large B-cell lymphoma (BCL)/high grade BCL, Richter transformation, and mantle cell lymphoma (79.5%, 8.4%, and 7.4%). Products included tisa-cel (47.9%), axi-cel (43.1%), brexu-cel (7.4%), and liso-cel (1.6%). Grade 3-4 neutropenia developed in 29% and 18% of pt at 30 days and 90 days post-CART. Median follow-up was 17 mo (0.5-63 mo). 48% were alive at time of analysis. Myeloid malignancy post-CART occurred in 7 pt with a median time to development of 29 mo (18-41 mo). Characteristics (Table) included complex karyotype, TP53 and chromosome 5/7 abnormalities. Cumulative incidence of secondary malignancy was 1%, 5%, and 6% at 2, 3, and 4 yr post-CART. Conclusions: We report on incidence of secondary myeloid malignancy in pt receiving CART for NHL. Mutational characteristics of secondary malignancies were those classically associated with therapy-related myeloid malignancy, thus presumed to be associated with prior exposure to chemotherapy (eg. alkylators/VP-16). Further investigation in larger cohorts with additional observation time, to allow for appropriate risk discussion, is required. [Table: see text]

Late Effects of Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma. Swiss Cohort Analysis 1997-2021

Background: despite rapid development of new highly efficient targeted and cellular-therapies, allogeneic stem cell transplantation (allo-HSCT) represents so far the only potentially curable treatment according to a longest follow-up in a setting of relapse/refractory Non-Hodgkin lymphoma (rrNHL). However, late effect (LE) issues of allo-HSCT in rrNHL seem to be underexplored. Here, we present the first analysis of a retrospective, multicenter, registry-based analysis (Swiss Blood Stem Cell Transplantation and Cellular Therapy, SBST) of LE in patients who underwent allo-HSCT for rrNHL in Switzerland. Methods: We retrospectively collected data from 109 patients with all types of rrNHL who underwent allo-HSCT in 3 University Hospitals of Switzerland (Zurich, Basel and Geneva) between May 1997 and November 2021. The inclusion criteria was 2 years survival after allo-HSCT. The primary endpoint was the cumulative incidence (CI) of LE and secondary endpoint were overall survival (OS), relapse incidence (RI) and type of LE according to organ/systems involved. Results: median of follow-up was 6.5 years. Patients who survived 2 years after allo-HSCT presented 5 and 10 years OS of 94% [95% CI 86.3 - 97.5] and 86% [95% CI 75 - 92.4] respectively. RI and CI of LE were 18.3% and 44% at 5 years and 34.4% and 58% at 10 years post allo-HSCT. A total of 79/109 (72%) of patients experienced any type of LE during the follow-up period. Renal dysfunction (21%), secondary malignancies (18%), cardiovascular disease (18%), osteoporosis (18%) and thyroid dysfunction (17%) were the most frequently observed. CI of secondary malignancies was 6.1% and 20% at 5 and 10 years respectively. Conclusions: Our analysis of a mixed-type rrNHL cohort confirms the efficacy of allo-HSCT in heavily pretreated/refractory patients, showing excellent OS at 5 and 10 years for those who survived 2 years. Both RI and LE present a competitive risk for survival benefit beyond 2 years after allo-HSCT. Secondary malignancies, renal and cardiovascular disease appear to be the most frequent types of LE, revealing the toxicity accumulated prior to allo-HSCT in the setting of rrNHL. These results should be interpreted with caution due to a retrospective nature of the analysis, the heterogeneity of the conditioning regimen and the NHL cohort. Figure 1. a) Overall survival (KM-estimate) b) cumulative incidence of late effects

Moderate Incidence but Striking Correlation with TBI of Secondary Malignancies after HSCT in Children with ALL: Long-Term Follow-up from the Prospective International BFM- and Forum-Trials

Introduction: Total body irradiation (TBI)-based conditioning was found to be associated with superior leukemia-free survival when compared to chemo-based conditioning for children with ALL undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in the prospective, international, randomized FORUM trial (Peters et al, JCO 2021). Nevertheless, TBI is considered as the major risk factor for developing secondary malignancies (SM). We and others have previously reported the incidence, risk factors, and outcomes of SM after HSCT in children with ALL (Eichinger et al, Leukemia 2022), but prospective studies of SM after HSCT in children are limited. Therefore, we analyzed the results of 2151 patients enrolled in the prospective BFM 2003 and the FORUM trial from 2003-2022. Patients and methods: We included data from all 668 patients (pts) treated in the BFM 2003 trial and from all 1483 patients treated in the FORUM trial with HSCT from HLA-identical family donors (MFD, 26% of patients), matched unrelated donors (MUD, 65%), and either related or unrelated mismatched donors (MMD, 9%). In the BFM 2003 trial pts >2 years (y) of age years were offered TBI/VP-16 (12 Gy TBI in 6 fractions of 2 Gy each, given as 2 fractions per day for 3 days; VP-16 60 mg/kg, maximum total dose 3600 mg) as conditioning. Only pts with contraindications for TBI received chemo-conditioning, which consisted of i.v. busulfan, cyclophosphamide and etoposide. In the FORUM trial pts >4y of age were randomized to receive either TBI- or chemo-based conditioning regimens; pts <4y were allocated to the chemo-conditioning arm consisting of fludarabine/thiotepa and either busulfan or treosulfan. Details on the transplant procedure have been previously described (C. Peters, et al. JCO 2015 /2021). Results: Centres from 31 countries on 5 continents contributed to the two studies. The median age was 9.2 (range 0.5-23) y. The majority were male (63%, 1356/2151) and >2 y of age at HSCT (94%, n=2024). TBI-based conditioning was applied in 64% (n=1429), while 34% (n=722) of pts received chemo-conditioning. TBI/VP16 was given in 27% (43/159) of age group 2-4y, and in 76% (1269/1672) of age group >4y. With a median follow-up of 3.29 (range 0.1-16.4) y, a total of 46 SM (33 in BFM 2003, 13 in FORUM) were diagnosed at a median of 5.12 (range 0.4-13.4) y post HSCT, all but one in the TBI group. Four pts experienced ALL relapse prior to the occurrence of the SM leaving 42/2151 cases for further analysis. The 5-, 8-, and 10-y cumulative incidence (CI) of SM, with relapse and non-relapse mortality being competing events, were 0.02 (±0.01), 0.06 (±0.01), and 0.13 (±0.03), respectively. Details of the SM are described in Table 1. Regarding age at HSCT, no SM was observed in the very young age group (<2 years) (0/127), 4 SM in the 2-4 years group (2.2%, 4/181), 20 SM in the 4-10 years group (2.3%, 20/867), and 22 SM in the >10 years group (2.25%, 22/976) (p=n.s.). Six patients developed an additional SM: these were MDS (n=2), and glioblastoma, breast cancer, basal cell carcinoma, and squamous cell carcinoma (one each). The first SM occurred at a median of 5.12 (range 0.4-13.4) y, and the additional SM at 10.7 (range 4.3-12.1) y after HSCT. The probability of OS after SM diagnosis was 0.65 (±0.008) at 5y and 0.32 (±0.17) at 10y. Causes of death were SM in 12/14 cases and 2/14 ALL relapse-associated. All 3 glioblastoma-pts died within 8 months after diagnosis. 17/18 pts (94%) with thyroid cancer were alive at last follow-up (0-10 y after SM diagnosis). As shown in Figure 1, the 8-y CI of SM differed significantly between TBI- and chemo-conditioning (0.08[±0.02] versus 0.04[±0.04], p=0.004) in both age groups (2-4 y and >4 y). No significant correlation was observed with patient characteristics such as age, gender and ALL remission status. In addition, we did not identify other statistically significant transplant-specific risk factors including donor type, stem cell source, grade II-IV and III-IV aGVHD and cGVHD. Conclusions Updated data from two prospective studies using uniform regimens confirmed TBI-based conditioning as a risk factor for SM in pediatric ALL. Further analysis is ongoing regarding the association with immune phenotype of ALL and details of genetic risk factors (e.g. TP53 mutations). Rigorous long-term FU of TBI patients is mandatory.

Outcome of Haematopoietic Cell Transplantation in 813 Children with Fanconi Anaemia: A Study on Behalf of the EBMT Severe Aplastic Anaemia Working Party and Paediatric Disease Working Party

Introduction: The SAAWP and PDWP of the EBMT performed a retrospective registry study on the largest cohort of 813 children (< 18 years) with Fanconi anaemia (FA) undergoing first haematopoietic cell transplantation (HCT) in 137 centers between 2010 and 2018. Methods: The primary endpoints were overall survival (OS), event-free survival (EFS; survival without graft failure, relapse and post-transplant malignancy) and GvHD-relapse free survival (GRFS; survival without grade III-IV acute GvHD (aGvHD), extensive chronic GvHD (cGVHD), graft failure, relapse and post-transplant malignancy). Secondary endpoints were cumulative incidence (CI) of grade II-IV aGvHD, cGvHD and graft failure. Subgroup differences in OS, EFS and GRFS were evaluated by log-rank test. Competing risks methods were used for the cumulative incidence of acute and chronic GVHD, with competing events being represented by death, graft failure, relapse and second transplant. Subgroup differences in cGvHD and aGvHD were evaluated by Gray's test. All estimates are reported with 95% confidence intervals. Results: Indications of transplant were bone marrow failure (BMF, n=778, 96%) and AML/MDS (n =35, 4%). Median age at transplant was 8.8 years (IQR, 6.5-11.5) and median follow-up was 3.7 years (3.4-4.0). Median interval between diagnosis and HCT was 2.1 years (IQR 0.8-4.5). Donors were MSD (n=342, 42%), MRD (n=99, 12%), MMFD (n=23, 3%), haploidentical donor (HID, n =66, 8%), MUD (n=162, 20%), MMUD (n= 121, 15%). Stem cell source was bone marrow (n=526, 65%), peripheral blood (n=226, 28%) or cord blood (CB; n=51, 6%) or BM+CB (n=9, 1%). Conditioning regimen was FluCy (n=91; 11%), FluCy /others (n=585, n=72%) and others (n=137, 17%). Ninety-six (12%) received TBI. Serotherapy was ATG (n=623, 77%), alemtuzumab (n=86, n=11%) and none (n=102, 13%). Eighty-five (11%) received T-cell depleted graft. The 5-year OS, EFS and GRFS were 83% (95% CI, 80-86%), 78% (75-81%) and 70% (67-74%). On univariate analysis, indications (p<0.001), age at HCT (p=0.009), donor type (p<0.001), stem cell source (p=0.02), conditioning (p=0.02), TBI (p=0.004), were significantly associated with OS. On multivariate analysis, indication (compared to BMF, AML/MDS had significant inferior OS, HR 5.12, p<0.001; BMF, 85%, 83-89%; AML/MDS 40%, 23-57%), donor type (compared to MFD, patients transplanted with MMUD/MMFD and HID had significantly inferior OS (2.11, p<0.001 and 2.63, p=0.013 respectively); MFD: 88%, 85-91%; MUD: 86%, 80-91%; MMUD/MMFD: 72%, 64-80%; HID: 70%, 59-82%; p<0.001) and serotherapy (compared to ATG, patients transplanted with alemtuzumab had lower mortality (0.35 (0.15-0.8), p=0.01)) (ATG: 82%, 79-85%; alemtuzumab: 93%, 88-98%; none: 83%, 80-88%; p=0.04) had significant impact on OS. In multivariate analysis, age at HCT, indications and donor type had significant impact on EFS and GRFS. In EFS, AML/MDS (HR=3.95, p<0.001) and older age (HR=1.76 per decade, p=0.015) were associated with worse outcomes. Event rate was significantly higher in HID and MMUD/MMFD (HR= 4.75 and 2.85 respectively, p<0.001). In GRFS, event rate was significantly higher in AML/MDS (HR=2.55, p<0.001) and all donor types compared to MFD (HR=2.05, 3.83 and 3.8 in MUD, HID and MMFD/MMUD respectively, p<0.001). Older age was associated with worse outcomes (HR=1.51 per decade, p=0.034). CI of grade II-IV aGvHD at day 100 and cGvHD at 1 year were 23% (20-26%) and 8% (6-10%). CI of secondary malignancies was 1% at one year and 3% at 5 years. Conclusion: This study demonstrates that MFD and MUD had comparable survival in paediatric FA; early HCT using MUD should be offered in the presence of peripheral cytopenia, as older age at HCT and development of MDS/AML are associated with inferior survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Follow-up of Bendamustine Plus Rituximab Regimen in 69 Treatment Naïve (TN) Patients with Waldenström Macroglobulinemia, a Study on Behalf of the French Innovative Leukemia Organization (FILO)

Background Waldenström macroglobulinemia (WM) is a rare hematological malignancy characterized by the accumulation of IgM-secreting clonal lymphoma cells with a lymphoplasmacytic morphological differentiation. Recently, BTK inhibition has emerged as a promising therapeutic strategy in WM (Buske, JCO 2022; Tam, Blood 2020). However, in real life, a large part of patients(pts) continue to be treated by chemoimmunotherapy (Buske, Lancet Hematol2018) including bendamustine (B)-rituximab (R) in salvage (Tedeschi , Leukemia Lymphoma 2015) or first line MW (Treon, ASH2016). We have previously reported a series of 69 WM pts treated by BR (Laribi, BJH 2018) and demonstrated that this regimen is efficient. However, the follow-up was relatively short and some questions remained unresolved in terms of long-range response and second cancer occurrence. Here we report results of this series with a longer follow-up. Methods Sixty-nine symptomatic previously untreated pts with WM diagnostic criteria according to the second WM Workshop recommendations were enrolled in this retrospective multi-center study between January 2013 and December 2017 in 13 French centers. MYD88L265P and CXCR4 mutations were searched using qPCR and or next generation sequencing. Del(17p) and/or TP53 mutation were investigated in 34 pts. All pts received a BR regimen consisting of 375 mg/m2 of R on day 1 and 90 mg/m2 of B on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Cumulative incidence of secondary malignancies and high-grade lymphomas were computed, considering death free of malignancies as a competing event. Event-free survival (EFS), time to next treatment (TNT), progression-free survival (PFS) and overall survival (OS) were plotted using the log rank test and Kaplan-Meier graphical comparison. Results Pts median age was 69 years old (yo; range 45-88) at WM diagnosis and 71 yo (range 46-88) at therapy initiation. MYD88 and CXCR4 mutations were present in 45/51 (88%) and 11/44 (25%) of pts, respectively. A complex karyotype was disclosed in 6/44 (14%) pts, and 1/34 (3%) had TP53 alteration. According to the IPSSMW score, 14 (22%) pts were low risk, 32(46%) intermediate, and 32 (46%) high risk. Using consensus response criteria, the overall response rate was 97% (very good partial response [VGPR] with negative immunofixation 19%, VGPR 37%, PR40%, MR 1%) and the major response rate was 96%. Cumulative incidence of VGPR or better was 47.8%, 53.6%, 55%, and 56% at 6, 12, 18, and 24 months, respectively. After a median observation time of 68.5 months (range 23.13-106) post BR, the median OS was not reached (83-NR) , and the median PFS was 82 months (75-NR). Median OS for pts with mutated or WT MYD88 was NR and 72.8 months, respectively (p=0.046). Median OS for pts with mutated or WT CXCR4 was 70.2 months and NR, respectively (p=0.64). Median OS related to disease or treatment was not reached, while median OS related to other causes was 106 months. Sixteen (23.2%) pts relapsed. Fourteen received second line therapy and 2 supportive care. Eight patients received ibrutinib, and 6 chemo-immunotherapy. TNT was 31.55 months (range 2.66-82.43). Median PFS after a second line of treatment (PFS2) was 45 (9.13-NR) or 21 months (range 9.13-NR), for pts receiving ibrutinib or not. Eleven pts developed a second cancer: 9 solid tumors (2 pancreatic, 2 gastric, 1colic, 1 pulmonary, 1 breast, 1 cutaneous), and 2 treatment-related myeloid neoplasms (TRMN). Median EFS, defined as occurrence of death, relapse or second cancer was 82 months (61-NR). The cumulative incidence of second cancer was 2.90%, 5.80%, 10.49%, and 17.6% at 12, 24, 48, and 96 months, respectively (figure 1). Univariate analyses on OS disclosed statistically significant differences for age at diagnosis (p=0.001), age at first therapy (p <0.001), IgM>70g/L (p: 0.018), complex karyotype (p=0.037), and high risk IPSSMW (p<0.01). In multivariate analysis, only IPSSMW remained statistically significant (p<0.001) (table1). Univariate analyses on PFS only singled out age at diagnosis (p=0.03) or at first therapy (p=0.049) as statistically significant. Mutated MYD88 or CXCR4 did not impact OS nor PFS. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes of Medulloblastoma Patients Treated with Proton Radiotherapy: A Systematic Review

<h3>Purpose/Objective(s)</h3> The aim of this study was to comprehensively review all studies examining clinical outcomes of proton therapy for craniospinal irradiation of medulloblastoma, to determine whether theoretical dosimetric advantages of proton therapy have translated into superior clinical outcomes, including survival and toxicities. <h3>Materials/Methods</h3> We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the PubMed (Medline), EMBASE, and Cochrane Library databases (inception to December 2021). The study was registered with PROSPERO, CRD42022302455. Articles in the English language reporting on clinical outcomes of pediatric and/or adult medulloblastoma patients treated with proton therapy were included. Two independent authors screened all titles/abstracts, reviewed full texts and extracted relevant data, with discrepancies resolved by consensus. Individual study quality was scored using Newcastle Ottawa Scale and overall evidence base by GRADE scale. <h3>Results</h3> Thirty-five studies were included, representing 629 unique patients. Publication dates ranged from 2011 to 2021, with the majority (n=32) from the United States. None of the studies were randomized, 12 were comparative, 9 were prospective, 3 mixed and 22 retrospective. Average mean/median follow up was 5.0 years (range = 4 weeks to 12.6 years). The majority of studies (n=19) reported on treatment with passive scatter proton beams exclusively. Average study quality score was 6.08 out of 9 (SD 0.688, median 5). Seven studies scored ≥8/9 on the Newcastle Ottawa Scale; an overall "moderate" GRADE score was assigned. Well-designed comparative cohort studies with adequate follow-up demonstrate superior neurocognitive outcomes, lower incidence of hypothyroidism (23% vs 69%) and reduced acute toxicities (including myelosuppression, esophagitis, diarrhea, weight loss and nausea/vomiting) in patients treated with protons compared to photons. The 10-year cumulative incidence of secondary malignancy is also lower for proton cohorts (2.1-4.9% vs 8%), but did not reach statistical significance in any individual study. Overall survival (10-yr) (85.3-86.9% for standard-risk disease), progression-free survival (10-yr), patterns of failure, and other endocrine outcomes such as incidence of GH deficiency, adrenal insufficiency and precocious puberty were similar to those reported for photon therapy. Quality of life, ototoxicity and incidence of CNS injury were also found to be comparable between proton and photon cohorts, albeit with lower quality of evidence. Overall, quality of evidence was most robust in the domains of intellectual outcomes, endocrinopathies and acute toxicity. <h3>Conclusion</h3> Moderate grade evidence supports proton beam therapy as a preferred treatment for craniospinal irradiation of medulloblastoma based on equivalent disease outcomes and comparable-to-improved toxicity versus photon beam radiotherapy.

Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies

PurposeTotal body irradiation (TBI) is a common part of the myelo- and immuno-ablative conditioning regimen prior to an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to concerns regarding acute and long-term complications, there is currently a decline in otherwise successfully established TBI-based conditioning regimens. Here we present an analysis of patient and treatment data with focus on survival and long-term toxicity.MethodsPatients with hematologic diseases who received TBI as part of their conditioning regimen prior to allo-HSCT at Frankfurt University Hospital between 1997 and 2015 were identified and retrospectively analyzed.ResultsIn all, 285 patients with a median age of 45 years were identified. Median radiotherapy dose applied was 10.5 Gy. Overall survival at 1, 2, 5, and 10 years was 72.6, 64.6, 54.4, and 51.6%, respectively. Median follow-up of patients alive was 102 months. The cumulative incidence of secondary malignancies was 12.3% (n = 35), with hematologic malignancies and skin cancer predominating. A TBI dose ≥ 8 Gy resulted in significantly improved event-free (p = 0.030) and overall survival (p = 0.025), whereas a total dose ≤ 8 Gy and acute myeloid leukemia (AML) diagnosis were associated with significantly increased rates of secondary malignancies (p = 0.003, p = 0.048) in univariate analysis. No significant correlation was observed between impaired renal or pulmonary function and TBI dose.ConclusionTBI remains an effective and well-established treatment, associated with distinct late-toxicity. However, in the present study we cannot confirm a dose–response relationship in intermediate dose ranges. Survival, occurrence of secondary malignancies, and late toxicities appear to be subject to substantial confounding in this context.

Incidence of Secondary Malignancies in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Era of Tyrosine Kinase Inhibitors (TKI)

IntroductionWith TKI therapy the survival of patients with CML-CP is approaching to that of general population. Data on the incidence of secondary malignancies in CML is conflicting given the rarity of CML and the low incidence of secondary malignancies. The aim of this study is to evaluate the incidence of secondary malignancies in patients with CML-CP in a large US-based database.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database identified 13,276 patients with newly diagnosed CML-CP during the period from 2001 to 2014. Patients who had prior history of cancer, concurrent diagnosis of other malignancies at the same diagnostic year, and patients who developed secondary leukemia after the diagnosis of CML were excluded. Cumulative incidence of secondary malignancies were estimated with the presence of competing risk of death. Standard incidence ratio (SIR) was calculated from person-years at risk divided by expected cases based on the age-adjusted incidence ratio of the 2000 U.S. standard population.ResultsOf 13,276 patients, secondary malignancies were observed in 597 patients (4%) with a median follow-up of 69 months (Table 1). The three most common secondary malignancies were male genital system 130 (22%), digestive system 124 (21%) and respiratory system, 92 (15%). The 5-year and 10-year cumulative incidence of death for all patients was 30.5% (95% confidence interval [CI], 29.6-31.4), and 41.8% (95% CI, 40.7-43.0). The 5-year and 10-year cumulative incidence of secondary malignancies were 4.4% (95% CI, 4.0-4.8), and 7.2% (95% CI, 6.6-7.9), respectively (Figure 1). Overall SIR was 1.204 (95% CI, 1.108-1.301). The increased SIRs were observed in male genital system of 1.593 (95% CI, 1.319-1.866); digestive system, 1.291 (95% CI, 1.064-1.519); skin, 1.588 (95% CI, 1.083-2.093); urinary system, 1.366 (95% CI, 1.008-1.724); and miscellaneous, 1.877 (1.033-2.721) (Figure 2). The decreased SIR was observed in breast cancer of 0.665 (95% CI, 0.479-0.852). Overall excess absolute risk was 1.714 per 1,000 person years at risk (95% CI, 0.622-2.805).ConclusionRelative incidence of overall secondary malignancies in CML-CP is slightly higher than that of general population with minimal increase in the excess absolute risk. Given the limitation of registry data, the uncertainty of use and type of TKI, and response status at the diagnosis of secondary malignancies, conclusions regarding actual risk should be cautiously interpreted. It is also at this stage not possible to determine whether any possible increased risk is associated with the diagnosis of CML-CP per se or the use of TKIs. Further analysis is needed. [Display omitted] DisclosuresKantarjian:Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. O'Brien:Amgen: Consultancy; Alexion: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Regeneron: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy. Wierda:Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Daver:Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding.

Ten-Year Follow-up of Newly Diagnosed Follicular Lymphoma Patients Treated with Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) As First-Line Therapy in JCOG0203 Trial

[Purpose]Rituximab combined with chemotherapy has been established as a standard of care for patients with newly diagnosed advanced stage follicular lymphoma (FL), especially with high tumor burden. However, the best chemotherapy partner of rituximab remains unclear. Owing to inevitable relapse and succumbing to histologic transformation (HT), there are prerequisites for first-line treatment to improve the outcome of FL patients. To elucidate the long-term outcome of FL patients more than 10 years after treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line therapy in a prospective clinical trial, we report the 10-year follow-up results of the patients allocated to either R-CHOP arm in a randomized phase II/III trial (JCOG0203, NCT00147121), in which both arms of R-CHOP-21 and R-CHOP-14 showed almost equal survival.[Patients and Methods]Patients with untreated indolent B-cell lymphoma in advanced stages were assigned to the potential standard arm; six cycles of R-CHOP-21 or the experimental arm; R-CHOP-14 with G-CSF. Rituximab maintenance was not allowed (JCOG0203 Trial; Watanabe T, et al, J Clin Oncol 2011;29:3990). Histopathologic specimens from all 300 patients were reviewed by 3 hematopathologists. The primary endpoint of the study was progression-free survival (PFS). According to the planned analysis after 10 years following enrollment of the last patient, clinical event information was updated. PFS and overall survival (OS) were estimated by using the Kaplan-Meier method, and Hazard ratio (HR) and its confidence interval were estimated through the Cox proportional hazards model. The incidences of HT and secondary malignancies were analyzed by cumulative incidence function.[Results]From September 1st, 2002 to February 28, 2007, 300 patients were enrolled. The number of patients lost to follow-up within 10 years from randomization was 19 in all eligible patients. Ten-year PFS were 32.8% (R-CHOP-21) vs . 38.8% (R-CHOP-14), and 10-year OS were 80.9% vs . 84.7%, respectively in 299 eligible patients; namely, there were no differences. According to the Follicular Lymphoma International Prognostic Index, there were no differences found for either PFS or OS in any of the three risk groups.We identified only male sex (HR: 1.57, 95% CI: 1.16-2.12) as a significant, unfavorable PFS factor, and age (>60) (HR: 2.03, 95% CI: 1.19-3.45) and increased LDH (>ULN) (HR: 2.38, 95% CI: 1.27-4.43) as significant, unfavorable factors of OS.The proportion of FL was comparable between the arms (133 and 132 patients), and therefore, the combined analyses of the two arms were performed. In a total of 265 FL patients, 5, 8, and 10-year PFS were 46.2, 39.6, and 36.8%, respectively. Five, 8, and 10-year OS were 93.6, 86.7, and 84.4%, respectively (Figure 1).HT was diagnosed in 27 of the 248 FL G1-3a patients (10.9% [95% CI: 7.3-15.5]), including 10 HT diagnosed clinically by the data including steep elevation of LDH levels or high accumulation of FDG (defined by SUVmax) in PET imaging (63.0% of HT was proved by biopsy). The pattern of the HT accumulation slope was similar to those reported previously but slightly different from that of PRIMA Trial, which showed more than half of them occurred within the first one year of follow-up; the cumulative incidence of HT at 3, 5, 8, and 10 years after enrollment were 2.4% (95% CI: 1.0-4.9), 3.2% (95% CI: 1.5-6.0), 8.5% (95% CI: 5.4-12.4), and 9.3 % (95% CI: 6.1-13.4), respectively (Figure 2).The incidence of secondary malignancies in the 248 FL G1-3a patients at 10 years was 8.1% (95% CI: 5.1-12.0) [hematologic malignancies; 2.9%].[Conclusions]R-CHOP may reduce the incidence of HT compared with previous reports in the pre-rituximab era and did not increase a 10-year cumulative incidence of secondary malignancies in previously untreated FL patients, compared with published data. Although 10-year OS of advanced FL patients treated with R-CHOP without rituximab maintenance in the first-line setting was favorable, 10-year PFS was unsatisfactory. Dose-dense immunochemotherapy did not improve either PFS or OS in patients with indolent B-cell lymphoma. Therefore, the new treatments to deepen remissions and to prolong time to progression of FL patients are needed. [Display omitted] DisclosuresTobinai:Chugai/Roche: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Kinoshita:Chugai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Jannsen: Honoraria; Kyowa Kirin: Honoraria; Bristol: Honoraria; Eisai: Honoraria; Takeda: Research Funding; Solasia: Research Funding; MSD: Research Funding. Yamaguchi:Eisai: Honoraria; Takeda Phamaceuticals: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharma: Honoraria; Nippon Shinyaku: Honoraria. Ando:Kyowa Hakko Kirin: Research Funding; Takeda Pharmaceutical: Research Funding. Ogura:Astrazeneca: Honoraria; Takeda: Consultancy, Honoraria; Mundipharma: Consultancy; Celltrion, Inc: Consultancy, Honoraria; SymBio: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; MeijiSeika Pharma: Consultancy. Tsukasaki:Chugai/Roche: Honoraria; Zenyaku Kogyo: Honoraria; Mundypharma: Research Funding; HUYA: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa-Kirin: Honoraria.

The Risk-Benefit Balance of Treatments for Hodgkin Lymphoma Reported in the Randomised and Non-Randomised Trial Setting: A Systematic Review

Introduction: Hodgkin lymphoma (HL) is a cancer that originates in the lymphocytes. Current standard of care (SOC) therapies include combination chemotherapy and/or radiotherapy regimens. However, optimising treatment to obtain high efficacy with low toxicity remains a challenge. A systematic literature review (SLR) was conducted to identify relevant clinical evidence for front line treatments in the management of patients with advanced Hodgkin lymphoma (HL) (defined as stage IIb, III, and IV).Methods: A SLR was performed in July 2016 to summarise the efficacy and safety of front-line treatments for the management of patients with advanced HL.Results: In total, 70 unique studies, 38 randomised controlled trials (RCTs) and 32 non-RCTs, were identified and included in the review. Of the 38 included RCTs, nine were open-label trials, while the remaining 29 trials did not report details of blinding. Most patients with advanced HL reported durable remissions following front-line SOC treatment (ABVD and escBEACOPP) (Table 1); however, these treatment options are associated with adverse events. Further, up to 30% of advanced HL patients relapse after frontline treatment, indicating an unmet need for new therapies. The incidence of secondary malignancy at long-term follow-up after HL treatment remains a major adverse effect. Nine of the included studies reported secondary malignancy in 1.7-8.3% of patients, with acute myeloid leukaemia and non-Hodgkin lymphoma the most commonly observed secondary malignancies. However, the follow-up across these studies ranged from 5 to 8 years and the incidence of secondary malignancy are potentially underestimated due to limited follow-up. A single study reported that the cumulative incidence of secondary malignancies was 48.5% at 40 years follow-up. The risk of secondary malignancy was increased in patients receiving combined modalities compared with chemotherapy or radiotherapy alone and the risk is greater in men compared with women. The risk of second malignancy increases after initial therapy and remains elevated at ≥35 years after treatment. In the majority of studies radiotherapy was administered either as adjuvant or consolidation therapy. The most commonly reported adverse effects observed in patients receiving radiotherapy were nausea/vomiting, infections, secondary malignancy, and toxicities related to cardiovascular and pulmonary systems. Pulmonary toxicity was reported in up to 36% of patients across 23 studies with bleomycin-containing regimens. Discontinuation or dose reduction of bleomycin was associated with a decrease in the incidence of pulmonary toxicity; however, the impact of bleomycin dose reductions on efficacy outcomes was not statistically significant. Neutropenia and febrile neutropenia are also dose-limiting events that occur during chemotherapy in patients with malignant lymphoma. Granulocyte colony-stimulating factor, a haematopoietic growth factor which prevents neutropenia/febrile neutropenia, was used for primary or secondary prophylaxis in 7 and 5 of the studies included in the SLR, respectively.Conclusion: Failure rates of up to 30% and serious adverse events are reported following treatment with current standard of care therapies in newly diagnosed patients with advanced HL. Therefore, there exists an unmet medical need for an effective and well-tolerated therapy in HL. [Display omitted] DisclosuresDalal:Takeda Pharmaceuticals International Co: Employment, Equity Ownership. Mitchell:DRG Abacus: Employment. McCloskey:DRG Abacus: Employment. Zagadailov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Takeda Pharmaceuticals International Co: Employment, Equity Ownership.

Risk of Secondary Malignancy in CLL Patients Treated with Novel Targeted Agents

Background: The introduction of novel targeted agents that inhibit specific cellular pathways has improved the prognosis of chronic lymphocytic leukemia (CLL) patients. CLL patients have a higher risk of secondary malignancies, but this risk has not yet been defined for patients treated with targeted agents, including inhibitors of BTK, PI3K or BCL2. Methods: We conducted a retrospective cohort study of CLL patients managed at a large tertiary care center between 1994 and 2018. Patients were classified according to whether they were treated with cytotoxic chemotherapy alone, chemoimmunotherapy or if they received a targeted agent (BTK inhibitor, PI3K inhibitor, BCL2 inhibitor) during the course of their disease. Time to first secondary malignancy corresponds to time elapsed between CLL diagnosis and the earliest secondary malignancy. Cumulative incidence of secondary malignancy was estimated considering competing risk of death. Multivariable analysis of cumulative risk of secondary malignancies was performed using Gray's method. Survival analysis was done with the Kaplan Meier method, comparisons were done using log - rank. Results: 265 CLL patients received care at our institution, median age (range) at diagnosis was 62 years (28-94), 168 (63.4%) were male, 199 (82.9%) were white, and 107 (41.5%) had Rai stage 3 or 4 at diagnosis. Median follow up was 10.5 years. Treatment was prescribed for 185 (70.1%) patients, 33 (17.7%) patients received only chemotherapy, 110 (59.1%) received chemoimmunotherapy, and 43 (23.1%) received targeted agents in the course of their disease. Median time to treatment was 11 months (IQR 1 - 177). Patients who did not receive therapy had a shorter median follow up (8.5 years) compared with treated patients (11.8 years) (p = &amp;lt;0.01), but there were no significant differences in the follow up times of patients receiving chemotherapy vs. chemoimmunotherapy vs. targeted therapy. We did not observe differences in the median number of treatment lines among treated patients. Patients treated with targeted agents had better overall survival (figure 1). Eighty patients developed a secondary malignancy (30.9%). The secondary malignancy of earliest onset was cutaneous malignancy in 40 patients (50.0%), solid tumor in 31 patients (38.8%), and hematologic malignancy in 9 patients (11.3%). Median time from diagnosis of CLL to secondary malignancy was 48 months (IQR 22 - 107), with 5- and 10-year cumulative incidence of secondary malignancy of 19.8% and 29.8%, respectively. Among solid tumors, cancers of the lung (8), colon (5), and prostate (4) were most common. Median time from diagnosis of CLL to solid tumor or hematologic malignancies was 48 months (IQR 24 - 91), with 5- and 10-year cumulative incidence of 10.7% and 18.4%, respectively. A total of 45 patients developed skin cancer following CLL diagnosis (20%); 17 of these patients were diagnosed with multiple cutaneous malignancies. Thirty-two patients were diagnosed with basal cell carcinoma, 27 with squamous cell carcinoma, and 5 with melanoma. Median time from diagnosis of CLL to cutaneous malignancy was 48 months (IQR 21 - 121), with 5- and 10-year cumulative incidence of 10.5% and 13.8%, respectively. Pairwise comparisons did not demonstrate statistically significant differences in median follow up of patients without secondary malignancy (9.6 years, 95% CI = 8.8-11.6), non-cutaneous secondary malignancies (10.8 years, 95% CI 9.5 -18.5), or cutaneous malignancies (11.8 years, 95% CI 10.6 -16.3). The cumulative incidence of secondary malignancies was not different among treatment groups (p = 0.9), but the cumulative incidence of cutaneous malignancies was higher among patients treated with targeted agents (p = 0.046) (figure 2). On multivariate analysis, age was the single risk factor associated with secondary malignancies (Figure 3), whereas the risk of cutaneous malignancies was also affected by treatment with targeted agents (hazard ratio = 3.1, 95% CI = 1.37-7.07) (figure 4). Conclusions: Secondary malignancies continue to be an important complication of CLL in the era of targeted therapies. We observed a higher cumulative incidence of cutaneous malignancies in patients treated with targeted drugs. As CLL patients treated with targeted agents experience improved survival, surveillance for secondary malignancies, in particular cutaneous cancers, remains an important health maintenance intervention. Disclosures Malek: Clegene: Other: Advisory board , Speakers Bureau; Takeda: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board, Speakers Bureau. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Celgene: Speakers Bureau; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Verastem: Other: Advisory Board; Amgen: Other: Advisory Board.

10-Year Breast Cancer Outcomes in Women ≤35 Years of Age

Breast cancer diagnosis at a very young age has been independently correlated with worse outcomes. Appropriately intensifying treatment in these patients is warranted, even as we acknowledge the risks of potentially mutagenic adjuvant therapies. We examined local control, distant control, overall survival, and secondary malignancy rates by age cohort and by initial surgical strategy. Female patients less than or equal to 35 years of age diagnosed with invasive breast cancer from January 1, 1990, to December 31, 2010, were identified. Control groups of those aged 36 to 50 years (n = 6246) and 51 to 70 years (n = 7294) were delineated from an institutional registry. Clinicopathologic and follow-up information was collected. Chi-squared test was used to compare frequencies of categorical variables. Survival endpoints were evaluated using Kaplan-Meier methodology. A total of 529 patients ≤35 years of age met criteria for analysis. The median age of diagnosis was 32 years (range 20-35). Median follow-up was 10.3 years. On multivariable analysis, factors associated with overall survival (OS) were tumor size (hazard ratio [HR] 1.14, P = .02), presence of lymphovascular invasion (HR 2.2, P <.001), estrogen receptor positivity (HR 0.64, P = .015), receipt of adjuvant chemotherapy (HR 0.52, P = .035), and black race (HR 2.87, P <.001). The ultra-young were more likely to experience local failure compared with the aged 36 to 50 group (HR 2.2, 95% CI 1.8-2.6, P < .001) and aged 51 to 70 group (HR 3.1, 95% CI 2.45 - 3.9, P <.001). The cumulative incidence of secondary malignancies at 5 and 10 years was 2.2% and 4.4%, respectively. Receipt of radiation was not significantly associated with secondary malignancies or contralateral breast cancer. Survival and recurrence outcomes in breast cancer patients ≤35 years are worse compared with those aged 36 to 50 or 51 to 70 years. Based on our data, breast conservation therapy is appropriate for these patients, and the concern for second malignancies should not impinge on the known indications for postoperative radiation therapy.

Second primary malignancies in patients with clinical T1bN0 esophageal squamous cell carcinoma after definitive therapies: Supplementary analysis of the JCOG trial, JCOG0502.

4565 Background: Esophageal squamous cell carcinoma (ESCC) is associated with synchronous or metachronous cancer at other primary sites. Previous studies have suggested that patients (pts) with ESCC are still at a high risk of second primary malignancies after definitive therapies. In particular, early-stage ESCCs result in good prognosis, which is associated with a higher risk of second primary malignancies. Methods: The JCOG0502 was a phase III trial, which included a randomized and a non-randomized part and compared esophagectomy with definitive chemoradiotherapy in clinical T1bN0 ESCC. We additionally reviewed data of all pts enrolled in the JCOG0502 for second primary malignancies. Lugol-voiding lesions (LVLs) were assessed in the noncancerous esophageal mucosa before the treatments. Results: Among 379 enrolled pts, 213 pts received esophagectomy and the remaining received chemoradiotherapy. Patient characteristics of overall cohort were as follows: male, 85%; median age, 63 (range, 41–75) years; upper- /middle- /lower thoracic esophagus, 11/63/27%; alcohol consumption history, 79%; smoking history, 66%; prevalence of no LVLs/several LVLs/many LVLs/unknown, 45/36/8/11%. With a median follow-up of 7.1 years, a total of 118 second malignancies were observed in 99 pts (26%). Cumulative incidences of second malignancies after 3, 5, 10 years were 9, 15, 36%, respectively. Most common primary tumor sites were head and neck (35%), followed by stomach (20%) and lung (14%). In multivariable analyses, several LVLs [hazard ratio (HR): 2.24, 95% confidential interval (CI): 1.32–3.81, vs. no LVLs] and many LVLs (HR: 2.88, 95% CI: 1.27–6.52, vs. no LVLs) were significantly associated with the development of second malignancies. Regarding the three most common types of cancers, 62 out of the 77 cancers (81%) were diagnosed in clinical stage 0–I. Seventeen pts died due to second primary malignancies. There were 4 and 3 deaths from head and neck and lung cancer, respectively. Whereas, mortality caused by stomach cancer was not observed. Conclusions: In the JCOG0502, the incidence of second malignancies was high, indicating that careful follow-up is required for ESCC pts even after treatment completion. The presence of LVLs in esophagus was identified as an independent predictive factor for second primary malignancies, which may be useful for surveillance strategies. Clinical trial information: UMIN000000551 .

Risk of second primary malignancies after definitive treatment for esophageal cancer: A competing risk analysis.

BackgroundEsophageal cancer is associated with synchronous or metachronous cancer at other primary sites. However, few studies have evaluated the second malignancies after the treatment of esophageal cancer. The present study aimed to clarify the frequency of and risk factors for the second malignancies after definitive therapy for esophageal cancer.Patients and MethodsWe included patients with esophageal cancer who received definitive therapy between 2000 and 2010. Exclusion criteria were synchronous cancer or a past history of cancer. Standardized incidence rate (SIR) was calculated using age‐ and sex‐specific incidence rates from the cancer registry data. To conduct risk analyses, we used the competing risk regression model, which defined death and the development of second malignancies as competing risks.ResultsA total of 758 patients were included, with 131 second malignancies occurring in 106 patients (14%), over a median follow‐up of 3.7 years. Cumulative incidences of second malignancies after 3, 5, and 8 years were 4.0%, 7.6%, and 13.8%, respectively. The risk of second malignancy was significantly elevated [SIR = 1.83, 95% confidence interval (CI): 1.50‐2.22]. The most common sites of primary tumor were the head and neck (20%), followed by the lung (17%), stomach (16%), colon and rectum (11%), and urinary tract (9%). Risk analyses revealed that age ≥ 65 years [subdistribution hazard ratio (sHR): 1.51, 95% CI: 1.01‐2.24, vs age < 65] and clinical stages 0‐I (sHR: 2.48, 95% CI: 1.46‐4.22, vs stage III and IV) and II (sHR: 2.10, 95% CI: 1.23‐3.58, vs stage III and IV) were significantly associated with second malignancies.ConclusionsCompared with the general population, an increased incidence of second malignancies was observed in the patients with esophageal cancer in the present study even after definitive treatment. Careful follow‐up is required, especially in patients at a higher risk of second malignancies.

Second Cancers in Adults with Acute Promyelocytic Leukemia (APL) Treated with or without Arsenic Trioxide (ATO): A SEER-Medicare Analysis

Background: ATO was approved by the U.S. Food and Drug Administration in 2000 for treatment of patients with relapsed/refractory APL and in 2018 in combination with all-trans retinoic acid (ATRA) for adults with newly-diagnosed low-risk APL. ATRA and ATO combinations result in long-term remissions in most patients with APL (Lo-Coco et al. NEJM 2013, Burnett et al. Lancet Oncol 2015). However, epidemiologic studies have shown associations between exposure to inorganic arsenic and development of skin, lung, bladder, and potentially liver, kidney, and prostate cancers (IARC 2004). The prescribing information for ATO includes a warning for carcinogenesis, with advice to monitor patients for development of second primary malignancies. Retrospective cohort analyses of second cancers in APL patients treated with ATO have been performed, finding incidence rates of 1-5% (Eghtedar et al. Leuk Lymphoma 2015, Au et al. Leuk Res 2007, Zhu et al. Blood 2016). We sought to perform an exploratory population-based analysis of second cancers in adults with APL treated with ATO compared to those treated with other systemic APL therapies without ATO using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Methods: Using SEER-Medicare linked data, we identified APL patients diagnosed from January 1, 2006 to December 31, 2015. Patients whose first SEER cancer diagnosis was APL, who were continuously enrolled in Medicare Parts A, B, &amp; D from the month of their APL diagnosis, and who received treatment with ≥ 1 systemic APL therapy within 1 year of diagnosis were included. Patients were followed from their first month of treatment group-defining APL therapy (ATO or non-ATO containing) until disenrollment from Medicare Parts A, B, or D, end of study period, or death. We determined the cumulative incidence of SEER-confirmed second cancers and overall survival (OS) according to whether patients were treated with or without ATO using the Kaplan-Meier method. We used a multivariate Cox proportional hazards model to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of cumulative incidence of second cancers and OS adjusted for relevant covariates of age, sex, and year of diagnosis. Results: We identified 1,442 APL cases, with 1,179 having APL as their first cancer diagnosis, of which 246 were enrolled in Medicare Parts A, B, and D. Of these, 64 received ATO and 60 received systemic APL therapy without ATO within 1 year of diagnosis. Characteristics, follow-up, and second malignancies for these cohorts are presented in the Table. Absolute incidence rates of second cancer were 3.4 per 1000 person-months compared to 1.4 per 1000 person-months in patients treated with and without ATO, respectively, and cumulative incidence rates at 24 months were 9.9% and 6.0%, respectively (p=0.20) (Figure 1). Mortality rates were 1.9 per 1000 person-months compared to 5.1 per 1000 person-months in patients treated with and without ATO, respectively, and OS rates at 24 months were 90.8% and 81.5%, respectively (p=0.10) (Figure 2). After adjusting for relevant covariates, HR for cumulative incidence of second malignancies in patients treated with ATO was 1.27 (95% CI 0.29-5.49; p=0.75) and for OS was 0.46 (95% CI 0.16-1.29; p=0.14) compared to APL therapy without ATO. Conclusions: This exploratory analysis revealed a high incidence of second malignancies in APL patients treated with ATO, although the risk was not significantly increased compared to patients who received other APL therapies. Most second malignancies following ATO were solid tumors, in line with prior epidemiologic studies of inorganic arsenic exposures. Despite the occurrence of second malignancies, there was a tendency towards longer OS in patients treated with ATO. Given the small sample size, short follow-up, potential selection and immortal time bias, and unaccounted for differences between comparator groups, firm conclusions cannot be inferred. However, the nearly 10% cumulative incidence of second malignancies at 24 months follow-up in Medicare patients with APL treated with ATO suggests the need for close monitoring for second malignancies following ATO therapy. Further prospective research into second malignancies following ATO is needed. Disclosures No relevant conflicts of interest to declare.

Long-Term Outcomes of Patients with Acute Myelogenous Leukemia Treated with Myeloablative Fractionated Total Body Irradiation TBI-Based Conditioning with a Tacrolimus- and Sirolimus-Based Graft-versus-Host Disease Prophylaxis Regimen: 6-Year Follow-Up from a Single Center.

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens.

Waldenström's macroglobulinemia front line treatment.

Waldenström's macroglobulinemia front line treatment.

Incidence of second malignancies in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) have near-normal life expectancies. With this comes the possibility of developing second cancers; we aimed to evaluate the incidence of second malignancies in patients with CML using Surveillance, Epidemiology, and End Results Program data. We identified 13,276 patients with CML newly diagnosed in 2001-2014. Patients who had prior history of cancer, a concurrent diagnosis of other malignancies in the same diagnostic year, or a second leukemia after CML diagnosis were excluded. Second malignancies were observed in 597 patients (4%) with a median follow-up of 69months. The 5- and 10-year cumulative incidences of death for all patients were 30.5% and 41.8%. The 5- and 10-year cumulative incidences of second malignancies were 4.4% and 7.2%, respectively. The overall standardized incidence ratio (SIR) was 1.204. Increased SIRs compared to the general population were observed for the male genital system, 1.593; digestive system, 1.291; skin, 1.588; and urinary system, 1.366. Overall excess absolute risk was 1.714 per 1000 person-years at risk. Our results suggest that relative incidence of overall second malignancies in CML is slightly higher than that of the general population, with minimal increase in the excess absolute risk.

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5). R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death. National Cancer Center and Ministry of Health, Labour and Welfare of Japan.