Second Primary Malignancies Research Articles

Once in a Blue Moon: Second Primary P16-Negative Tonsillar Carcinoma after Temporal Bone Squamous Cell Carcinoma

Second primary malignancy (SPM) is a well-known long-term cause of mortality in head and neck squamous cell carcinoma (HNSCC). The high incidence of head and neck SPM after HNSCC is related to field cancerisation, tobacco and alcohol exposure. Early detection of head and neck SPM is paramount to allow appropriate treatment and have better functional and survival outcomes. Further genomic study is warranted for better understanding about the risk, outcome and to improve survival of SPM. We reported the first case of second primary tonsillar carcinoma that was presented sixteen years after diagnosis of temporal bone squamous cell carcinoma (SCC) in a non-smoker patient. We highlighted the importance of having a long-term surveillance follow up in HNSCC, not only to look for locoregional recurrence and metastases but also to asses for SPM.

Long-Term Treatment Outcomes of Hypopharyngeal Cancer Using Different Surgical Modalities

Background and Objectives In the present study, we evaluated the treatment results of hypopharyngeal squamous cell carcinoma (HPSCC) patients and analyzed the occurrence of secondary primary malignancies. Treatments were based on two different surgical modalities (conventional pharyngo-laryngectomy vs. transoral surgery). In addition, prognostic factors of the patients were evaluated.Subjects and Method We analyzed medical data of 232 patients diagnosed with HPSCC and underwent surgery at our hospital from January 2006 to December 2019.Results The 5-year recurrence-free survival was 67.2% for the stage I-II group and 64.9% for the stage III-IV group. The 5-year disease-specific survival was 78.2% for the stage I-II group and 54.5% for the stage III-IV group. N classification was significantly correlated with disease relapse and patient mortality. Patient age, sex, perineural invasion, extranodal extension, initial tumor stage, and early recurrence (within 6 months) were significantly associated with successful salvage treatment. The two surgical modalities did not yield different oncological outcomes. Secondary primary malignancies occurred most frequently in the esophagus, with no observed inferior survival rate in patients with second malignancies.Conclusion The 5-year survival rate for HPSCC patients who received surgical treatment was 78% for stage I-II and 54% for stage III-IV. While no difference in oncological outcome was observed based on surgical modality, the transoral surgery group showed better functional outcomes.

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant

BackgroundThere is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT).MethodsPatients aged 0–39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed.ResultsTwo hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6–39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03).Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0–196.6) months after ASCT, and SPM was the cause of death in five (50%) of them.ConclusionsCAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Genotype-phenotype correlations of neurofibromatosis type 1: a cross-sectional study from a large Chinese cohort.

Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients. We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains. A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy. Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.

Mortality patterns of patients with tonsillar squamous cell carcinoma: a population-based study.

Tonsillar squamous cell carcinoma (TSCC) and second primary malignancies (SPMs) are the most common causes of mortality in patients with primary TSCC. However, the competing data on TSCC-specific death (TSD) or SPM-related death in patients with TSCC have not been evaluated. This study aimed to analyze the mortality patterns and formulate prediction models of mortality risk caused by TSCC and SPMs. Data on patients with a first diagnosis of TSCC were extracted as the training cohort from the 18 registries comprising the Surveillance, Epidemiology, and End Results (SEER) database. A competing risk approach of cumulation incidence function was used to estimate cumulative incidence curves. Fine and gray proportional sub-distributed hazard model analyses were performed to investigate the risk factors of TSD and SPMs. A nomogram was developed to predict the 5- and 10-year risk probabilities of death caused by TSCC and SPMs. Moreover, data from the 22 registries of the SEER database were also extracted to validate the nomograms. In the training cohort, we identified 14,530 patients with primary TSCC, with TSCC (46.84%) as the leading cause of death, followed by SPMs (26.86%) among all causes of death. In the proportion of SPMs, the lungs and bronchus (22.64%) were the most common sites for SPM-related deaths, followed by the larynx (9.99%), esophagus (8.46%), and Non-Melanoma skin (6.82%). Multivariate competing risk model showed that age, ethnicity, marital status, primary site, summary stage, radiotherapy, and surgery were independently associated with mortality caused by TSCC and SPMs. Such risk factors were selected to formulate prognostic nomograms. The nomograms showed preferable discrimination and calibration in both the training and validation cohorts. Patients with primary TSCC have a high mortality risk of SPMs, and the competing risk nomogram has an ideal performance for predicting TSD and SPMs-related mortality. Routine follow-up care for TSCC survivors should be expanded to monitor SPMs.

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

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

Longitudinal Screening of Mutant Hematopoietic Progenitor Cells (HPC) in Multiple Myeloma (MM) and Its Association with Secondary Primary Malignancies (SPM)

Background: The incidence of SPM in transplant eligible MM patients (pts) receiving lenalidomide maintenance is ≥ 12% and is associated with inferior overall survival (OS). Recent evidence suggests that while clonal hematopoiesis does not increase the risk of SPM, specific TP53 mutant HPC may expand under lenalidomide treatment and give rise to therapy related myeloid neoplasms and acute lymphoblastic leukemia. Genetic screening may facilitate personalized treatment to minimize the risk of SPM. However, there are no longitudinal studies in purified HPC to inform on the evolution of specific gene mutations and its association with clinical outcomes. Aim: Analyze the mutational landscape of HPC at diagnosis and throughout lenalidomide based regimens. Methods: This study included 335 pts: 43 with high risk smoldering MM, 223 transplant eligible and 69 ineligible active MM respectively enrolled in the CESAR, GEM2012MENOS/GEM2014MAIN and CLARIDEX clinical trials. Of the 335 pts analyzed at diagnosis, 60 were further investigated after induction, 30 at day 100 after autologous transplant (ASCT) and 47 during maintenance. Two or more studies were available throughout treatment in 36 pts. Fluorescence activated cell sorting of CD34+ HPC was performed in a total of 500 bone marrow aspirates. DNA was analyzed with a panel of 55 genes recurrently mutated in myeloid neoplasms. Sequencing depth was &amp;gt;1000x in 95% of nucleotides. Criteria to filter out included synonymous, intronic, invalid-transcript, 5'UTR, panel error and single nucleotide polymorphisms. The criteria to filter in was a AMP/ACMG classification of uncertain significance, likely pathogenic or pathogenic. Only the latter two were included in downstream analysis. Results: HPC from 184 of the 335 (55%) pts were mutated. The frequency in high-risk smoldering MM, transplant eligible and ineligible active MM was 46%, 26% and 35%, respectively. The genes more frequently mutated were DNMT3A (n=94, 52%), TP53 (n=29, 16%) and TET2 (n=28, 15%). The median variant allele frequency was 4.9, 7.5 and 7.0, respectively. In a pt-paired analysis between diagnosis and induction, 8 mutations were present in both time points, 25 became undetectable and 22 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 14 of the 60 (23%) pts. In the 30 pts with paired samples at diagnosis and at day 100 after ASCT, 4 mutations were present in both time points, 48 became undetectable and only 3 were acquired during treatment ( ATRX, MPL and SAMDL9). Thus, the frequency of mutant HPC was higher at diagnosis vs ASCT (23% vs 5%, P &amp;lt;.001). In a pt-paired analysis between diagnosis and maintenance, 13 mutations were present in both time points, 12 became undetectable and 30 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 24 of the 47 (51%) pts screened at both time points, and after a median of 5 years since diagnosis. With a median follow-up of 6 years, 17 of the 335 (5%) pts developed SPM. Mutant HPC were detected in 13 of the 17 pts. Accordingly, presence of mutant HPC was associated with a 2-fold increased risk of SPM (OR: 2.3; P = .03). Of the 13 pts, 3 showed mutations at diagnosis and in 8 these emerged during maintenance. The only case developing a myeloid neoplasm had a TP53 mutation present during maintenance that was undetectable at diagnosis. Pts with mutant vs non-mutated HPC at diagnosis showed similar OS (6y rates of 86% and 81%, respectively; P =.46). Similarly, there were no differences in OS of pts with emerging mutations vs those without mutant HPC after treatment (6y rates of 85% and 83%, respectively; P =.65). Specific mutations in DNMT3A, TP53 and TET2 and were not associated with inferior OS. Conclusions: To our knowledge this is the first study analyzing the mutational landscape of purified HPC throughout lenalidomide based regimens in high risk smoldering MM as well as transplant eligible and ineligible active MM. Deep sequencing of CD34+ HPC uncovered that the frequency of mutations is similar between precursor and malignant disease, and that TP53 is amongst the top mutated genes. There was considerable volatility with presence of both transient and emerging mutations throughout treatment. Importantly, the detection of mutant HPC was associated with increased risk of SPM without differences in survival. Thus, this study supports the longitudinal screening of HPC for the identification of patients at risk of developing SPM.

A Randomized Phase II Study of Daratumumab, Ixazomib, and Dexamethasone (DId, Arm A) Vs Daratumumab, Bortezomib and Dexamethasone (DVd) Followed By Daratumumab, Did (Arm B) in Newly Diagnosed Multiple Myeloma (DeRIVE) Study

Introduction: The safety and efficacy established by daratumumab (a CD38 monoclonal antibody)-based induction therapies for both transplant-eligible myeloma patients (based on CASSIOPEIA, and GRIFFIN trials) and transplant-ineligible patients (based on MAIA trial) have gained an accelerated momentum for adoption into regular clinical practice. In this context, to find the most optimal non-IMID based daratumumab-combination therapy as induction, we conducted a randomized phase 2 study to evaluate the safety and efficacy for in-class transition from bortezomib to ixazomib, stratified by transplant-eligibility and R-ISS. Methods: Patients were randomized to receive Arm A [daratumumab, ixazomib and dexamethsone (DId) X 8 cycles)] or Arm B [(daratumumab, bortezomib and dexamethsone (DVd) x 3) followed by (DId x 5 cycles)] for the primary endpoint of ≥ very good partial response rate (VGPR) rate post-induction cycle 8. Several other secondary endpoints were evaluated including safety, overall repsonse rate (ORR), progression free survival (PFS) and overall survival (OS). Standard dosing schedule was used [DId: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), ixazomib - 4 mg PO on Days 1, 8, and 15 every 28 days and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days; DVd: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), bortezomib - 1.3 mg/m2 SC on days 1, 4, 8 and 11 every 21 day and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days]. Transplant eligible patients may receive stem cell collection and transplant after cycle 8. During the maintenance phase, patients receive DId as maintennace therapy for a total of 32 cycles. 52 subjects were enrolled at Winship Cancer Institute of Emory University between 07/2019 and 05/2022. Results: The median age was 64 years for the 48 evaluable subjects [25 (52%) in arm A, 68 (48-87) and 23 (48%) in arm B, 61 (37-80), p&amp;lt;0.25]. 56% of the cohort was male (64 vs 48%, p=0.20), 48% were black (40% vs 56.5%, p=0.245). 20.8% had t(11;14), 29.2% had 1q abnormalities, 70.8% had hyperdiploidy, 25% had complex karyotype and 10.4% were high-risk [defined as presence of del17p, t(4;14) or t(14;16)]. 38 (81%) patients underwent an autologous stem cell transplant (72% in Arm A and 90.9% in Arm B, p=1.00). The primary endpoint favored arm B (Arm A vs Arm B ≥VGPR rate: 28% vs 56.5%, p&amp;lt;0.043). Similarly, the ORR favored arm B as well (Arm A vs Arm B ORR: 76% vs 95.7%, p&amp;lt;0.062). Post transplant ≥VGPR rates and ORR were 88.9% vs 95%, p=0.458 and 100% vs 100%, p=NS, respectively. At a median follow up of 35.2 months, 80% of the patients remain progression free as shown in figure 1. The adverse event profile was similar across both cohorts (grade 3/4 events occurred in 6 (24%) vs 7 (30%) for Arm A and B, respectively, p=0.27). There was no grade 3/4 peripheral neuropathy (PN), though grade 1/2 PN were higher in Arm B. There were two secondary primary malignancy reported in Arm B (prostate adenocarcinoma, esophageal adenocarcinoma). All together the safety signals were comparable between both arms. Conclusion: This is one of the first studies showing the safety and efficacy of non-IMID based dara-combination induction therapies with in-class transition of bortezomib to ixazomib yielding higher response rates post-induction and post-transplant without compromising on the safety. 3-year PFS rate of close to 80% across both arms is for daratumumab and proteasome inhibitor combination therapy are highly encouraging and may be an alternative regimen for patients that may not tolerate IMIDs or that have a contraindication to receive IMIDs.

Clinical and Diagnostic Challenges in Patients with Concomitant Plasma Cell Disorders and Myeloproliferative Neoplasms

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell precursor disease that regularly precedes the development of multiple myeloma (MM). It accounts for about 4.5% in the entire population, however patients with myeloproliferative neoplasms (MPN) seem at a higher risk for MGUS with a reported rate of concomitant disease at 3-14%. The reason for this co-occurrence of MGUS and MPN remains unclear, and a common cell of origin has not yet been defined. Inversely, constant MPN-driven inflammation in the bone marrow microenvironment (BM) may stimulate the expansion of a pre-existing plasma cell clone thereby promoting the transition from MGUS to active MM. Here, we investigated the clinical and molecular characteristics of a comprehensive series of cases treated for MGUS/MPN overlap at our center. Methods: Patients who were diagnosed with concomitant MGUS/MM and MPN between 2006 and 2023 were identified by retrospective chart review, yielding a total of 13 cases. Results: We identified 5/13 patients with a confirmed diagnosis of MGUS and 8/13 cases with active MM, all coinciding with a diagnosis of MPN (5 polycythemia vera (PV), 4 chronic myelomonocytic leukemia (CMMol), 3 primary myelofibrosis (PMF), 1 chronic myelogeneous leukemia (CML)). Median age at diagnosis was 66 (range 44-78) years for MGUS/MM and 64 (range 43-81) years for MPN. Overall survival in our cohort was rather short at a median of 8.2 (range 0-16) years. For clinical management, anti-MM therapy was prioritized over MPN treatment in the majority of patients, with the exception of CMMol. MPN-related organ restrictions significantly limited treatment options for MM, including bleeding disorders, infectious complications and impaired hematopoiesis (in PMF). High-dose concepts were performed in transplant-eligible cases, including autologous in 4 and allogenic stem cell transplantation in 2 patients. Two out of 6 patients died under transplant (1 autologous graft failure), indicating a comparably high transplant-related mortality. Another patient died from MM progression as PMF-induced anemia did not allow for more intense treatment. To examine the evolutionary path from MGUS to MM and the potential impact on this transformation by a concomitant MPN, we next examined the clinical course of disease in each patient. Six out of 13 patients had secondary MPN after prior MGUS/MM diagnosis, 5/13 patients were diagnosed with MPN first, and for 2/13 cases BM assessment revealed coincidental findings of MPN/ MM at the same time. For the cases of secondary MPN after initial diagnosis of MM/MGUS, latency between both diseases was shorter, than vice versa (40.2 vs. 73.6 months, P=0.19). No association was observed between secondary MPN and prior treatment for MM, as only 1/6 patients was diagnosed with PV following high-dose melphalan chemotherapy, potentially pointing towards a negligible role of treatment-induced secondary primary malignancies the context of MM/MPN overlap. In contrast, MGUS progression to active MM was observed in 1 patient with hyperdiploid IgG kappa MM (including trisomy 9) and long-term coexistent JAK2-mutated PV. Another patient was diagnosed with IgG kappa MM and 9p gain along with concomitant JAK2-mutated PMF. Whole-genome sequencing (WGS) is currently ongoing for these patients to decipher the temporal relationship of MM/MGUS and JAK2-mutated MPN. Conclusions: The prevalence of MGUS/MM in MPN patients seems modestly increased as compared to the entire population. From a clinical viewpoint, overlap of both diseases poses significant challenges to healthcare providers as treatment-related mortality tends to be higher than in patients with mutually exclusive MPN/ MM. Improved understanding of the molecular interplay of both diseases will inform risk-adjusted treatment decisions and will lead to improved outcomes in this highly challenging subgroup of patients.

Incidence and mortality of second primary malignancies after lymphoma: a population-based analysis

Background: Second primary malignancies (SPMs) account for an increasing proportion of human malignancies. We estimated the incidence, risk factors and outcomes in lymphoma survivors with SPMs. Methods: Patients diagnosed with SPMs after primary lymphoma from 2010 to 2021 were included in this study. The incidence, mortality and clinical characteristics of SPMs in our center and Surveillance, Epidemiology, and End Results database were delineated and analyzed. Standardized incidence ratio quantified second cancer risk. Results: A total of 2912 patients of lymphoma were included, 63 cases of SPM met the inclusion criteria, with the prevalence of SPMs after lymphoma was 2.16%. The male-to-female ratio of 2.32:1. The majority of these patients were older (≥60 years old, 61.90%) and previously treated with chemotherapy (68.25%). The common types among SPMs were digestive system tumors (42.86%), respiratory system tumors (20.63%) and urinary system tumors (12.70%). Additionally, cancer risks were significantly elevated after specific lymphoma though calculating the expected incidence. In terms of mortality, the diagnosis of SPMs was significantly associated with an increased risk of death over time. Moreover, although the outcome was favorable in some SPM subtypes (thyroid and breast cancer), other SPMs such as stomach and lung tumors had a dismal prognosis. Conclusion: With the improvement of medical standards, the survival of lymphoma patients has been prolonged. However, the incidence of SPM is increasing, particularly among men and older lymphoma survivors. Therefore, more attention should be invested in the SPM to further improve the prognosis of these patients.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - &amp;gt;160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed &amp;gt;1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (&amp;lt;3 - 600, n=48), falling to 28.1U/ml following induction (&amp;lt;3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (&amp;lt;3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (&amp;lt;3 to 517, n=72), falling to 31.2U/ml 4 months post induction (&amp;lt;3 - 287, n=42) and recovering to 51.3U/ml after 1 year (&amp;lt;3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be &amp;lt;20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (&amp;lt;3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (&amp;gt;20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Incidence of Secondary Primary Malignancies after Long-Term Follow up of Multiple Myeloma Patients Treated with Autologous Stem Cell Transplantation - Report from Croatian Cooperative Group for Hematologic Malignancies (KroHem)

Background: Autologous stem cell transplantation (ASCT) after induction treatment is standard of care for multiple myeloma (MM) for the last 30 years. Two transplantations up-front (so-called tandem transplant) were standard of care for all MM patients. With the use of new antimyeloma agents (such as proteasome inhibitors, immunomodulators and especially monoclonal antibodies) this approach has changed and tandem transplant is now reserved mainly for patients with high-risk disease, defined by revised international staging system (R-ISS). There have been reports which cast further doubts on the value of the more aggressive tandem ASCT approach, as well as reports suggesting higher incidence of secondary primary malignancies (SPM) after high dose therapy and ASCT. Aims: To describe long-term outcomes of MM patients treated with ASCT (single, delayed, and tandem) and the rate of secondary primary malignancies. Methods: a retrospective analysis of outcomes of 577 MM patients who underwent 865 ASCT procedures between 1993 and 2017 was performed. Data were collected from 3 transplant centres and 9 other haematological centres in which MM patients were treated pre- and post-transplant. During that period treatment strategies changed significantly from single to tandem to salvage second ASCT. Results: there were 577 patients included. Median age at first transplant was 58 years (range 22 - 74). There were 295 female and 282 male patients. 346 patients received VAD (vincristine, doxorubicin, dexamethasone) and 231 received bortezomib and/or thalidomide (PI/IMiD) based regiments as induction therapy. All patients received high dose melphalan for pretransplant conditioning, 32 in combination with total body irradiation. Tandem ASCT (defined as second transplantation performed within 6 months after the first) was performed in 226 patients, single ASCT in 262 and salvage second (after relapse and/or progression) in 89 patients. Median overall survival (OS) for the entire group is 81.9 months and median progression free survival (PFS) 38.9 months. Tandem ASCT in comparison to single and second salvage transplantation resulted in statistically significant better OS (115 vs. 83 vs. 67 months respectively, p &amp;lt; 0.0001) and PFS (48 vs. 32. vs. 28 months respectively, p &amp;lt; 0.0001). There was no difference in outcomes regarding type of induction therapy, VAD vs. PI/IMiD based: median OS was 83 vs. 80 months, respectively (p=0.39) and median PFS was 39 vs. 38 months, respectively (p=0.15). 17.6% percent of patients who were treated with tandem ASCT are progression-free more than 10 years after the procedure while 10-year OS is 31.9%. 51 patients (8.8%) developed secondary malignancies (SPM). Most common SPM were lung carcinoma (10 patients), colorectal carcinoma (7 patients), myelodysplastic syndrome/acute myeloid leukaemia (6 patients), breast carcinoma (4 patients) and melanoma (4 patients). Of those 19 died due to SPM (3% of the entire patient group). There was no correlation between number of ASCT and SPM (p=0.87). Conclusion: in our group of patients tandem ASCT resulted in superior OS and PFS in comparison to single and/or salvage ASCT. Interestingly, we did not observe benefit of new drugs (PI/IMiD) in induction therapy regarding outcomes. This peculiar result might be due to rather late availability of these drugs in front line settings (bortezomib and thalidomide since 2015) and time period taken for analysis (up to 2018). SPM rate was similar to other reports and did not show significant correlation with number of ASCT. More than 15% of patients treated with tandem ASCT experienced very prolonged PFS and almost 32% had OS longer than 10 years.

The Phase 2 CARTITUDE-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1-3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B)

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months. Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs). Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related). Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.

Risk prediction of second primary malignancies in patients after rectal cancer: analysis based on SEER Program

BackgroundThis study will focus on exploring the clinical characteristics of rectal cancer (RC) patients with Second Primary Malignancies (SPMs) and constructing a prognostic nomogram to provide clinical treatment decisions.MethodsWe determined the association between risk factors and overall survival (OS) while establishing a nomogram to forecast the further OS status of these patients via Cox regression analysis. Finally, we evaluated the performance of the prognostic nomogram to predict further OS status.ResultsNine parameters were identified to establish the prognostic nomogram in this study, and, the C-index of the training set and validation set was 0.691 (95%CI, 0.662–0.720) and 0.731 (95%CI, 0.676–0.786), respectively. The calibration curve showed a high agreement between the predicted and actual results, and the receiver operating characteristic (ROC) curves verified the superiority of our model for clinical usefulness. In addition, the nomogram classification could more precisely differentiate risk subgroups and improved the discrimination of SPMs’ prognosis.ConclusionsWe systematically explored the clinical characteristics of SPMs after RC and constructed a satisfactory nomogram.

Influence factors of the survival in colorectal cancer patients with second primary malignancy after surgery: A SEER database analysis.

The survival rate is significantly reduced in patients with colorectal cancer (CRC) who developing a second primary malignancy (SPM), and however, little has known about the factors that contribute to the mortality of SPMs among CRC survivors. This study aims to explore the influence factors in both the all-cause and cancer-specific mortality of patients with SPMs after CRC surgery. Data of adult CRC patients with SPMs were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in this retrospective cohort study. The associations between potential influence factors and all-cause mortality and cancer-specific mortality were explored using univariate and multivariate Cox proportional hazards analyses. The evaluation indexes were hazard ratios (HRs), and 95% confidence intervals (CIs). We also drew pie charts to respectively reflect the distributions of SPMs sites and time interval in study population. A total of 1202 (56.14%) patients died for all-cause, and 464 (21.67%) died due to CRC. The results showed that after adjusting for covariates, age, sex, marital status, T stage of CRC, second primary cancer site, stage of SPMs, grade of SPMs, TNM stage of SPMs, and time interval were associated with all-cause mortality, while marital status, stage of CRC, T stage of CRC, chemotherapy, second primary cancer site, stage of SPMs, grade of SPMs, TNM stage of SPMs, and time interval were associated with cancer-specific mortality in patients with CRC. In addition, colon (23.5%) was the most common site of SPMs, followed by digestive system (19.0%), and the time interval between CRC and SPMs in most patients was over 5 years (28.4%). Our findings may assist clinicians to identify high-risk patients for SPMs after CRC surgery. Also, the postoperative long-term follow-up and close attention on the key systems where the SPMs may occur are of great necessary in patients with CRC.

Second primary malignancies in patients with lymphoma in Denmark after high-dose chemotherapy and autologous haematopoietic stem-cell transplantation: a population-based, retrospective cohort study

Second primary malignancies (SPMs) are known complications after chemotherapy, but the risk is not well characterised for patients with lymphoma treated with high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the rate of SPMs in this population relative to matched control individuals from the general population. In this retrospective, population-based cohort study, patients aged 18 years or older with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT in Denmark between Jan 1, 2001, and Dec 31, 2017, were included from the Danish Lymphoma Registry and matched (1:5) to control individuals from the general population on birth year and sex via the Danish Civil Registration System. Patients were eligible if they had a registered date of autologous HSCT and patients with primary CNS lymphoma were excluded. Exclusion criteria for both patients and matched control individuals were HIV infection, organ transplantation, or other malignancies before inclusion. The key endpoint was the incidence of SPMs assessed in all study participants. The effect of treatment on SPMs was also investigated in patients who were followed up from first lymphoma diagnosis, with high-dose chemotherapy and autologous HSCT as a time-dependent exposure. Of 910 patients with lymphoma assessed, 803 were included (537 [67%] were male and 266 [33%] were female); 4015 matched control individuals were included (2685 [67%] were male and 1330 [33%] were female). Ethnicity data were not available. Median follow-up was 7·76 years (IQR 4·77-11·73). The SPM rate was higher among patients receiving high-dose chemotherapy and autologous HSCT than matched control individuals (adjusted hazard ratio [HR] 2·35, 95% CI 1·93-2·87, p<0·0001). Patients receiving high-dose chemotherapy and autologous HSCT had a higher rate of non-melanoma skin cancer (2·94, 2·10-4·11, p<0·0001) and of myelodysplastic syndrome or acute myeloid leukaemia (AML; 41·13, 15·77-107·30, p<0·0001) than matched control individuals, but there was no significant difference in the rate of solid tumours (1·21, 0·89-1·64, p=0·24). The cumulative risk of SPMs at 10 years was 20% (95% CI 17-23) in patients compared with 14% (13-15) in matched control individuals. High-dose chemotherapy and autologous HSCT was associated with an increased risk of SPMs when analysed as a time-dependent exposure from first lymphoma diagnosis (adjusted HR 1·58, 95% CI 1·14-2·17, p=0·0054). High-dose chemotherapy and autologous HSCT was associated with an increased risk of non-melanoma skin cancer and myelodysplastic syndrome or AML but not with increased risk of solid tumours in patients treated for lymphoma. These findings are relevant for future individualised risk-benefit assessments when choosing between high-dose chemotherapy and autologous HSCT and chimeric antigen receptor T-cell therapy in this setting. Danish Cancer Society.

Real-World Pitfalls of Analyzing Real-World Data: A Cautionary Note and Path Forward.

Real-world data (RWD) are pervasive in oncology research and offer insights into clinical trends and patient outcomes. However, RWD have shortcomings, making them prone to pitfalls during survival analyses. The American Society of Clinical Oncology (ASCO) CancerLinQ Discovery (CLQD) multiple myeloma (MM) data set was used to demonstrate some common pitfalls when analyzing survival from RWD: using incorrect surrogate markers for missing data and/or classification errors, ignoring deaths at time zero, and failing to account for guarantee-time bias. The ASCO CLQD MM data set (July 19, 2021, release) was used to compare overall survival (OS) in patients with a known versus presumed date of MM diagnosis, in patients with secondary AML (sAML) with early deaths (ie, 0 months) included versus dropped, and in patients with second primary malignancies (SPMs) matched versus unmatched to control for time-related confounding factors (ie, guarantee-time bias). Analyses were conducted using STATA Version 17.0 (College Station, TX). In the CLQD MM data set, 28% of patients were missing a diagnosis date. Attempts to use the presumed diagnosis date (ie, first bortezomib or lenalidomide administration) as a surrogate marker for missing diagnosis dates were not successful as median OS was significantly different in patients with a recorded versus presumed diagnosis date (107 v 40 months, hazard ratio [HR], 2.5; 95% CI, 2.39 to 2.64; P < .001). Dropping deaths within 1 month of sAML diagnosis resulted in an exaggerated median OS (46 v 39 months). OS in patients with MM with SPMs differed substantially before and after incorporation of matching methods to account for guarantee-time bias (HR, 0.73; 95% CI, 0.67 to 0.78; P < .001 before matching, HR, 1.30; 95% CI, 1.18 to 1.43; P < .001 after matching). To fully maximize the benefits of RWD in oncology research, clinicians must be aware of analytic methods that can overcome pitfalls in survival analyses.

Beyond remission: secondary primary malignancies in patients with lymphoma after autologous haematopoietic stem-cell transplantation

Beyond remission: secondary primary malignancies in patients with lymphoma after autologous haematopoietic stem-cell transplantation

P-468 Risk of secondary primary malignancies after multiple myeloma in the novel therapy era: a nationwide case-control cohort study

P-468 Risk of secondary primary malignancies after multiple myeloma in the novel therapy era: a nationwide case-control cohort study

Immunotherapy with PD-1 Inhibitor Nivolumab in Recurrent/Metastatic Platinum Refractory Head and Neck Cancers-Early Experiences from Romania and Literature Review.

Prognosis in recurrent/metastatic head and neck squamous-cell carcinoma (HNSCC) refractory to platinum-based chemotherapy is poor, making therapy optimization a priority. Anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody Nivolumab was approved in such cases. We present the early experience with Nivolumab immunotherapy at three cancer clinics from south and northeast Romania, aiming to describe the main characteristics and outcomes relative to literature reports, and to suggest patient selection criteria. Diagnostic, clinical, biological, therapeutic, and outcomes-related data from January 2020 until March 2023 were analyzed retrospectively. Eighteen patients with platinum refractory HNSCC (85.7% men, median age 58.9) were administered Nivolumab for 1-14 months (median 5.6 months) in addition to other treatments (surgery, radiotherapy, chemotherapy), and monitored for up to 25 months. Median neutrophil-to-lymphocyte ratio (NLR) ranged from 2.72 initially to 6.01 during treatment. Overall survival (OS) was 16 months, and patients who died early had the sharpest NLR increases (13.07/month). There were no severe immune-related adverse events. Lower NLR values and combined intensive chemotherapy, radiotherapy, and immunotherapy were related to better outcomes. To our knowledge, we also report the first two cases of second primary malignancy (SPM) in the head and neck region treated with Nivolumab in Romania (for which the sequential administration of radiotherapy and immunotherapy seems better). The work of other Romanian authors on the role of HPV status in HNC is also discussed. Multi-center trials are needed in order to investigate and confirm these observations.