This secondary analysis of the GHSG HD21 randomized clinical trial evaluates the tolerability and impact of BrECADD vs escalated BEACOPP on health-related quality of life for patients with Hodgkin lymphoma.

INTRODUCTION:Older patients with cancer are at increased risk for adverse drug events due to chronic conditions and complex medication regimens often leading to polymedication. A pharmacist-led medication review has the potential to reduce drug-related problems and enhance medication safety. Oncogeriatric scores are effective in predicting chemotherapy-associated toxicity. However, risk scores are only of benefit for the patient if the results lead to therapeutic consequences. This study aimed to develop and evaluate an interprofessional risk-adapted medication management intervention (IrMa) to reduce the symptom burden caused by adverse drug events in older patients with cancer. MATERIALS AND METHODS:The individualized care approach entailed adapting the intensity of care to the toxicity risk of each patient. This was determined prior to tumor therapy by using the Cancer and Aging Research Group (CARG) score and existing polymedication. Based on their individual risk, patients were divided into different groups and received either standard care ("low-risk patients"), or, for high-risk patients, symptom counseling, medication review, or both. Feasibility and acceptability of the intervention were investigated as primary outcome. Toxicity and patient-reported symptom burden were documented and analyzed as secondary outcomes. A non-inferiority analysis was conducted to assess whether high-risk patients who received the IrMa intervention experienced a similar level of toxicity or symptom burden as low-risk patients, despite their higher risk. This analysis aimed to identify preliminary efficacy signals. RESULTS:The intervention was feasible and well accepted. Out of 101 enrolled patients, 96 patients aged between 70 and 88 years were stratified. Implementation rates were 100% for medication reviews and 74% for symptom counseling. Of the identified drug-related problems requiring intervention, 73.9% were resolved. In the first cycle, the overall toxicity rate (CTCAE grade ≥ 3) was 67.5% in low-risk patients and 80.4% in high-risk patients. Preliminary efficacy signals were identified for patient-reported mucositis, vomiting, constipation and diarrhea in the first cycle but not for toxicity grade ≥ 3. DISCUSSION:The interprofessional, risk-adapted medication management for older patients with cancer is a feasible and accepted approach to improve patient safety. Patient-reported outcomes indicate a preliminary efficacy in reducing symptoms that can be influenced by appropriate supportive care.

PURPOSE:Positron emission tomography (PET)-guided therapy with 4-6 cycles of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) is highly effective in younger patients with advanced-stage classic Hodgkin lymphoma (AS-cHL). We report feasibility and efficacy of PET-guided BrECADD as first-line treatment in older patients with AS-cHL. PATIENTS AND METHODS:Patients with AS-cHL aged 61-75 years were enrolled in a phase II single-arm cohort of the HD21 trial (ClinicalTrials.gov identifier: NCT02661503). Patients with negative PET/computed tomography after 2×BrECADD (PET2) received a total of 4×BrECADD, while PET2-positive patients received 6×BrECADD. The primary end point was the centrally reviewed complete remission (CR) rate after the end of chemotherapy (EOC). Secondary end points included feasibility, adverse events, treatment-related morbidity (TRMB), progression-free survival (PFS), overall survival (OS), and health-related quality of life (HRQoL). RESULTS:Between June 2020 and April 2023, 85 patients were enrolled, of whom 83 with a median age of 67 years (range, 61-75) were analyzed in the intention-to-treat cohort. Most prevalent ≥grade 3 toxicities included leukopenia (n = 80 [96%]), thrombocytopenia (n = 71 [86%]), anemia (n = 57 [69%]), and febrile neutropenia (n = 46 [55%]). Forty-eight (60%) of 80 patients with centrally reviewed PET2 were scheduled for 4×BrECADD and 32 (40%) for 6×BrECADD. Of these, 71 patients (89%) received the target number of cycles. Sixty-eight patients (82%; 95% CI, 72 to 90) achieved CR at EOC. PFS and OS estimates at 2 years were 91.5% (95% CI, 85 to 98) and 90.8% (95% CI, 84 to 98), respectively. No death was attributed to study treatment. Initially, impaired HRQoL scores improved during follow up and on average reached population reference values. CONCLUSION:PET-guided BrECADD in older patients is feasible and effective. With a PFS rate on par with that of younger patients, short duration, and limited anthracycline exposure, BrECADD is a valuable treatment option also for older patients with AS-cHL.

Abstract Background Daratumumab (Dara) combined with either VRd or Rd is a standard treatment for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). However, lenalidomide often requires dose reductions in elderly patients, especially in those with renal impairment. Dara-VCd, while approved for AL amyloidosis, has also been explored in myeloma. Methods The multicenter GMMG DADA study (NCT04656951) evaluated Dara-VCd as first-line therapy for transplant-ineligible NDMM patients across 24 hospitals and community practices in Germany. Patients received 8 cycles of 4 weeks (total duration 32 weeks) induction with Dara-VCd, followed by Dara-Vd maintenance until progression or intolerance. Daratumumab was given subcutaneously (1800 mg) at weekly intervals for cycles 1-2, biweekly for cycles 3-6 and then monthly. Subcutaneous bortezomib (1.3 mg/m2) was given weekly for induction, and biweekly for maintenance. Cyclophosphamide 500mg/m2 was given intravenously once per cycle for 8 cycles and then stopped. Dexamethasone was given orally at 20 mg weekly during induction and biweekly during maintenance. At first relapse, patients transitioned to Dara-Rd per protocol to explore re-treatment with Dara using a different backbone. Primary endpoint was the rate of VGPR or better after 8 cycles of Dara-VCd, assessed by central laboratory. Here we report first results of the Dara-VCd regimen as part of the trial. Results Between study start and the end of recruitment in June 2024, 74 patients were screened. After excluding 7 screening failures 67 patients were eligible for the study. With 3 withdrawals before starting treatment, 64 patients received at least one dose of Dara-VCd and constituted the safety population per protocol. Age at enrollment ranged from 56 to 84 years, median age was 75 years in male patients and 71 years in female patients. 2 patients did not complete the first cycle of Dara-VCd (1 early death, 1 withdrawal of consent). 62 patients completed at least 1 cycle of Dara-VCd and were analyzed per protocol as efficacy population. Four patients did not complete 8 cycles of Dara-VCd (1 lost to follow-up, 3 patient withdrawals in VGPR or CR). In addition, there was missing response data in 2 patients. Among 58 evaluable patients at the end of cycle 8, 14 achieved CR, 30 VGPR, 8 PR, 2 SD, and 4 PD. The VGPR-or-better rate in the efficacy population was 71.0% (44/62), the overall response rate was 83.9% (52/62). In addition, central MRD assessment by bone marrow flow cytometry (10-5 sensitivity) after 8 cycles of Dara-VCd was available for 50 patients, with 27 (54%) achieving MRD-negativity. Safety A total of 72 serious adverse events occurred in the safety population, including infections (n=25; 4 COVID-19), hematologic (n=5), skeletal (n=5), renal (n=5), cardiac (n=4), neurological (n=3) and gastrointestinal (n=3) events. The most common grade 3/4 adverse events were infections (n= 25, 39.1%, including 4 COVID-19), anemia (n=18, 28.1%), neutropenia (n=9, 14.1%) and renal failure (n=6, 9.4%). Peripheral neuropathy (PNP) of any grade was noted in 26 patients (40.6%). It was predominantly grade 1 or 2, while only 2 patients were found to have grade 3 PNP. Overall, no new safety signals for Dara-VCd were observed. Conclusion This prospective, multicenter trial demonstrates the feasibility of Dara-VCd as first-line therapy in transplant-ineligible NDMM patients, including those with renal impairment, dialysis dependence, and without upper age limit. The safety results showed a manageable toxicity with a remarkably low rate of severe PNP, underlining the advantage of a weekly bortezomib regimen. After 8 cycles, 71% of patients achieved a VGPR or better, and 54% were MRD-negative, suggesting efficacy comparable to other quadruplet regimens despite the absence of an IMiD. These findings support Dara-VCd as a potential alternative for elderly patients, particularly those with renal dysfunction.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Cardiovascular adverse events (CVAE) are clinically relevant side effects during treatment with the proteasome inhibitor carfilzomib. We investigated the predictive value of cardiac biomarkers for onset of CVAE in patients with newly diagnosed high-risk multiple myeloma treated with isatuximab, carfilzomib, lenalidomide, and dexamethasone in the GMMG-CONCEPT study (NCT03104842). Patients included in this prospective, multicenter correlative study were eligible if a serum sample before treatment initiation and at ≥ 1 later study time point were available. N-terminal pro-b-type natriuretic peptide (NT-proBNP) and high-sensitive Troponin I (hsTropI) were measured using immunoassays. Time-to-event analyses were performed using Kaplan–Meier estimators and log-rank test was used for statistical analysis. Among 126 patients included in this study, 40 reported incident CVAE. No significant differences were observed for age, sex, cardiovascular risk factors and cardiovascular comorbidities between patients who experienced CVAE compared to patients without CVAE. NT-proBNP levels were elevated at baseline in 96 (76 • Marked elevation of NT-proBNP levels is common in newly diagnosed multiple myeloma and not predictive of cardiovascular adverse events. • Low hsTroponin I levels are of negative predictive value for the risk of cardiovascular adverse events in newly diagnosed multiple myeloma.

B ackground: PET-adapted therapy with four or six cycles of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (4-6x BrECADD) is highly effective in patients up to 60 years with Advanced-stage classic Hodgkin lymphoma (AS-cHL; Borchmann P et al. The Lancet 2024). However, highly effective treatments are still an unmet need for older patients with AS-cHL. Here we report feasibility, safety and efficacy of PET-guided BrECADD as first-line treatment of AS-cHL in patients 61-75 years of age, who have been treated within the GHSG HD21 study. Methods: We designed a phase II single-arm cohort within the international HD21 trial (NCT02661503) for patients with AS-cHL aged 61-75 years to receive BrECADD. PET/CT restaging was done after 2x BrECADD (PET2). If PET2 was negative (i.e. Deauville score (DS) 1-3), treatment was reduced to a total of 4x BrECADD, while patients with PET2-positive lymphoma residuals (DS >3) were scheduled to receive 6x BrECADD. Consolidation radiotherapy was recommended for PET-positive residuals after central review of PET/CT at end of chemotherapy (EOT). The primary endpoint for this cohort was the complete response (CR) rate after EOT according to central review. Secondary endpoints included adverse events, treatment-related morbidity (TRMB, defined as the occurrence of relevant acute non-hematologic organ toxicity ≥ grade 3 or relevant hematologic toxicity grade 4), feasibility, progression-free survival (PFS) and overall survival (OS). Results: Between June 2020 and April 2023, 85 patients with AS-cHL were enrolled in the HD21 Older Cohort. Following disconfirmation of cHL by expert pathology review in one patient, the final ITT population consisted of 84 patients. Median age was 66.5 years (range: 61-75, IQR 63-70) and a majority had Eastern Cooperative Oncology Group (ECOG) performance status ≥1 (52%, range 0-2), stage IV (54%), B-symptoms (75%) and an IPS ≥3 (73%). Comorbidities were reported in 87% of patients with a mean Cumulative Illness Rating Scale-Geriatric (CIRS-G) sum score of 3.7 (SD: 2.7, range 0-10). All patients in the ITT cohort started trial treatment. Most patients were PET-2-negative (48/80, 60%) according to central review and therefore scheduled for a total of 4x BrECADD. Overall, 85% of patients received the scheduled number of cycles and 12% of patients received consolidating radiotherapy. Neutropenic fever occurred in 54% of patients and the TRMB rate was 77% (95%CI: 67-86). Sensory neuropathy of any grade occurred in 38% of patients, with grade >2 in one patient (1%). There were eight patients without centrally evaluated response assessment at EOT. Of the 76 patients with central response evaluation at EOT, 66/76 (87%), 9/76 (12%) and 1/76 (1%) had CR, partial remission or progressive disease, respectively. After a median follow-up of 23 months, PFS estimates at 1 year (1y) and 2 years (2y) were 95.1% (95%CI: 90-100) and 91.5% (95%CI: 85-98), respectively. Corresponding 1y-OS and 2y-OS rates were 96.2 (95%CI: 92-100) and 90.7% (95%CI: 83-98). No death was attributed to study treatment. Eleven second primary malignancies were reported during follow-up, most of which were other lymphomas (n=6). Conclusions: PET-guided BrECADD is feasible and safe in older patients but requires more frequent dose adjustments than in younger patients. Importantly, BrECADD resulted in an exceptionally high 2-year PFS rate, which is in the range observed for younger patients in HD21. We thus recommend PET-guided BrECADD as treatment strategy for newly diagnosed AS-cHL patients 61-75 years of age.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Supplementary Table 2 from Breast Cancer Risk Reduction and Membrane-Bound Catechol O-Methyltransferase Genetic Polymorphisms

Introduction:The use of high-dose chemotherapy followed by tandem autologous hematopoietic stem cell transplantation (auto-HSCT) has resulted in improved outcomes for patients with multiple myeloma (MM) While auto-HSCT is recognized as a standard of care for newly diagnosed transplant-eligible MM patients due to the improved long-term disease control and survival it provides, the exposure to high-dose chemotherapy is associated with an increased risk of second primary malignancies (SPMs), with a subset of SPMs categorized as second hematologic malignancies (SHM).Our study aims to provide the incidence of SPMs and SHMs on patients treated on TT I-IIIB based on long-term follow up Methods: Patients enrolled on total therapy I (NCT00580372), II (NCT00083551), IIIA (NCT00081939) and IIIB (NCT00572169) between 1989-2008 were included.Patients were treated at the University of Arkansas for Medical Sciences with combination-based chemotherapy, tandem auto-HSCT and maintenance therapy, and followed for development of SPMs and SHMs.Results: Among 1379 patients with newly diagnosed MM enrolled on four TT trials with a median follow up range of 15-25 years.SPMs (including SHMs and excluding non-melanoma skin cancer) occurred in 11.8% of patients of which 64.4% of SPMs were solid tumors (most common were prostate cancer (n=22), colorectal cancer (n=20), breast cancer (n=15), lung cancer (n=11), and bladder cancer (n=7).A total of 4.2% (n=58) of patients developed a SHM.SHMs include acute lymphoblastic leukemia (ALL) (n=4), acute myeloid leukemia (2.4%, n=33), myelodysplastic syndrome (0.7%, n=9), B-cell lymphoma (n=10), chronic myelomonocytic leukemia (n=1) and unspecified leukemia (n=1).Median time to first SHM in patients treated on TT I, TT II (+thalidomide), TT II (-thalidomide), TT IIIA, TTIIIB were 10. 7, 7.67, 10.3, 5.56, and 6.23 years, respectively.No statistical difference between risk of SHMs and enrollment on specific clinical trial, was observed.However, all four ALL cases occurred in patients who were exposed to an immunomodulatory drug.No difference in SPMs were observed in patients treated on TT IIIB when compared to TT IIIA.Conclusions: The occurrence of SHMs in patients who were treated with tandem-autologous hematopoietic stem cell transplantation on earlier TT protocols and followed up for a median of more than 15 years was 4.2%.The risk of AML and/or MDS was 3.1%.Our long-term follow up indicates that the risk of developing SHMs is relatively low.With the improvement in long-term outcomes of MM patients it is important to consider the risk of developing various cancers and consider appropriate.

Objective Lung cancer is the second most frequent cancer type and the most common cause of cancer-related deaths worldwide. Alteration of gene copy numbers are associated with lung cancer and the determination of copy number variations (CNV) is appropriate for the discrimination between tumor and non-tumor tissue in lung cancer. As telomerase reverse transcriptase ( TERT ) and v-myc avian myelocytomatosis viral oncogene homolog ( MYC ) play a role in lung cancer the aims of this study were the verification of our recent results analyzing MYC CNV in tumor and non-tumor tissue of lung cancer patients using an independent study group and the assessment of TERT CNV as an additional marker. Results TERT and MYC status was analyzed using digital PCR (dPCR) in tumor and adjacent non-tumor tissue samples of 114 lung cancer patients. The difference between tumor and non-tumor samples were statistically significant (p < 0.0001) for TERT and MYC . Using a predefined specificity of 99% a sensitivity of 41% and 51% was observed for TERT and MYC , respectively. For the combination of TERT and MYC the overall sensitivity increased to 60% at 99% specificity. We demonstrated that a combination of markers increases the performance in comparison to individual markers. Additionally, the determination of CNV using dPCR might be an appropriate tool in precision medicine.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

PURPOSE The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity.METHODS This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10(-5), next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS).RESULTS Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for >= 1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm.CONCLUSION Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Supplementary Table 3 from Breast Cancer Risk Reduction and Membrane-Bound Catechol O-Methyltransferase Genetic Polymorphisms

Supplementary Table 1 from Breast Cancer Risk Reduction and Membrane-Bound Catechol O-Methyltransferase Genetic Polymorphisms