Treatment Of Hodgkin Lymphoma Research Articles

Betulin and Crinum asiaticum L. bulbs extract attenuate pulmonary fibrosis by down regulating pro-fibrotic and pro-inflammatory cytokines in bleomycin-induced fibrosis mice model

BackgroundPulmonary fibrosis (PF) is a lung disease characterized by scaring of lung tissue that impairs lung functions. The estimated survival time of patients with pulmonary fibrosis is 3–5 years. Bleomycin (BLM) is used clinically in the treatment of Hodgkin lymphoma and testicular germ-cell tumors. Bleomycin’s mechanism of action is the inhibition of DNA and protein synthesis. This happens when leukocytes induce the release of cytokines and chemokines which increase the pro-fibrotic and pro-inflammatory cytokines such as IL-6, TNF-alpha, IL-13, IL-1β and transforming growth factor-beta 1 (TGF-β). Crinum asiaticum L. bulbs (CAE) are widely found in parts of Africa, Asia and Indian Ocean Island. It is also prevalent in southern part of Ghana and traditionally used by the indigenes to treat upper respiratory tract infections, and for wound healing. Betulin (BET) is found in the bulbs of Crinum asiaticum L. but widely isolated from the external bark of birches and sycamore trees. Betulin as a lupine type triterpenes has been researched for their pharmacological and biological activities including anticancer, anti-inflammatory, antimicrobial activities and anti-liver fibrosis effects.Aim of the study: The aim was to study the anti-pulmonary fibrosis effect of Crinum asiaticum L. bulbs extract and betulin in bleomycin-induced pulmonary fibrosis in mice. Materials and methodThere was a single oropharyngeal administration of bleomycin (80 mg/kg) in mice followed by the treatment of CAE and BET after 48 h of exposure to BLM. ResultsThere was increased survival rate in CAE and BET treatment groups compared to the BLM induced group. There was a marked decreased in the levels of hydroxyproline, collagen I and III in the CAE and BET treatment groups compared to BLM-treated group. The treatment groups of CAE and BET significantly down regulated the levels of pro-fibrotic and pro-inflammatory cytokines concentrations such as TGF-β1, MMP9, IL-6, IL-1β and TNF-alpha compared to an increased in the BLM treated groups. The histological findings of the lungs suggested the curative effects of CAE and BET following BLM induced pulmonary fibrosis in mice, the study showed improved lung functions with wide focal area of viable alveolar spaces and few collagen fibers deposition on lungs of treatment groups. ConclusionCAE and BET attenuated pulmonary fibrosis by down regulating pro-fibrotic and pro-inflammatory cytokines as well as improving lung function. This could be a lead in drug discovery where compounds with anti-fibrotic effects could be developed for the treatment of lung injury.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Hodgkin lymphoma (HL) in children, adolescents, and young adults (CAYA) is highly curable. Patient experiences during cancer treatment vary substantially and may influence later quality of life (QOL). We sought to: (1) describe patient-reported QOL during treatment for high-risk classical HL in CAYA with HLHR13, a brentuximab-incorporating chemotherapy regimen with response-adapted radiotherapy (r-aRT); (2) compare QOL among patients treated on HLHR13, high-risk HL patients treated with Stanford V chemotherapy and r-aRT (HOD99), and healthy CAYA. Methods: Eligible patients were ≤18 (HLHR13) or ≤21 years old (HOD99) upon diagnosis of Stage IIB, IIIB, or IV HL. For HLHR13 and HOD99, QOL was assessed with PedsQL 4.0 Generic Core Scales and PedsQL 3.0 Cancer Module. HLHR13 consisted of 2 “AEPA” cycles (brentuximab, etoposide, prednisone, and doxorubicin) and 4 “CAPDac” cycles (cyclophosphamide, brentuximab, prednisone, and dacarbazine) with r-aRT (25.5 vs. 0 Gy). HLHR13 chemotherapy lasted 20 weeks including 6 rest weeks. HOD99 consisted of 12 weeks of Stanford V (bleomycin, doxorubicin, mechlorethamine, prednisone, vinblastine, and vincristine) with r-aRT (25.5 vs. 15 Gy). Despite differing regimen durations, QOL assessments were compared at timepoints considered equivalent. HLHR13 incorporated 2-year off-therapy long-term follow up QOL assessments. Patient demographics and QOL scores were summarized by descriptive statistics. We used Wilcoxon rank-sum tests to compare PedsQL 3.0 scores in HLHR13 patients vs. HOD99 patients and pooled two sample t-tests to compare patient and healthy CAYA PedsQL 4.0 scores. Raw p-values were corrected for multiple comparisons. Results: At study entry, HLHR13 patients’ (n = 63) QOL was significantly worse than healthy CAYA and consistent with HOD99 patients’ (n = 78) QOL as measured by PedsQL 4.0 Generic Core Scales. HLHR13 patients’ QOL gradually improved. Compared to HOD99 patients, HLHR13 patients had better cancer-specific QOL scores (PedsQL 3.0 Cancer Module) during treatment, particularly for nausea, worry, cognitive problems and treatment anxiety. Two years off therapy, HLHR13 patients (n = 39) reported better QOL in social and emotional domains than did healthy CAYA. Conclusions: Among similar groups of CAYA with HL, HLHR13 treatment was associated with higher patient-reported cancer-specific QOL than was HOD99 despite longer treatment duration and more intensive administration schedule. PedsQL 3.0 Cancer Module distinguished cancer-specific experience differences between HLHR13 and HOD99. Mechlorethamine in HOD99 may have produced excess nausea. Two years after treatment, HLHR13-treated CAYA reported better social and emotional QOL than healthy peers. Observed excellent QOL could reflect positive psychosocial impacts of living beyond lymphoma or a biased group of CAYA continuing in survivorship care. Keywords: chemotherapy, late effects in lymphoma survivors, Hodgkin lymphoma The research was funded by: St. Jude Children's Research Hospital and Seagen Inc Conflicts of interests pertinent to the abstract: M. P. Link Research funding: Seagen, Inc J. E. Flerlage Research funding: Seagen, IncSS

Impact of PET‐2 guided treatment de‐escalation on time‐to‐recovery from cancer‐related fatigue in advanced stage Hodgkin Lymphoma: results from the GHSG HD18 study

Introduction: Persisting cancer related fatigue (CRF) has impact on health related quality of life (HRQoL) and social re-integration of patients with Hodgkin lymphoma (HL). The GHSG HD18 trial established treatment PET-2 guided de-escalation of treatment for advanced-stage HL as new standard. Here, we investigate the impact of treatment de-escalation in HD18 on long-term HRQoL domains and time-to-recovery from fatigue (TTR-F). Methods: Mean fatigue scores (FA) of the EORTC QLQ-C30 questionnaire are reported descriptively for baseline, interim, end-of-treatment, and yearly follow-up. TTR-F was defined as time from end of chemotherapy until first occurrence of FA <30 or the time of last questionnaire (censored). TTR-F was analyzed and compared using time-to-event methods including cumulative incidence and cox proportional hazard models, as recommended by the SISAQoL consortium. Effect of disease, patient and treatment characteristics on 2y HRQoL domains was analyzed using multiple regression. Results: 2101 patients aged 18–60 years with advanced-stage HL were recruited in HD18, of whom 156 were found ineligible before or after randomization. PET-2 negative Patients were randomized between 8x eBEACOPP (arm C, n = 288) and 4x eBEACOPP (arm D; n = 285), and between 6x eBEACOPP (arm C6; n = 216) and 4x eBEACOPP (D4; n = 216). HRQoL questionnaires at baseline were available in 83.9% of all randomized patients. Overall, baseline FA and age were significantly associated with TTR-F, whereas sex was not. TTR-F differed between trial arms for PET-2 negative, but not for PET-2 positive patients. Particularly, treatment reduction from 8 to 4 cycles of eBEACOPP led to a significantly shorter TTR-F (HR 1.41, p = 0.008). Reducing the cycle number of eBEACOPP from 8 to 6 cycles (HR 1.21, p = 0.2) or 6 to 4 cycles (HR 1.22, p = 0.18) speeded TTR-F accordingly but was not statistically significant. For PET-positive patients a significantly slower TTR-F was observed with addition of Rituximab (HR 0.7, p = 0.0163). In PET-2-negative patients, median TTR-F was 19 months (CI95: 13–28) in arm C, 13 months (CI95: 10–20) in arm C6, 12 months (CI95: 8–15) in arm D and 10 months (CI95: 8–13) arm D4. HRQoL at baseline and age were the main determinants of 2y HRQoL domains. The research was funded by: Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG. Keywords: Chemotherapy, Hodgkin lymphoma, Late Effects in Lymphoma Survivors No conflicts of interests pertinent to the abstract.

ROLE OF CHECKPOINT INHIBITION IN GERMANY

Immune checkpoint inhibition (ICI) has demonstrated an overall excellent benefit-to-risk profile in the treatment of classical Hodgkin lymphoma (cHL); however, cure remains an exception to the rule. The German Hodgkin Study Group (GHSG) has identified several areas of unmet need for ICI development in cHL. First, we aim to better understand the role of immune checkpoints in the interplay between Hodgkin/Reed-Sternberg malignant cells and the abundant microenvironment. Second, we aim to improve efficacy of ICI in multiple relapsed/refractory (r/r) cHL patients, as complete response rates are infrequent and median PFS is still quite limited. Therefore, combination therapies with alternative ICIs targeting TIGIT, LAG3, or TIM3, or combinations with conventional cytotoxic drugs need to be investigated. The GHSG has focused on evaluating the abscopal effects of radiotherapy to improve ICI in multiple r/r cHL. Third, the GHSG strongly believes that ICI should be able to improve first-line therapy of cHL. The GHSG is currently conducting clinical trials to de-escalate the chemotherapy intensity. In early favourable stage cHL patients, we hypothesize that ICI can replace chemotherapy in the combined modality therapy approach. In early unfavourable stage cHL, we use our PET-adapted design to select well-responding patients and remove chemotherapy and/or radiotherapy from the treatment strategy. In advanced stage cHL, we aim to reduce cumulative exposure to conventional chemotherapy. We hypothesize that the combination of anti-PD-1 antibody therapy with our intensive chemotherapy should act synergistically and more patients should achieve an early metabolic complete response. These patients could then be treated with only 4 cycles of combined PD1 chemotherapy. Overall, this new treatment principle should serve to overcome chemotherapy resistance and improve the efficacy of established therapeutic regimens, while reducing the treatment burden for our cHL patients. Keywords: Hodgkin lymphoma, immunotherapy No conflicts of interests pertinent to the abstract.

Toxicities at one year follow‐up in patients with advanced stage classical Hodgkin Lymphoma: results from the randomized phase III HD21 trial by the German Hodgkin Study Group

Introduction: The HD21 trial compares BrECADD with eBEACOPP for the first-line treatment of advanced stage classical Hodgkin Lymphoma (AS-cHL). We previously reported a superior acute tolerability profile for BrECADD. However, persisting treatment sequelae as peripheral neuropathy or gonadal dysfunction are a major concern for survivors of AS-cHL. Accordingly, resolution of organ toxicities is highly relevant from the patient´s perspective. Therefore, we report treatment-related toxicities at twelve months follow-up (FU12) after treatment in HD21. Methods: Adult patients ≤60 years of age with AS-cHL were included in this ongoing international open label randomized phase III trial and randomized in a 1:1 ratio to receive PET2-guided 4–6 cycles of either standard eBEACOPP or experimental BrECADD treatment. For detection of treatment sequelae at FU12, non-hematological adverse events and serum levels of FSH levels are reported. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries. Baseline characteristics were well balanced between treatment arms. Documented FU12 was available in 1395/1470 (94.9%) patients in the ITT cohort. 557 (80.8%) and 566 (80.2%) patients had no documented toxicity following eBEACOPP and BrECADD, respectively. At FU12, grade 2 or higher PNP was reported for 17 (2.7%) patients following eBEACOPP and for 12 (1.9%) patients following BrECADD; however, no or only grade 1 PNP was reported for most patients in both treatment groups with 97.3% for eBEACOPP and 98.1% for BrECADD. Rate of PNP was numerically higher in patients receiving 6 cycles of chemotherapy (3.0%) compared to 4 cycles (1.9%). FSH levels at FU12 were available for 597 patients and were higher for patients who received eBEACOPP (mean FSH 29.4 and 31.8 after 4 and 6 cycles, respectively) compared to BrECADD (mean FSH 18.3 and 20.5 after 4 and 6 cycles, respectively. Other than PNP, most frequent organ toxicities at FU12 were classified as respiratory, thoracic or mediastinal disorders (4.4%), and cardiac disorders (2.9%). All other organ toxicities were rare and equally distributed between trial arms. Conclusions: Complete resolution of acute adverse events is frequent following either regimen in the GHSG HD21 study. However, less patients report higher grade PNP or impaired gonadal function at FU12 after treatment with BrECADD than after eBEACOPP. Accordingly, persisting toxicities were reported in only few patients after BrECADD. Although these results are indicate good overall tolerability, they still need to be complemented by patient-reported outcomes for which analyses are ongoing. The non-inferiority of the experimental BrECADD regimen also remains to be demonstrated to draw definitive conclusions. The research was funded by: Takeda Keywords: Hodgkin lymphoma, Molecular Targeted Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. P. Borchmann Consultant or advisory role: Takeda Oncology, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Amgen, Miltenyi Biotech Honoraria: Takeda Oncology, Novartis, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Miltenyi Biotech, Incyte, Abbvie Research funding: Takeda Oncology, Roche, Novartis, Merck Sharp & Dohme, Amgen

Pharmacokinetics and safety of bendamustine in the BEABOVP regimen for the treatment of pediatric patients with Hodgkin lymphoma.

The Stanford V chemotherapy regimen has been used to treat Hodgkin lymphoma (HL) patients since 2002 with excellent cure rates; however, mechlorethamine is no longer available. Bendamustine, a drug structurally similar to alkylating agents and nitrogen mustard, is being substituted for mechlorethamine in combination therapy in a frontline trial for low- and intermediate-risk pediatric HL patients, forming a new backbone of BEABOVP (bendamustine, etoposide, doxorubicin, bleomycin, vincristine, vinblastine, and prednisone). This study evaluated the pharmacokinetics and tolerability of a 180mg/m2 dose of bendamustine every 28days to determine factors that may explain this variability. Bendamustine plasma concentrations were measured in 118 samples from 20 pediatric patients with low- and intermediate-risk HL who received a single-day dose of 180mg/m2 of bendamustine. A pharmacokinetic model was fit to the data using nonlinear mixed-effects modeling. Bendamustine concentration vs time demonstrated a trend toward decreasing clearance with increasing age (p = 0.074) and age explained 23% of the inter-individual variability in clearance. The median (range) AUC was 12,415 (8,539, 18,642)µg hr/L and the median (range) maximum concentration was 11,708 (8034, 15,741)µg/L. Bendamustine was well tolerated with no grade 3 toxicities resulting in treatment delays of more than 7days. A single-day dose of 180mg/m2 of bendamustine every 28days was safe and well tolerated in pediatric patients. While age accounted for 23% of inter-individual variability observed in bendamustine clearance, the differences did not affect the safety and tolerability of bendamustine in our patient population.

Long-Term Results with Thiotepa-Containing Conditioning Regimens for Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most frequently used conditioning regimen; however, owing due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results in ASCT with a TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) conditioning regimen from 2000 to 2013. We aimed to update our experience with the TECAM regimen by adding our experience from 2013 to 2020 to the previously reported cohort. Moreover, we aimed to use the detailed data for the 2 transplant cohorts to identify improvements in ASCT outcomes in the recent era. We retrospectively analyzed all lymphoma patients who underwent ASCT at our center between January 2000 and December 2020. A total of 353 lymphoma patients were included (142 in the newer cohort added to 211 previously reported patients), all of whom were treated with our standard TECAM conditioning regimen. The cohort included 127 patients with HL, 107 with DLBCL, and 119 with other NHL subtypes. The newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) prior to ASCT (45.7% versus 19.3% with ECOG-PS ≥1; P < .01), whereas a higher proportion of patients entered transplantation in complete response (CR) (71.9% versus 47.8%; P < .01). The median follow-up after ASCT was 136.4 months (95% confidence interval [CI], 91.4 to 181.4 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates post-ASCT for the entire cohort were 59.8% and 79.3%, respectively. Evaluating the 303 of 353 patients (86.4%) who entered ASCT with a responsive disease-a population that represents today's approach to the selection of patients for ASCT-the 3-year PFS and OS rates were 61.5% and 81.9%, respectively. In this population, the 3-year PFS rate was 62.2% for HL, 62.6% for DLBCL, 64.3% for primary central nervous system lymphoma (PCNSL), and the 3-year OS rate were 90.1%, 75.2%, and 78.6%, respectively. OS was significantly better in the newer cohort (P < .01), but not when evaluating only patients who entered ASCT with responsive disease. Dose reductions, poor disease status, and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. In accordance with our previous report, patients entering transplantation for DLBCL with a partial response achieved similar outcomes as those with a CR. Eighteen patients died within the first 100 days, 8 due to disease progression and 10 due to transplantation-related complications (2.8%). There were no cases of interstitial pneumonitis syndrome. Twenty-two cases (6.2%) of secondary malignancies were documented. Our results confirm that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHLs, including favorable results in PCNSL. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, driven by better lymphoma control pretransplantation. In the DLBCL cohort, ECOG-PS had more prognostic value than achieving a CR pre-ASCT, a finding relevant to the optimal allocation of patients to different treatment options in the era of chimeric antigen receptor T cell availability.

Effects of ABVD chemotherapy on ovarian function: epidemiology, hormonal dosages and ultrasound morphologic analyses in 270 patients with Hodgkin's disease.

Classical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients' survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients' age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported. Data were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17β-oestradiol (17β-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints. The average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17β-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one. Based on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting.

Work and education interruption in long-term Hodgkin lymphoma survivors: an analysis among patients from nine EORTC-LYSA trials

Background Disease-specific studies on the impact of Hodgkin lymphoma (HL) on education or work interruption and resumption are lacking. Material and methods In a cross-sectional study conducted among long-term HL survivors enrolled from 1964 to 2004 in nine randomised EORTC-LYSA trials, the interruption and resumption of education/work was investigated. Survivors alive 5–44 years after diagnosis who were studying or working at time of diagnosis were included (n = 1646). Patient and treatment characteristics were obtained from trial records. Education and work outcomes were collected using the Life Situation Questionnaire. Logistic regression was used to model education or work interruption; Cox regression was used to study resumption rates. Results Among survivors studying at time of diagnosis (n = 323), 52% (95% CI: 46–57%) interrupted their education; however, it was resumed within 24 months by 92% (95% CI: 87–96%). The probability of interruption decreased with time: the more recent the treatment era, the lower the risk (OR 0.70 per 10 years, 95% CI: 0.49–1.01). Treatment with radiotherapy (yes vs. no) was associated with a higher education resumption rate (HR 2.01, 95% CI 1.07–3.78) whereas age, sex, stage, radiotherapy field and chemotherapy were not. Among survivors working at time of diagnosis (n = 1323), 77% (95% CI: 75–79%) interrupted their work. However, it was resumed within 24 months by 86% (95% CI: 84%-88%). Women were more likely to interrupt their work as compared to men (OR 1.90, 95% CI: 1.44–2.51) and, when interrupted, less likely to resume work (HR 0.70, 95% CI: 0.61–0.80). Survivors with a higher educational level were less likely to interrupt their work (OR 0.68 for university vs. no high school, 95% CI: 0.46–1.03); and when interrupted, more likely to resume work (HR 1.50 for university vs. no high school, 95% CI: 1.21–1.86). Increasing age was also associated with lower resumption rates (HR 0.62 for age ≥50 vs. 18–29 years, 95% CI: 0.41–0.94). Conclusion An interruption in education/work was common among long-term HL survivors. However, most of the survivors who interrupted their studies or work had resumed their activities within 24 months. In this study, no associations between survivors’ characteristics and failure to resume education were observed. Female sex, age ≥50 years, and a lower level of education were found to be associated with not resuming work after treatment for HL.

Excellent results of screening for subsequent breast cancers in long-term survivors of childhood Hodgkin's lymphoma-Results of a population-based study.

Subsequent breast cancer (SBC) represents a major complication in childhood cancer survivors and screening for SBC in survivors after incidental irradiation of breasts is recommended. In this article, we report the results and discuss benefits of SBC screening in female pts treated for Hodgkin's lymphoma (HL) in Slovenia in a period of 45 years. Between 1966 and 2010, 117 females were treated for HL under the age of 19 in Slovenia. One hundred five of them survived for 5 years and were included in our study. They were 3-18 (med. 15) years old at diagnosis and followed for 6-52 (med. 28) years. Eighty-three percent of them had chest RT with a median dose of 30 Gy. Ninety-seven (92%) of 105 pts were regularly followed according to the international guidelines including yearly screening mammography/breast MRI in those who received chest RT. We diagnosed 10 SBCs in eight pts 14-39 (med. 24) years after diagnosis at the age of 28-52 (med. 42) years. At 40 years of follow-up, cumulative incidence of SBCs in females who got chest RT was 15.2%. Seven of eight patients (with 9 SBCs) got chest RT with 24-80 (med. 36) Gy at the age of 12 to 18 (median 17) years. Two patients in this group got bilateral SBC. One patient got invasive SBC after being treated with ChT containing high-dose of anthracyclines without chest RT at the age of 13. All eight invasive SBCs were invasive ductal cancers, HER2 receptors negative, all but one with positive hormonal receptors. Six invasive cancers were of stage T1N0, one T1N1mi, only one, diagnosed before era of screening, was of T2N1. None of 8 pts died of SBC. After introduction of regular breast screening in our female patients, who received chest RT in childhood, all SBCs were of early stage and no patients died of SBC. Survivors of pediatric HL should be informed about the risk of late sequelae of treatment for HL, including SBC. Regular follow-up with breast cancer screening and breast self-examination is of vital importance in those treated with chest RT.

Brentuximab vedotin plus doxorubicin and dacarbazine innonbulky limited-stage classical Hodgkin lymphoma.

ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).

Long-term outcomes in Hodgkin lymphoma survivors. Temporary trends and comparison with general population.

The high cure rates of Hodgkin lymphoma (HL) make this oncological disease among those with the greatest number of long-term survivors. This single-institution study including 383 HL patients with up to 45years of follow-up, analyses the morbidity and mortality of this population after treatments in comparison with the overall Spanish population, and investigates whether it has changed over time stratifying by periods of time, as a consequence of therapeutic optimization. The median age was 34.8years (range 15-87) with median overall survival of 30years, significantly higher in women (HR 0.58, 95% CI 0.42-0.79) (p=0.0002). 185 late-stage diseases were noted (35% patients), cardiovascular disease (CVD) being the most frequent (23.2%). 30% of patients developed at least one second malignant neoplasm (SMN) to give a total of 174 SMNs. 20.9% of the patients died from HL and 67.0% died from non-HL causes (32.2% from SMN, 17% from CVD). The overall standardized mortality ratio (SMR) was 3.57 (95% CI: 3.0-4.2), with striking values of 7.73 (95% CI: 5.02-8.69) and of 14.75 (95% CI: 11.38-19.12) for women and patients <30years at diagnosis, respectively. Excluding HL as the cause of death, the SMRs of those diagnosed before 2000 and from 2000 were proved to be similar (3.88 vs 2.73), maintaining in this last period an unacceptable excess of mortality due to secondary toxicity in patients cured of HL. Our study confirm that HL treatment substantially reduces the life expectancy of patients cured of HL. In recent periods, despite therapeutic optimization, deaths from toxicity continue to occur, mainly from CVD and SMN. Risk-factor monitoring should be intensified, prevention programs developed, and therapeutic optimization of LH investigated, especially in two vulnerable groups: those aged <30years at diagnosis, and women.

Advances in the treatment of Hodgkin lymphoma: Current and future approaches.

Hodgkin lymphoma (HL) is a rare type of lymphoma with unique histologic, immunophenotypic, and clinical features. It represents approximately one-tenth of lymphomas diagnosed in the United States and consists of two subtypes: classical Hodgkin's lymphoma (cHL), which accounts for majority of HL cases, and nodular lymphocyte predominant Hodgkin lymphoma represent approximately 5% of Hodgkin lymphoma cases. From this point, we will be focusing on cHL in this review. In general, it is considered a highly curable disease with first-line chemotherapy with or without the addition of radiotherapy. However, there are patients with disease that relapses or fails to respond to frontline regimens and the standard treatment modality for chemo sensitive cHL is high dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT). In recent years, targeted immunotherapy has revolutionized the treatment of cHL while many novel agents are being explored in addition to chimeric antigen receptor (CAR) T-cell therapy which is also being investigated in clinical trials as a potential treatment option.

Reproductive ability in survivors of childhood, adolescent, and young adult Hodgkin lymphoma: a review.

Owing to a growing number of young and adolescent Hodgkin lymphoma (HL) survivors, awareness of (long-term) adverse effects of anticancer treatment increases. The risk of impaired reproductive ability is of great concern given its impact on quality of life. There is currently no review available on fertility after childhood HL treatment. The aim of this narrative review was to summarize existing literature on different aspects of reproductive function in male and female childhood, adolescent, and young adult HL survivors. PubMed and EMBASE were searched for articles evaluating fertility in both male and female HL survivors aged <25 years at diagnosis. In females, anti-Müllerian hormone (AMH), antral follicle count, premature ovarian insufficiency (POI), acute ovarian failure, menstrual cycle, FSH, and pregnancy/live births were evaluated. In males, semen-analysis, serum FSH, inhibin B, LH, testosterone, and reports on pregnancy/live births were included. There was profound heterogeneity among studies and a lack of control groups; therefore, no meta-analyses could be performed. Results were presented descriptively and the quality of studies was not assessed individually. After screening, 75 articles reporting on reproductive markers in childhood or adolescent HL survivors were included. Forty-one papers reported on 5057 female HL survivors. The incidence of POI was 6-34% (median 9%; seven studies). Signs of diminished ovarian reserve or impaired ovarian function were frequently seen (low AMH 55-59%; median 57%; two studies. elevated FSH 17-100%; median 53%; seven studies). Most survivors had regular menstrual cycles. Fifty-one studies assessed fertility in 1903 male HL survivors. Post-treatment azoospermia was highly prevalent (33-100%; median 75%; 29 studies). Long-term follow-up data were limited, but reports on recovery of semen up to 12 years post-treatment exist. FSH levels were often elevated with low inhibin B (elevated FSH 0-100%; median 51.5%; 26 studies. low inhibin B 19-50%; median 45%; three studies). LH and testosterone levels were less evidently affected (elevated LH 0-57%, median 17%; 21 studies and low testosterone 0-43%; median 6%; 15 studies). In both sexes, impaired reproductive ability was associated with a higher dose of cumulative chemotherapeutic agents and pelvic radiotherapy. The presence of abnormal markers before treatment indicated that the disease itself may also negatively affect reproductive function (Females: AMH<p10 9%; one study and Males: azoospermia 0-50%; median 10%; six studies). Reports on chance to achieve pregnancy during survivorship are reassuring, although studies had their limitations and the results are difficult to evaluate. In the end, a diminished ovarian reserve does not exclude the chance of a live birth, and males with aberrant markers may still be able to conceive. This review substantiates the negative effect of HL treatment on gonadal function and therefore young HL survivors should be counseled regarding their future reproductive life, and fertility preservation should be considered. The current level of evidence is insufficient and additional trials on the effects of HL and (current) treatment regimens on reproductive function are needed. In this review, we make a recommendation on reproductive markers that could be assessed and the timing of (repeated) measurements.

Multi-Phenotypic Breast Cancer Post-Radiotherapy for Hodgkin Lymphoma: A Case of Secondary Malignancy.

Morbidity and mortality associated with radiation-induced secondary malignancies (RISMs) have shifted treatment paradigms to minimize or eliminate radiation from treatment regimens. In this case, a 48-year-old woman was diagnosed with Hodgkin lymphoma (HL) and treated with radiotherapy in 2000. In 2018, she was diagnosed with ductal carcinoma in situ (DCIS) of the right breast and treated with a mastectomy. Soon after, she developed triple-negative invasive ductal carcinoma (IDC) in her reconstructed breast. The patient underwent a left lumpectomy, and pathology showed ER-/PR-/HER2+ IDC. This patient's multi-phenotypic DCIS and IDC presentation are suspected to be RISM due to her previous HL treatment regimen.

Efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in treating non-Hodgkin lymphoma: A systematic review and meta-analysis of clinical trials.

Immunotherapy with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has been widely used in the treatment of solid tumors and Hodgkin lymphoma, demonstrating powerful efficacy and good safety. However, there is no systematic review and meta-analysis to fully investigate the efficacy and safety of PD-1/PD-L1 inhibitors in treating non-Hodgkin lymphoma (NHL). We searched PubMed, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and abstracts of conference proceedings of annual meetings up to January 23, 2022, to identify eligible clinical trials. To evaluate the efficacy of PD-1/PD-L1 inhibitors, objective response rate (ORR), complete response rate (CRR), 1-year overall survival rate, and 1-year progression-free survival rate were analyzed. For safety analysis, we calculated rates of any grade and grade ≥3 treatment-related adverse events. Overall 22 studies and 1150 participants were enrolled in this meta-analysis. The pooled ORR, CRR, 1-year overall survival, and 1-year progression-free survival rates were 0.43 (95% confidence interval [CI], 0.33-0.54), 0.21 (95% CI, 0.13-0.31), 0.72 (95% CI, 0.58-0.89), and 0.42 (95% CI, 0.29-0.62), respectively. The ORR and CRR in the combination immunochemotherapy subgroup (0.65 and 0.41) were higher than those in the monotherapy (0.27 and 0.09) and combination chemotherapy (0.39 and 0.19) subgroups. This study was registered with PROSPERO (#CRD 42022316805). Given that there were limited clinical trials and relatively few relevant studies, we conducted this meta-analysis to fully elucidate the efficacy and safety of PD-1/PD-L1 inhibitors in NHL. Our results suggested that PD-1/PD-L1 inhibitors improved outcomes of responses as well as survival rates in NHL patients with tolerable adverse events. More well-designed randomized clinical trials are still needed to further confirm our findings.

Incorporating novel agents into frontline treatment of Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is associated with excellent outcomes with standard frontline chemotherapy or combined modality therapy. However, up to 25% of patients will have relapsed or primary refractory (RR) cHL. Improving the cure rate with frontline treatment, treatment-related complications and late effects, and poor therapy tolerance with high relapse rates in older patients are unmet needs in the initial management of cHL. The introduction of novel therapies, including the CD30-directed antibody drug conjugate brentuximab vedotin and PD-1 blockade (ie, pembrolizumab or nivolumab), has transformed the treatment of RR cHL and has the potential to address these unmet needs in the frontline setting. Incorporation of these potent, targeted immunotherapies into frontline therapy may improve outcomes, may allow for de-escalation of therapy without sacrificing efficacy to reduce treatment complications, and may allow for well-tolerated and targeted escalation of therapy for patients demonstrating an insufficient response. In this article, we provide a case-based approach to the use of novel agents in the frontline treatment of cHL.

Modern approaches in relapsed and refractory Hodgkin lymphoma treatment: literature review and own experience

An advance of Hodgkin lymphoma (HL) diagnostic and treatment protocols promoted between fatal and high-curative disease. Modern treatment programs can reach many-year survival rate in 8097% even in patients with advanced (IIIIV) HL stages and unfavorable prognostic factors pre- sence. Nevertheless, relapses and refractory (r/r) HL appears in 830% patients and depend on treatment scheme, prognostic factors and comorbi- dity. Second-line therapy (ViGePP and ICE) is a common platform for r/r HL treatment in pediatric patients, but results of 3-year relapse-free survival (RFS) not to exceed 7075%. For increase RFS rate in patients with r/r HL as combinatorial partners to schemes ViGePP and ICE add monoclonal antibodies (brentuximab vedotine) and immune chekpoint inhibitors (nivolumab), cell (auto-/allogenic stem cell transplantation) and genetically engineered (CAR-T) products. In the current issue literature and own experience in r/r HL treatment presented. It is showed, that inclusion a brentuximab vedotine in ViGePP scheme increased 3-year RFS up to 8311.2%.

Replacing Procarbazine with Dacarbazine in Escalated Beacopp Dramatically Reduces the Post Treatment Haematopoietic Stem and Progenitor Cell Mutational Burden in Hodgkin Lymphoma Patients with No Apparent Loss of Clinical Efficacy

Introduction When treating Hodgkin lymphoma (HL), it is common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. A similar replacement of procarbazine in COPP (to COPDac) has reduced gonadal toxicity and conferred a comparable long-term event-free survival to children (EuroNet-PHL-C1 trial; Mauz-Körholz et al Lancet Oncol 2021). Our own retrospective study has shown that adults treated with first-line escalated BEACOPDac (eBPDac) have a reduced blood transfusion requirement and earlier return of menstrual periods compared with real-world eBPP patients (pts) with no loss of clinical efficacy compared to HD18 eBPP pts (Santarsieri et al Blood 2021). To better understand the toxicity differences, we performed this study to compare the haematopoietic stem and progenitor cell (HSPC) mutational burden in pts who have received procarbazine and dacarbazine containing regimens. Chemotherapeutic agents are known to damage DNA and this mutational process likely causes many of the long-term chemotherapy toxicities. Little is known about the mutational signatures and mutation burdens caused by HL therapies, although a novel mutational signature (SBS25) has recently been described in two HL cell lines (Petljak et al Cell 2019). Methods We whole genome sequenced 6-8 single-cell derived HSPC colonies from each of 12 advanced stage HL pts (n = 91; mean sequencing depth 26X). The pts were all in remission > 6 months and had been previously treated with either eBPDac (6 cycles (n=2); 4 cycles (n=2)), eBPP (6 cycles (n=3); 5 cycles (n=1); 4 cycles (n=1)) or ABVD (n=3; all 6 cycles). Single HSPC somatic mutation burdens and mutation spectra from these chemotherapy exposed individuals were compared to those from our previously published normal cohort (n = 110; mean sequencing depth 24X) (Mitchell et al Nature 2022). In addition we have updated the outcomes of our retrospective multi-centre study of pts treated with eBPDac including additional pts and longer follow-up of the entire cohort. Mutational analysis The somatic single nucleotide variant mutation burden in normal adult HSPCs ranges from approximately 400 aged 20yr to 1500 aged 80yr; an average of 18 mutations accumulate with every year (Figure 1A). The HSPCs from ABVD and eBPDac-treated pts had similar minor excess somatic mutation burdens compared to aged-matched normal HSPCs of 183 (CI95%= 110-256) and 291 (CI95%= 242-340) mutations respectively. In contrast, the HSPCs from eBPP-treated pts had a striking and significantly increased excess mutation burden of 1153 (CI95%= 937-1369). Of the eBPP pts, the single patient who received 4 cycles had the lowest number of excess mutations, but noting the inter-patient variation, we cannot yet conclude that eBPP cycle number correlates with the number of mutations. Descriptive analysis of the mutational profiles (Figure 1B) revealed that every patient who received procarbazine had a clear SBS25-like mutational signature, characterised by T>A base substitutions, demonstrating for the first time that this DNA mutational signature is directly attributable to procarbazine. Clinical data analysis The clinical data presented last year have been updated with more pts and longer follow-up (n=288; median 2.3 yr). With this high-risk group of advanced stage pts, our data suggest that the eBPDac pts have reduced red cell transfusion requirements, reduced hospitalisation, improved menstrual period recovery and improved sperm count preservation compared with eBPP pts. The eBPDac 24-month PFS is similar to HD18 3-yr PFS (94.9% vs 92.3%) and appears superior to RATHL 5-yr PFS (81.4%). The eBPDac 24-month OS estimate is 99%. Conclusions We have shown that dacarbazine-containing regimens (ABVD and eBPDac) confer a lower mutation burden to HSPCs compared with procarbazine-containing eBPP and that procarbazine is the agent responsible for the SBS25 mutational signature. This work provides a model example of how genomic analysis could be used to inform therapeutic decision making in cancer. Our retrospective analysis provides strong supportive evidence that eBPDac is a highly efficacious HL treatment and noting the clear benefits in terms of HSPC genomic health, we would encourage clinicians offering eBPP to HL pts to consider replacing procarbazine with dacarbazine. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of Second Primary Malignancies in Lymphoma Survivors: A Prospective Cohort Study in the Modern Treatment Era

Background: Improved treatments for Hodgkin and non-Hodgkin lymphoma has resulted in a growing population of long-term survivors, many of whom are cured. A focus of long-term care of these patients (pts) has in turn moved toward optimizing survivorship, including identification and management of second primary malignancies (SPM). In this prospective cohort study initiated in the modern treatment era, we describe the incidence and factors associated with risk of SPM. Methods: Pts were identified from the Molecular Epidemiology Resource (MER) cohort of the University of Iowa/Mayo Clinic Lymphoma SPORE, which offers enrollment to all consecutive patients with newly diagnosed lymphoma aged 18+ years. Clinical and treatment data are abstracted from medical records using a standard protocol. Pts are prospectively contacted regularly to assess disease status and development of SPM. All reported SPM through 2021 were validated against medical records. For this analysis, SPM were defined as any cancer other than lymphoma diagnosed >90 days from lymphoma diagnosis. Cumulative incidence of SPM and 95% confidence intervals (CI) were calculated with death as a competing risk, and associations with patient and treatment characteristics were estimated with Cox models. To evaluate the incidence of SPM in the MER against expected population rates, we calculated the standardized incidence ratio (SIR) using the Iowa component of the Surveillance, Epidemiology and End Results (SEER) database, accounting for age, sex, calendar year and person-time. Results: Of 6929 pts enrolled into the MER from 9/2002 - 6/2015, 59% were male; median age at enrollment was 61 yrs (IQR: 51-70). 763 pts developed SPM through 2021, including 37 acute myeloid leukemia and myelodysplastic syndrome (AML/MDS), 341 non-melanoma skin, 133 genitourinary (GU), 57 gastrointestinal (GI), 49 breast, and 52 lung cancers. The 10-year cumulative incidence of SPM was 12% (CI: 11-13), and 31% (CI: 30-32) for the competing risk of death (Fig 1A). Skin cancers had highest 10-year cumulative incidence of 6.6% (CI: 5.9 -7.4), followed by GU 2.4% (CI: 2.0-2.9), breast 1.0% (CI: 0.8-1.4), lung 1.0% (CI: 0.8-1.3), GI 0.9% (CI: 0.7-1.3), and AML/MDS 0.7% (CI: 0.5-1.0)(Fig 1B). The MER cohort had a lower than expected rate of any SPM (excluding non-melanoma skin cancer, which SEER does not collect) compared to the general Iowa population (SIR=0.61, CI: 0.5-0.7), as well as lower than expected rates of GU (SIR=0.60, CI: 0.5-0.7), GI (SIR=0.45, CI: 0.3-0.6), breast (SIR=0.69, CI: 0.5-0.9), and lung (SIR=0.47, CI: 0.4-0.6) cancer. In contrast, the MER showed a 5-fold higher than expected rate of AML/MDS (SIR=5.2, CI: 3.6-7.1). Risk of SPM increased with age: compared to pts age 18-40 years, those 41-60 yrs had a 3-fold (CI: 1.9-4.5) and >60 yrs had a 6.3-fold (CI: 4.2-9.6) elevated risk of SPM. Females were at lower risk of SPM (HR=0.7, CI: 0.6-0.9). After adjustment for age and sex, there was no association with lymphoma subtype. For initial treatment class (adjusted for age, sex and subtype), risk of a SPM was associated with use of a systemic chemotherapy (HR=1.3, CI: 1.1-1.6); was inversely associated with initial observation (HR=0.8, CI: 0.6-0.9); and was not associated with use of local radiation (HR=0.9, CI: 0.7-1.2), an anthracycline (HR=1.0, CI: 0.8-1.3), alkylator (HR=1.2, CI: 1.0-1.4) or R-monotherapy (HR=1.0, CI: 0.7-1.3). In joint modeling of initial treatment adjusted for age, sex and subtype, compared to pts not receiving systemic chemotherapy, pts with systemic therapy including an alkylator but no anthracycline (HR=1.4, CI: 1.1-1.7) or systemic therapy without an alkylator or anthracycline (HR=1.3, CI:1.1-1.7) had increased risks of SPM, while those receiving both an alkylator/anthracycline were not at significantly elevated risk (HR=1.2, CI: 0.9-1.5). Conclusions: In the rituximab era, the cumulative incidence of any SPM increased over time and at 10 years after diagnosis was 12%, with about half of these due to non-melanoma skin cancers. While the cumulative incidence of AML/MDS at 10 years was low (0.7%), this represented a 5-fold excess risk over expected population rates, consistent with prior eras. In contrast, solid tumors were below expected population rates. Older age, male sex and systemic chemotherapy were associated with higher risk of SPM. Prevention and management of SPM continues to remain an important need for lymphoma survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal