Positron Emission Tomography–Driven Strategy in Advanced Hodgkin Lymphoma: Prolonged Follow-Up of the AHL2011 Phase III Lymphoma Study Association Study

PURPOSE The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747 ) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results. METHODS Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2– and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment. RESULTS In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% v 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; P = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; P = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2–/PET4–, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4– and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; P < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4– patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; P = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; P = .038) had a significant lower OS than PET2–/PET4– patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively. CONCLUSION The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.

Controversies in the management of early-stage Hodgkin lymphoma

Positron emission tomography (PET)–adapted chemotherapy and radiotherapy approaches are currently used for the initial treatment of early-stage Hodgkin lymphoma (HL) with progression-free survival and overall survival exceeding 85% and 95%, respectively. However, despite general agreement on the prognostic value of interim PET in HL, frontline treatment approaches vary among institutions with respect to how pretreatment clinical risk factors determine treatment selection, the definition of PET negativity, which chemotherapy regimen to initiate and how many cycles to administer, and when to incorporate radiation. Furthermore, as recent trials have confirmed improved efficacy and manageable toxicity when brentuximab and checkpoint inhibitors are combined with frontline regimens such as doxorubicin, vinblastine, and dacarbazine in advanced-stage HL, these agents are now under evaluation as frontline therapy in early-stage HL. A number of issues will affect the use of these agents in early-stage HL, including the costs, early and late toxicities with these agents, patient population (favorable or unfavorable risk groups), how to incorporate them (concurrently or sequentially), and whether they can ultimately replace cytotoxic therapy with similar efficacy and fewer late effects. Future treatment paradigms for early-stage HL may change significantly once randomized studies are completed incorporating these agents into frontline therapy. Ideally, frontline use of brentuximab and checkpoint inhibitors in early-stage HL will result in improved outcomes compared with current PET-adapted approaches with decreased risks of late toxicities that continue to afflict long-term survivors of HL.

Is It Better to Start Treatment with ABVD and Continue with PET2-Adapted Approach or Should We Use 2 Cycles of Beacopp Escalated and 2 Cycles of ABVD and Irradiation in Early Unfavorable Hodgkin Lymphoma?

Introduction. EORTC H10 trial confirmed better selection of patients who needed reduced or more intensive treatment using PET response after 2 cycles of ABVD in early stages of classical Hodgkin lymphoma (cHL). GHSG HD17 showed that radiotherapy can be safely omitted in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated plus 2 cycles of ABVD (2+2 chemotherapy). We compared PET2-adapted approach including 30Gy involved-node radiotherapy (INRT) with 2+2 chemotherapy followed by 30 Gy INRT (or involved-field radiotherapy, IFRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors. Methods. Overall 243 patients with early unfavorable cHL (aged 18-60 years) prospectively observed in the Czech Hodgkin lymphoma study group registry between 2003-2020 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were not included into this analysis as they were treated with BEACOPP escalated only. Chemotherapy 2+2+30 Gy INRT/IFRT received 213 patients. Overall 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT. Results. Median age at the time of cHL diagnosis was 32 (range 18-59) years. Median follow-up was longer in the 2+2+INRT/IFRT group (91.3, range 6.2-211.2) months when compared to the PET2-adapted approach (19.4, range 6.4-90.4) months. The estimated 2-year progression-free survival (PFS) did not differ in both groups (100% [95% CI 100-100] both), however, the estimated 5-year PFS was significantly better in the 2+2+INRT/IFRT group (99.5% [95% CI 98.5-100]) in comparison to PET2-adapted treatment (75.0% [95% CI 32.5-100]), p&lt;0.001. The estimated 5-year overall survival was comparable in both groups (2+2+INRT/IFRT: 99.5% [95% CI 98.5-100]; PET2-guided treatment: 100% [95% CI 100-100]). Hematological toxicity was reported in most of the patients in both groups. Grade 3 non-hematological toxicity occured in 3 patients in the 2+2+INRT/IFRT approach (2 infections, 1 deep vein thrombosis). Conclusion. This retrospective analysis indicates that 2+2+INRT/IFRT is more effective in the long-term disease control, but there is no difference in overall survival in both groups. The current approach includes 2+2 chemotherapy and INRT is added in PET4-positive patients. This work was supported by the Research project Q 28 Progres awarded by the Third Faculty of Medicine of Charles University in Prague in the Czech Republic. Disclosures Belada: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding.

Classical Hodgkin Lymphoma; Real-World Observations from Physicians, Patients, and Caregivers on the Disease and Its Treatment (CONNECT): Observations of Physicians on Treatment and Interim PET-Adapted Regimens

Background Current NCCN guidelines recommend 1 of 3 first-line (1L) regimens for stage III or IV classical Hodgkin lymphoma (cHL): ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine), or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone); preferred regimens vary by region (e.g., North America vs Europe). The NCCN recommends positron emission tomography/computerized tomography (PET/CT) imaging after cycle 2 (interim PET2) to guide ABVD escalation or de-escalation. We surveyed physicians on their cHL treatment decision-making process and how PET/CT scan access, reimbursement, and comprehension influence their choices as part of CONNECT, the first real-world survey of physicians, patients, and caregivers in cHL. Methods Medical oncologists, hematologist/oncologists, or hematologists who treat cHL were invited to participate in an Institutional Review Board-approved, 30-minute online anonymous survey. Eligible participants had ≥2 years of practice experience in the United States (US) and treated ≥1 adult (aged ≥18 years) with stage III or IV cHL and ≥1 adult with cHL in the 1L setting within the prior 12 months. Surveys were completed from October 19, 2020-November 16, 2020. Results Of 301 participating physicians, 80% were hematologist/oncologists with a median practice duration of 15 years; 62% practiced in community and 38% in academic settings. Participants were located in the US (South, 34%; Northeast, 26%; West, 21%; Midwest, 20%) and spent 90% of their professional time in direct patient care. In the preceding 12 months, participants treated a median (interquartile range) of 16 (7-40) patients with active cHL (stage III [median], 4; stage IV, 5) and 15 (8-40) cHL survivors. When treating cHL, 88% of participants reported giving NCCN guidelines somewhat/significant consideration. Overall, 94% of participants (n=284) reported using a PET/CT combined scan to diagnose/stage cHL, in line with current guideline recommendations. Of these participants, 97% reported typically getting an interim PET/CT scan for stage III or IV cHL with 65% typically getting the scan after cycle 2 (Figure A). Participants reported both escalating and de-escalating treatment based on interim PET/CT results (Figure B) with 61% making decisions after cycle 2. Of participants using a PET/CT scan, 42% reported receiving both a Deauville score and a standardized uptake value (SUV; Figure C) with 62% of participants noting that the Deauville score was the primary system used for reviewing PET/CT results (Figure D). However, 19% of participants reported challenges interpreting PET/CT results. Among participants using a Deauville score (n=209), consensus was limited on what defined a positive scan (≥3, 44%; ≥4, 37%). Challenges obtaining PET/CT scans were reported by 16% of participants using PET/CT scans. However, despite not reporting challenges 55% of participants on average were unable to obtain a PET/CT scan 20% of the time. Of participants using PET/CT scans, 86% reported typically receiving results within 2 business days and 14% within 3-5 business days. Twenty-one percent of participants reported that delays in PET/CT results affected their ability to use a PET-adaptive approach. Forty-nine percent of those using PET/CT scans reported increased difficulty in PET/CT access for stage III or IV cHL due to lack of insurance coverage. In absence of a PET/CT scan, 36% of participants reported using an interim biopsy and 63% an interim CT scan to inform treatment choices. Among all participants, 36% reported increased difficulty in getting patients with cHL access to PET/CT scans due to COVID-19. Conclusions Although participants consider NCCN guidelines when treating cHL, interim PET scans are not universally obtained after cycle 2 for stage III or IV cHL, with 65% of participants who use PET/CT scans obtaining an interim PET scan after cycle 2 for stage III or IV cHL. When PET/CT scans are obtained, Deauville scores are commonly provided; however, there is variability in what is termed a positive or negative Deauville score. Challenges in obtaining PET/CT scans, with increased difficulty during COVID-19, were reported. Also, there are other barriers, such as lack of insurance, that may prohibit the optimal adherence to guidelines on interim PET/CT utilization. Figure 1 Figure 1. Disclosures Parsons: SeaGen: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Kumar: Seagen, Inc: Consultancy. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Flora: Seagen, Inc: Research Funding.

Prognostic Significance of PD1, PD-L1 Expression , Pathological Subtypes and Metabolic Activity on 18F-FDG PET/CT in Refractory /Relapsing Pediatric Hodgkin Lymphoma

Background: Hodgkin Lymphoma (HL) is a unique disease entity both in its pathology and the young patient population that it primarily affects. Several meta-analyses have demonstrated that high PD-L1 expression levels are correlated with adverse clinical and pathologic features. Objectives: The aim of this study is to evaluate the correlation between the expression of PD-L1 and clinicopathological features, as well as the prognostic significance of PD-L1 expression with regard to interim PET response in relapsing / refractory pediatric HL. Methods: We measured the expression of PD-1/PD-L1 in the baseline diagnostic samples of children with relapsing/ refractory classical HL. The results were correlated with the pathological subtypes as well as the clinical outcome. Results: Of the 88 included patients, 77% had advanced stage HL. PD-1 expression was detected in 50% of cases, whereas PD-L1 (membranous) was expressed by tumor cells in 60% of the cases, and strongly expressed in 16% of cases. Notably, PD-L1 (cytoplasmic) was detected in 55% of the cases. There was a significant differences in the expression levels of PDL-1 between the different pathological subtypes (p = 0.006). OS of patients with PD-L1expression (Cytoplasmic) was 83% vs 91% in patients with absent expression (P=0.001). There was no prognostic significance of PD-L1 expression with regard to PET response (p=0.31). Conclusion: Although PD-L1 expressions did not show statistically significance with well-established prognostic factors, our preliminary data indicate that pathological subtypes and cytoplasmic expression of PD-L1 may have a prognostic implication on survival in pediatric HL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Optimizing First-Line Therapy for Advanced-Stage Classic Hodgkin Lymphoma

Goals of first-line therapy in classic Hodgkin lymphoma (cHL) should focus on balancing risk versus benefit to the individual while increasing efficacy and decreasing toxicity. Overall, the ABVD regimen is well tolerated but slightly less effective, with a better safety profile compared with escalated BEACOPP. BV-AVD is somewhere in between ABVD and escalated BEACOPP on the cure/morbidity scale. Interim PET is predictive, but new prognostic biomarkers are emerging that may better identify patients at high risk for treatment failure. In patients with interim PET-negative cHL, de-escalating therapy does not impact overall survival along 1) with no proven role for radiotherapy. cHL is largely a disease of young people, and the choice of treatment should always take into account the potential for both short- and long-term toxicity with the goal of optimizing survivorship.

Aberrant patterns of PET response during treatment for DLBCL patients with MYC gene rearrangements

Purpose MYC gene rearrangements in diffuse large B-cell lymphoma (DLBCL) patients are associated with poor prognosis. Our aim was to compare patterns of 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET/CT) response in MYC + and MYC- DLBCL patients. Methods Interim PET/CT (I-PET) and end of treatment PET/CT (EoT-PET) scans of 81 MYC + and 129 MYC- DLBCL patients from 2 HOVON trials were reviewed using the Deauville 5-point scale (DS). DS1-3 was regarded as negative and DS4-5 as positive. Standardized uptake values (SUV) and metabolic tumor volume (MTV) were quantified at baseline, I-PET, and EoT-PET. Negative (NPV) and positive predictive values (PPV) were calculated using 2-year overall survival. Results MYC + DLBCL patients had significantly more positive EoT-PET scans than MYC- patients (32.5 vs 15.7%, p = 0.004). I-PET positivity rates were comparable (28.8 vs 23.8%). In MYC + patients 23.2% of the I-PET negative patients converted to positive at EoT-PET, vs only 2% for the MYC- patients (p = 0.002). Nine (34.6%) MYC + DLBCL showed initially uninvolved localizations at EoT-PET, compared to one (5.3%) MYC- patient. A total of 80.8% of EoT-PET positive MYC + patients showed both increased lesional SUV and MTV compared to I-PET. In MYC- patients, 31.6% showed increased SUV and 42.1% showed increased MTV. NPV of I-PET and EoT-PET was high for both MYC subgroups (81.8–94.1%). PPV was highest at EoT-PET for MYC + patients (61.5%). Conclusion MYC + DLBCL patients demonstrate aberrant PET response patterns compared to MYC- patients with more frequent progression during treatment after I-PET negative assessment and new lesions at sites that were not initially involved. Trial registration number and date of registration HOVON-84: EudraCT: 2006–005,174-42, retrospectively registered 01–08-2008. HOVON-130: EudraCT: 2014–002,654-39, registered 26–01-2015