Negative Interim PET Research Articles

THE LOW‐RISK EARLY‐STAGE HODGKIN LYMPHOMA PATIENTS WITH INADEQUATE RESPONSE TO CHEMOTHERAPY. THE PRELIMINARY EXPERIENCE FROM THE RAFTING TRIAL

Introduction: Early-stage Hodgkin Lymphoma (eHL) treated with a combined modality approach (CMT): chemotherapy (CT) and radiotherapy (RT) is a highly curable disease. However, for 70% of eHL patients (pts.) CT alone might be sufficient for cure. The RAFTING trial is a phase 2, multicenter, international prospective study investigating risk-adapted treatment strategy in eHL pts. We hypothesized that CT alone will be sufficient for to cure low-risk pts. Here we would like to present the clinical characteristics of low-risk pts. for whom CT was not sufficient to achieve a complete response (CR). Methods: Treatment intensity in RAFTING is tailored to two risk categories: low or high risk. Low-risk pts. are defined by low baseline metabolic tumor volume (MTV) and negative interim PET after 2 ABVD cycles. High-risk pts. were defined by high baseline MTV and/or positive iPET2. Within the low-risk group the pts. without any risk factors according to modified EORTC (mEORTC) criteria (largest nodal mass (LNM) 5–10 cm, Age > 50 yo, ESR > 50 mm/h, ≥4 nodal areas (NA)) (group 1a) are treated with 2 ABVD cycles only whereas pts. with at least 1 risk factor (group 1b)—with 4 ABVD cycles. High-risk pts. (group 3) receive “triple” therapy (4 ABVD cycles, RT and nivolumab for 12 months; RT-NIV). In case of “limited relapse” (i.e., within initially involved lymph nodes and/or up to 3 new nodal areas) pts. receive delayed RT-NIV. Results: In a per-protocol analysis, out of 77 stratified pts. in March 2023, seven pts. (9%) with low-risk disease, had inadequate response to ABVD alone (defined as achievement less than CR or early relapse (<6 months after the end of the CT): 2 pts. from group 1a and 5 pts. from group 1b. Specifically, one pt. from Group 1a had an extended and symptomatic (B symptoms) relapse, and underwent salvage therapy with ASCT and two pts. from group 1b were withdrawn due to PI decision. While 4 pts. (1 in Group 1a and 3 in Group 1b) with less than CR (2 pts.) or early relapse (2 pts.) received RT + NIV. The most frequent risk factor among 1b pts. was LNM, which was observed in 4 pts., age >50 yo—in 2 patients, and ≥4 NA—in 1 pt. More than 1 risk factor had 2 pts. In 4 cases the confirmatory biopsy was done and was positive for HL in 3 out of 4 cases. Conclusion: The frequency of inadequate response after CT alone observed in the RAFTING trial was similar to that reported by the literature. The most frequent adverse prognostic factor presented in these small pts. subset was a LNM. Keywords: combination therapies, Hodgkin lymphoma, radiation therapy No conflicts of interests pertinent to the abstract.

Should Adolescents and Young Adults with Hodgkin Lymphoma be Treated As Children or Adults?

Background Hodgkin lymphoma (HL) is one of the most common cancers in adolescents and young adults (AYA). While no specific recommendations exist for this age group, AYA with HL can be treated according to pediatric or adult therapeutic strategy, with the same major challenge: maintaining optimal efficacy with less long-term toxicity and promoting treatment adherence. Adult strategies are mainly based on ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) with/without radiotherapy, whereas pediatric protocols include OEPA (vincristine, etoposide, prednisolone, doxorubicin) and COPDAC (cyclophosphamide, vincristine, prednisolone, dacarbazine) with radiotherapy for inadequate early responses. Despite different treatment regimens, both approaches have shown excellent efficacy with 5-year overall survival (OS) rates above 95% in patients under 25 years old. However, very few studies have compared the outcome of AYA with HL treated with a pediatric protocol to that of AYA treated with an adult protocol. Methods From 2012 to 2018, 148 patients aged from 15 to 25 were treated at Saint-Louis Hospital for newly diagnosed HL. Among them, 71 were treated using an adult strategy and 77 according to the pediatric EuroNet protocol. The primary objective of this study was to compare the 5-year progression-free survival (PFS) by treatment group. Secondary objectives were to compare the 5-year OS, the interim PET response, the cumulative doses of chemotherapy received, the short-term toxicity profile, and the number of hospitalization days. Results Patients in both treatment groups were comparable in terms of baseline characteristics. In the adult group patients were older than in the pediatric group (median age 21.8 vs 18.6, p<0.0001) and more often overweight (BMI>25kg/m², 27% vs 9%, p=0.005). EORTC risk stratification was comparable between the 2 groups (14% localized, 41% unfavorable localized and 45% advanced stage). The median follow-up was 4.3 years (3.6 years in pediatric vs 5 years in adult group). The 5-year OS and PFS was respectively 100% and 85% for the whole cohort, with no significant difference between treatment groups (85% in pediatric vs 86% in adult group, HR=0.84, 95%CI [0.35-2.04], p=0.7) (Figure 1). In both strategies, the 5-year PFS was 100% for localized stage and 78% for advanced stage. Early response assessed by interim PET was associated with a shorter PFS in both groups. We observed a partial response at interim PET in 21% of pediatric and 10% of adult patients, associated with a 5-year PFS of respectively 68% and 44%, with no significant difference. In patients with negative interim PET, the 5-year PFS was 90% in both groups. Regarding early toxicities, cytopenias and infectious complications were comparable between the 2 types of regimens. However, pediatric treatments induced more steroid-related (weight gain, psychiatric disorders or osteo-necrosis) or vincristine-related adverse events (peripheral neuropathies). Due to the short follow-up, the late effects in both groups could not be evaluated. However, patients treated with adult regimens were exposed to higher cumulative doses of bleomycin (86mg/m² vs 1 mg/m², p<0.001), anthracycline (240mg/m² vs 167 mg/m², p<0.001), dacarbazine (3.0g/m² vs 2.1g/m², p<0.001), procarbazine (802mg/m² vs 0mg/m², p<0.001) and radiotherapy (30% vs 5% in pediatric group, p<0.001), whereas pediatric protocols included higher doses of corticosteroids (3.5g/m² vs. 0.4g/m², p<0.001), cyclophosphamide (2.7g/m² vs 1.5g/m², p<0.001) and etoposide (1.3g/m² vs 0.7g/m², p<0.001). (Figure 2) Pediatric protocols required more hospitalization days than adult protocols (26 vs 12 days) for the whole treatment, which may have an impact on quality of life. Conclusion Both adult and pediatric therapeutic strategies yield excellent and comparable OS and PFS in AYA with HL. The toxicity profile was different, with a higher risk of short-term steroid-related toxicities and more hospitalizations in pediatric regimens, and a higher expected risk of late toxicities in adult regimen. These results justify a tailor-made therapeutic decision, adapted to each patient, and highlights the importance of managing these AYA patients in dedicated units with professionals trained in the specificities of this particular age group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes of Consolidative Autotransplant for High-Risk Large B-Cell Lymphoma

Background: Although there have been significant recent advances in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL), there remains a substantial unmet need to optimize the frontline management of high-risk LBCL. Patients with high International Prognostic Index (IPI) scores 4-5 have particularly poor progression-free survival (PFS) rates of ~50% with R-CHOP, and 2-year PFS may be as low as 10-25% for patients with positive interim PET scans. In the phase III DLCL04 and SWOG-9704 trials, the use of upfront consolidative autologous stem cell transplantation (ASCT) after R-CHOP resulted in significant improvements in PFS, with the latter study also demonstrating a significant improvement in overall survival (OS) in the age-adjusted high IPI subgroup. Furthermore, the GAINED trial demonstrated favorable outcomes using an interim PET-adapted strategy, where consolidative ASCT appeared to overcome the poor prognostic impact of a positive interim PET. However, there is only limited and conflicting data from prospective or retrospective studies concerning ASCT consolidation for the highest risk patients with LBCL and IPI score 4-5, particularly those with positive interim PET scans. Methods: This retrospective, multicenter study included consecutive patients with newly diagnosed LBCL and high IPI score 4-5 who received consolidative ASCT as a planned part of first-line therapy at the Tom Baker Cancer Centre and Cross Cancer Institute in Alberta, Canada. Patients were excluded if they had primary central nervous system (CNS) lymphoma, previously treated indolent B-cell lymphoma, or underwent ASCT for r/r LBCL. PFS, OS, and disease-specific survival (DSS) were determined using the Kaplan-Meier method. Results: We included 114 patients with median age 60 years (range 18-73) and median follow-up time 5.6 years. High-risk features at diagnosis included IPI score 4 in 81 (71%), IPI score 5 in 33 (29%), stage IV in 112 (98%), >1 extranodal site in 109 (96%), non-GCB cell of origin by Hans’ algorithm in 32 (28%), double-hit lymphoma in 26 (23%), and secondary CNS involvement in 15 (13%). The most common induction regimen was R-CHOP (n=102) and 25 (22%) patients received 1-3 cycles, 71 (62%) received 4 cycles, and 18 (16%) received 5-6 cycles of induction. Rituximab with dose-intensive cyclophosphamide, etoposide, and cisplatin (R-DICEP) was frequently used (n=69) to intensify induction and for peripheral blood stem cell mobilization. Interim PET was performed during induction for 45 patients and was positive (Deauville 4-5) in 24 (53%) and negative (Deauville 1-3) in 21 (47%). Pre-ASCT disease status was complete response (CR) in 68 (60%), partial response (PR) in 43 (38%), and unknown in 3 (3%) patients. The most common ASCT conditioning regimens were BEAM in 41 (36%), BuMel in 39 (34%), and TBM in 13 (11%) patients. At 2 years, PFS was 82% (95% CI 74-88%), OS was 86% (95% CI 78-91%), and DSS was 87% (95% CI 79-92%). At 5 years, PFS was 72% (95% CI 62-80%), OS was 74% (95% CI 64-81%), and DSS was 80% (95% CI 71-87%). Relapse occurred in 21 (18%) patients at median 284 days (range 168-2229) after ASCT. There was 1 (1%) death due to early transplant-related infection and 3 (3%) late deaths from pulmonary fibrosis and therapy-related myeloid neoplasms. There were no significant differences in DSS for patients with versus without CNS involvement (77% vs. 80%, p=0.62), double-hit lymphoma versus DLBCL NOS (85% vs. 78%, p=0.80), GCB versus non-GCB cell of origin (78% vs. 80%, p=0.89) and positive versus negative interim PET (83% vs. 74%, p=0.51). Discussion: In this study of 114 selected patients with high-risk LBCL with IPI score 4-5, consolidative ASCT was associated with excellent outcomes with long-term disease-specific survival in 80%. Importantly, the efficacy of consolidative ASCT appeared to be independent of adverse prognostic factors including CNS involvement, double-hit status, non-GCB cell of origin, and interim PET positivity. The results of our study are consistent with those of previous clinical trials and provide real-world evidence confirming that consolidative ASCT can be considered a reasonable treatment option for eligible patients with high-risk LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P041: Low percentage of T lymphocytes in Hodgkin’s Lymphoma lymph nodes, measured by flow cytometry, is associated with inferior progression free survival regardless of negative interim pet scan status

Figure 1: Kaplan-Meier estimates of progression free survival stratified according to T-lymphocyte percentage in lymph node biopsies in Hodgkin lymphoma Background: Tumor microenvironment (TME) can influence antitumor immunity and survival in Hodgkin lymphoma (HL) as previously published. However, most of this data has sparse clinical applicability. Flow cytometry (FC) has limited utility in HL diagnosis but its potential to assess TME has not been fully explored yet. Aims: To determine the prognostic impact on survival of the percentage (%) of tumor infiltrating lymphocytes (TIL) and CD4/CD8 ratio in lymph nodes (LN) measured by FC. Methods: We selected patients (pts) with HL, available LN FC data at diagnosis and i-PET scan, treated at our center from 2012–2020. FC was performed with 8-color panels according to Euroflow protocols. TIL % and CD4/CD8 ratio in LN by FC were compared to normal values reported (Battaglia, Immunology 2003) and stratified as low, normal and high. Response was assessed per Lugano recommendations. Progression free survival (PFS) was estimated with Kaplan-Meier, multivariate analysis with Cox regression, and variables were compared with log-rank test. Results: 46 pts were included. Median age: 34 years. 24/27 with early stage had unfavorable risk and 11/19 with advanced disease had IPS≥3. 95% received ABVD. Complete response rate was 91.3%. 2 pts died. Median PFS: not reached (NR), 75th percentile 43 months (m), and median follow up: 49 m. i-PET negative (neg) pts had significantly better PFS (median NR vs 13.7 m in i-PET positive subgroup, p:0.014). Low LN TIL % was associated with inferior PFS (median 24.4 m vs. NR in pts with normal or high TIL, p:0.024). Regarding CD4/CD8 ratio, PFS rates were 100%, 75% and 60% in normal, low and high subgroups respectively, p:0.041. Both low TIL and positive i-PET remained independent predictors of survival on multivariate analysis with HR of 11.8 (CI 95% 1.9–72.7, p:0.021), and 7.7 (CI 95% 1.6–36.4, p:0.01) respectively. LN TIL % could further stratify outcomes in pts with neg i-PET scans. In this subset, pts with low TIL had a median PFS of 24.4 m and PFS rates of 33.3% vs. median NR in normal and high subgroups and PFS rates of 88.9 and 87.5% respectively, p:0.006. Conclusions: LN TIL % measured by FC showed prognostic impact in our cohort of HL pts. Pts with low TIL had inferior PFS, even in those with optimal interim response where the median was only 2 years. This finding denotes the critical role of T cells to achieve cure. Checkpoint blockade might constitute an appealing approach in these pts to restore effective antitumor immunity.

P1085: EVALUATION OF GONADAL FUNCTION IN YOUNG WOMEN DIAGNOSED WITH HODGKIN AND NON-HODGKIN LYMPHOMA

Background: ABVD chemotherapy (CT) is the standard treatment approach for Hodgkin lymphoma (HL), with a negative interim PET. R-DA-EPOCH and R-CHOP are the most frequently used regimens used in primary mediastinal/high grade B-NHL and DLBCL, respectively. Young women are often affected by these types of lymphoma and may be cured in >80% of the cases. Thus, treatment-related complications are being increasingly recognized, among which, gonadal insufficiency with its major psychological consequences. This is more prevalent in female patients, in whom collection and cryopreservation of oocytes/ovarian tissue are not applied in everyday clinical practice. Published data are scarce on this subject. Moreover, little is known about the kinetics of gonadal function and sex hormones during chemotherapy to safely guide contraceptive measures. Aims: The aim of this study is the prospective evaluation of gonadal function in young women with malignant lymphoma who are receiving CT. We here present our preliminary results on 50 patients with HL and B-NHL. Methods: This is a prospective study of gonadal function in female patients≤40 years. Hormonal measurements were performed at pre-specified time points: before treatment (t0), during CT(t1), at the end of CT(t2) and every six months(t6,t12) thereafter. The following hormones were measured: follicle-stimulating hormone (FSH), lutenizing hormone (LH), progesterone (PG), estradiol (Ε2), anti-Mullerian hormone (ΑΜΗ). The study included:32 HL [median age: 29 years, 32 ABVD] and 18 B-NHL patients [median age:27 years, 9 RDAEPOCH, 7 RCHOP, 2 other]. FSH reflects gonadal function in women (increased levels indicate gonadal dysfunction). AMH is considered to be the most sensitive biomarker for gonadal reserve (decreasing values correlate with ovarian insufficiency). E2 and progesterone are the major sex hormones. Results: HL-ABVD: FSH constantly increased from the beginning, peaking in the middle (fsh0-1 p<0.0001), remaining high until the end (fsh0-2 p<0.0001), without reaching normal levels at 6 months (fsh0-6 p=0.002), finally normalizing at 12 months after the end of treatment. Consistently with FSH, AMH sharply decreased during treatment: [median values: 2,85IU/mL(t0), 0,45IU/mL(t1), 0,62IU/mL(t2), p<0.0001 for both]. A rebound increase was observed at 6 months and slowly decreased again to normal values at 12 months after the end of CT. Estradiol and progesterone were not affected throughout the treatment. B-NHL: Gonadal damage, reflected by the increase in FSH, was evident, though with slightly different kinetics compared to HL: [median values: 4,1IU/mL(t0), 8,3IU/mL(t2), fsh0-2 p=0,035]. FSH gradually increased during treatment, reaching a peak towards the end. FSH slowly reached normal values after six months from the end of treatment. In parallel to HL, AMH values sharply decreased during CT: [median values: 7,3IU/mL(t0), 0,17IU/mL(t1), 1,57IU/mL(t2), amh0-1 p=0.002, amh0-2 p=0,043). However, in contrast to HL, no clear rebound was seen and AMH values remained extremely low, even at 18 months after the end of treatment (median values: 0,23IU/mL), highlighting the gonadotoxic effect of CT. Estradiol and progesterone did not change significantly. Image:Summary/Conclusion: Gonadal function in female patients with malignant lymphomas is affected during CT in both HL and B-NHL, though with different kinetics. In HL patients treated with ABVD, gonadal function normalized at 6 months, whereas, in B-NHL gonadal dysfunction remained even at 18 months after the end of CT, possibly indicating a chemotherapy-dependent genotoxic effect.

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

The Impact of the COVID-19 Pandemic on the Diagnosis and Management of Patients with Classical Hodgkin Lymphoma: A Single-Center Experience

Background: The coronavirus disease 2019 (COVID-19) pandemic has brought life to a standstill all over the world. Especially in Istanbul, the most populated city in Turkey, many hospitals served as pandemic hospitals and suspended the examination of patients who were not infected with COVID-19. On the other hand, in this period, lockdown was applied frequently to control the pandemic and to reduce the transmission. It is known that the delay in the diagnosis and treatment of cancer can sometimes be fatal. Initial treatment choice in classical Hodgkin lymphoma (cHL) patients is determined by various factors including the stage of the disease. Therefore, detection of the disease at an early stage has prognostic importance. Our aim was to compare the time from symptom onset to diagnosis and period between diagnosis and treatment initiation, as well as the distribution of stages and treatment responses in cHL patients diagnosed and treated during the COVID-19 pandemic and in the pre-pandemic period.Methods: Patients who were diagnosed within the 2 years before the pandemic (between March 2018 and March 2020) and in a 12-month period during the pandemic (between March 2020 and March 2021) were compared in terms of demographic data, disease related factors, time interval between symptom to diagnosis, and interim treatment response. Clinical data were obtained from manual and electronic medical records retrospectively. PET scans were performed at baseline, after two cycles of chemotherapy, and end of treatment (EOT). The Deauville five-point scale (5-PS) was used in the initial staging and assessment of treatment response. The 5-PS; a score of 1, 2, or 3 was considered negative. The 5-PS score 4 or 5 was positive.Results: This single-center study included 90 newly diagnosed cHL patients, with a median age of 33.5 years (range, 17 - 70 years) and a male predominance (53.3%). The most common presenting symptom was a lump in the neck (41.1%), and also, 61.1% (n=55) of the cases had at least one B symptom. Patient characteristics were summarized in Table 1. Age and sex distributions were similar in both groups. Also, the number of patients >60 years was comparable (p=0.868). The most common histopathological subtype in both groups was nodular sclerosis (47.7% vs. 48%). In the pre-pandemic period and during the pandemic, the percentages of patients with early unfavorable disease were 66.7% and 77.8%, respectively (p=0.526). Although the percentage of patients with advanced-stage disease was higher during the pandemic than that observed in the pre-pandemic period (64% vs. 53.8%), this difference did not reach statistical significance (p=0.384). The median interval between symptom onset to diagnosis was significantly longer during the pandemic than was observed within the pre-pandemic era (16 weeks vs. 8 weeks, p=0.042). The median durations between diagnosis and treatment initiation were similar in both groups (13 days vs. 15 days, p=0.253). The majority of patients in both groups received ABVD as first-line therapy, and IFRT was performed in some patients with early-stage cHL (Figure 1). Among all patients (n=90), 85% of the cases had negative interim PET scan results, and this percentage was similar for both patient groups (84.6% vs. 88%, p=0.999). In the pre-pandemic period, 80% of the patients had complete response at EOT, on the other hand, no comparison was performed between two groups regarding response level at EOT, since nearly half of patients (48%) treated during the pandemic were not evaluated for the EOT response at the time of the analysis.Discussion & Conclusion: In our cohort, the time interval between symptom onset to diagnosis was significantly prolonged during the pandemic. Most probably the patients were afraid of admitting to the hospital due to the fear of contagion, or patients might have experienced difficulties in applying to a health facility, and lastly maybe they had tolerable symptoms, which might all have roles in the diagnostic delay during the pandemic. Higher percentage of patients with advanced-stage disease during the pandemic might also be associated with this delay, however, fortunately, this difference did not translate into a significant difference regarding interim treatment response in both groups. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Controversies in the Management of Early-Stage Hodgkin Lymphoma

Early-stage Hodgkin lymphoma is a highly curable malignancy, but controversies surrounding treatment recommendations persist due to the sheer number of treatment choices available, as well as the effort to balance risk versus benefit for each individual patient. The gold standard for treatment has evolved over the years. Currently, in the PET era, fine-tuning therapy approaches is largely focused on avoiding giving too much therapy to patients with a negative interim PET and too little therapy to those with a positive interim PET. Careful patient selection for therapy has become increasingly important, as patient risk factors for early-stage disease are variably defined by German Hodgkin Study Group, EORTC, and NCCN criteria.

Enhanced Outcome Prediction in Early Stage Classical Hodgkin Lymphoma Using Pre-Treatment Biomarkers and Interim PET (BioPET); A Sub-Analysis of the UK NCRI RAPID Trial

Enhanced Outcome Prediction in Early Stage Classical Hodgkin Lymphoma Using Pre-Treatment Biomarkers and Interim PET (BioPET); A Sub-Analysis of the UK NCRI RAPID Trial

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

The SEMITEP trial: De-escalating chemotherapy in low-volume metastatic seminoma based on early FDG-PET.

387 Background: A negative FDG-positron emission tomography/computerized tomography (PET) predicts the absence of viable seminoma cells after chemotherapy in men with metastatic seminoma. In this study, we assessed whether patients (pts) with low-volume metastatic seminoma can be treated with 2 cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) on the basis of a negative interim PET, thereby limiting the burden of toxicity. Methods: In this non-randomised, multiple-center, phase 2 trial (NCT01887340), we enrolled pts with low-volume metastatic seminoma (with good prognosis according to IGCCCG and the Medical Research Council classifications). All pts with baseline PET-positive received EP for two cycles. After completion of first two cycles, pts underwent a second PET to assess response. Patients with a persistent positive PET (based on local review) proceeded directly to two additional EP cycles (for a total of 4); those who achieved a PET-negative received only one cycle of CARBO (AUC=7). The primary outcome was the proportion of pts who were PET-negative on interim PET and received de-escalating chemotherapy. Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Between June 2013 and July 2017, 102 pts were enrolled in the study. Three pts were deemed ineligible or not evaluable and thus 99 patients received treatment. After 2 first EP cycles, PET was available in 94 pts. Interim PET was negative in 68 pts (72%) and positive in 26 pts (28%). Overall, 63 pts (67.0%; 95% CI 57.5-76.5) were PET-negative and proceeded to one single cycle of CARBO. Overall, 24 (25.5%, 95% CI 17.1-34.9) patients had a PET positive after 2 EP and received 2 additional cycles of EP. After a median follow-up of 34.4 months, only 8 patients relapsed (2 in EP group and 6 in CARBO group). 2-year PFS rates were respectively 93.7% (95% CI 84.9-97.5) in the CARBO group and 92.9% (95% CI 77.4-98.0) in the EP group. Only one patient died during the 2 first cycles. Conclusions: De-escalating treatment based on a negative PET after 2 cycles of chemotherapy appears to be safe and feasible in the majority of patients with low-volume metastatic seminoma. Clinical trial information: NCT01887340.

Short-Course Therapy in Newly Diagnosed Immunodeficiency-Associated Aggressive B-Cell Lymphoma

Background: While six cycles of chemotherapy is the standard curative approach in diffuse large B-cell lymphoma (DLBCL), patients with immunodeficiencies and/or organ compromise may experience significant toxicity with this duration of therapy. Hence, balancing the competing needs of optimal aggressive lymphoma therapy with tolerable treatment-related toxicity is a challenge in this population. Previously, abbreviated therapy with short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and dose-dense rituximab (SC-EPOCH-RR) - where most patients received 3 cycles of therapy - demonstrated high efficacy in HIV-associated DLBCL (Dunleavy et al. Blood 2010; 115:3017-24). 79% of patients received 3 cycles of therapy and overall 91% of patients achieved a complete response (CR). Here we retrospectively evaluate the outcome of patients with newly diagnosed DLBCL who had an underlying immunodeficiency and/or chronic renal failure and received SC-EPOCH-RR at our institution. Methods: We included patients who had a new diagnosis of DLBCL (including primary effusion lymphoma (PEL)) associated with immunodeficiency (HIV or post-organ transplant) and/or chronic renal failure. Therapy consisted of SC-EPOCH-RR (R was omitted in the patient with PEL) with intrathecal prophylaxis (as previously described). A total of three to four cycles of therapy was planned if an interim FDG-PET (following 2 cycles) was negative by Deauville criteria. A Deauville score of 1-3 was considered negative and 4-5 positive. In patients who were HIV positive, anti-retroviral therapy (ART) was continued as long as there were no significant ART-chemotherapy interactions. Results: Characteristics of 7 included patients are as follows: median age 43 (25-75); 5 (71%) were male; 6 (85.7%) had stage 3 or 4 disease; 6 (85.7%) had elevated LDH at diagnosis; 5(71.4%) had an International Prognostic index (IPI) score of 3-5; 5 (71%) were HIV positive and 3 (43%) had chronic renal failure (including 1 patient on chronic immunosuppression post-renal transplant for granulomatosis with polyangiitis). All had a diagnosis of DLBCL, 4 who were GCB and 2 non-GCB by the Hans algorithm, while 1 had extra-cavitary PEL. Two patients had c-MYC rearrangements by FISH. For HIV positive patients, the median CD4 count at diagnosis was 266 (32-292). No patient had CNS disease. All patients received 3 (4 patients) or 4 (3 patients) cycles of therapy. Responses were CR in all patients as assessed by end of therapy (EOT) FDG-PET. All patients had a negative interim PET by Deauville criteria (scores 1-3). One patient with HIV-associated DLBCL (CD4 count 32 at diagnosis and non-GCB subtype by immunohistochemistry) relapsed with CNS disease 4 weeks after achieving a negative EOT-PET and died from disease progression several weeks later. All other patients (6/7) are progression-free with a median follow-up time of 6 months. Conclusions: Albeit small numbers and short follow-up in our series, in a 'real-world' setting, abbreviated therapy was highly effective in patients with immunodeficiency-related DLBCL and/or in the setting of chronic renal failure. Using an interim PET guided approach, 3-4 cycles of therapy is highly effective and importantly limits toxicity in this population. Though the series was not large enough to accurately identify poor prognostic clinical and tumor factors, the patient with progression had a non-GCB tumor and was severely immunosuppressed, characteristics previously shown to be associated with adverse outcomes in this population. We continue to expand our series and follow-up. Additional studies are needed evaluating abbreviated therapy (SC-EPOCH-RR) in immunosuppressed and organ-compromised patients with aggressive B cell lymphomas for whom there is a paucity of experience and toxicity concerns limit delivery of standard, potentially curative therapy. Disclosures Smith: EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dunleavy:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Bleomycin Use in the Treatment of Hodgkin Lymphoma (HL): Toxicity and Outcomes in the Modern Era

BACKGROUND: Historically, one in five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT), a life-threatening interstitial pneumonitis. The current treatment paradigm consists of prompt discontinuation of bleomycin, administration of corticosteroids, antibiotics, hospital admission, respiratory therapy, or intensive care. BPT represents a challenge for patients with HL as it not only impairs respiratory function, but also has negative impacts on clinical outcomes. A collection of a dozen studies suggest BPT has a mortality rate just short of 10% of patients who develop BPT. Given recent data on bleomycin omission with negative interim PET scan, we assessed changes in BPT rates and severity over the past 15 years. Overall, treatment protocol characterization and patient characteristics most responsive to BPT treatment are poorly understood. OBJECTIVES: In this study, we investigated the clinical impact and treatment strategies in patients with BPT. Our goals were to: 1) Identify HL patients in the last decades who developed BPT and identify risk factors for BPT, 2) evaluate the impact of BPT on long-term clinical outcomes, and 3) characterize patterns of treatment strategies among patients with HL who develop BPT. METHODS: A single-center, retrospective analysis was preformed using patient data from the Mayo Clinic Lymphoma Database (Rochester, MN) consisting of 1,299 patients diagnosed with HL. All patients were diagnosed between 2003-2018. Inclusion criteria included 1) newly diagnosed, biopsy proven HL, 2) upfront treatment with ABVD, 3) treatment was received at our institution. All patients were assessed for clinically relevant HL characteristics including stage of disease, presence of bulky disease, presence of B symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, BPT risk factors, and bleomycin treatment regimen. BPT was clinically defined as 1) Presence of pulmonary symptoms, 2) bilateral interstitial infiltrates on imaging, and 3) no evidence of infectious etiology. Patients treated in the "Early Era" (2000s) were compared to patients in the "Recent Era" (2010s). Comparison of continuous variables between BPT groups was assessed with Wilcox rank-sum test. OS and PFS were estimated via the Kaplan-Meier method. Approval of the protocol by the Mayo Clinic Institutional Review Board (IRB) was obtained and all patients were consented accordingly. RESULTS: One-hundred twenty six patients met the inclusion criteria for this study. Median follow-up for PFS and OS was 5.5 years (95%CI = 4.8-6.4) and 5.8 years (95%CI = 5.0-7.0), respectively. The 10-year OS and PFS among all patients were 85.1% (95%CI = 77.8-93.1) and 86.3% (95%CI = 80.1-93.0), respectively. Forty-seven patients (37% of all patients) met criteria for BPT. The estimated 10-year OS for BPT and non-BPT patients were 74.7% (95%CI = 61.8-90.5) and 91.7% (95%CI = 83.9-100.0), respectively. The estimated 10-year PFS for BPT and non-BPT patients were 84.7% (95%CI = 74.8-95.8) and 87.0% (95%CI = 79.1-95.8), respectively. In univariable analysis, BPT negatively impacted OS (HR=3.6, 95%CI: 1.2-10.6). However, bleomycin omission did not impact OS (HR=1.3, 95%CI=0.5-3.7). BPT-mortality was 17%. In multivariable analysis, BPT was not significantly associated with OS after adjusting for baseline characteristics (HR=3.0, 95%CI=0.9-9.9). Patients were older (median: 46 vs 33 years) and received less bleomycin (median: 107 vs 215 units) compared to non-BPT patients. BPT was most often managed with bleomycin omission with 59% of patients (74 of 126 patients) having omitted bleomycin at some point during treatment. Patients treated in the "Recent Era" (2010s) had lower BPT rates (28% vs 48%), mortality (10% vs 21%), bleomycin dose (143 vs 204 units), and bleomycin cycles (7 vs 12 cycles), yet higher prophylactic bleomycin omission (59% vs 8%) compared to "Early Era" (2000s). Patients treated in the Recent Era compared to Early Era had a reduction of BPT treatment with steroids, hospital admission, respiratory therapy, and ICU admission by 12%, 22%, 14%, 13%, respectively. CONCLUSION: Overall, our data suggests BPT continues to impact OS in HL patients treated with ABVD, however BPT treatment is decreasing as management changed in recent years. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding.

ACOPP Chemotherapy for Frontline Treatment of Older Patients with Hodgkin Lymphoma - a Pilot Study

Introduction: Approximately 20% of patients with Hodgkin lymphoma (HL) are aged 60 years or older. There is no standard of care for such patients, who have a markedly inferior prognosis compared with younger patients and are significantly underrepresented in clinical trials. Escalated BEACOPP chemotherapy has been demonstrated to be highly effective in frontline HL management, but when used in older patients (even at non-escalated doses) there is an unacceptable rate of toxicity-related death. We proposed that a modification of the BEACOPP regime by removing bleomycin and etoposide and dose reduction of cyclophosphamide ('ACOPP') would potentially be a well-tolerated and effective regimen for older HL patients. Methods: This is a single centre pilot study investigating the feasibility of ACOPP chemotherapy for frontline management of older patients with HL who were deemed unfit for more intensive management approaches. Patients received intravenous (IV) Doxorubicin (35mg/m2) and Cyclophosphamide (650mg/m2) on day 1 along with oral Procarbazine (100mg/m2) for 7 days and oral Prednisolone (40mg/m2) for 14 days. IV Vincristine (1.4mg/m2, max 2mg) was given on day 8 and subcutaneous granulocyte colony stimulating factor given on days 9-13. Treatment was delivered as an outpatient every 21 days to a maximum of 6 cycles. Interim PET/CT assessment was performed after 2 cycles of treatment. Results: Seven patients with a median age of 81 years (range 58-92) were treated between March 2018 - March 2019. All patients had histologically confirmed classical Hodgkin lymphoma. 6/7 patients had advanced stage disease with median IPS 3. One patient had unfavourable stage 2 disease by EORTC criteria. Median Charlson Comorbidity Index (CCI) score was 6 with further details outlined in Table 1. All 7 patients completed at least 2 cycles of therapy and all had a complete metabolic response on interim PET with ongoing response confirmed on end of treatment CT. Four patients completed 6 cycles of therapy, with the other 3 patients completing 2, 4 and 5 cycles respectively. Reasons for completing less than 6 cycles of therapy were physician concerns over increased frailty in patient 5, concurrent diagnosis of Parkinsons disease with resultant physical deconditioning in patient 3 and postural hypotension (possibly secondary to vincristine) in patient 7. Grade 3/4 neutropenia was seen in 5/7 patients but only 1 patient had an episode of febrile neutropenia. Thrombocytopenia (2 patients, both grade 3, none requiring platelet transfusion) and anaemia (5 patients, all grade 3 and required red cell transfusion) were also seen. Peripheral neuropathy occurred in 2 patients (grade 1, grade 2). 6/7 patients required admission to hospital during therapy - primary reasons for admission were infection (n=2), constipation (n=2), anaemia (n=1) and autonomic neuropathy (n=1). All 7 patients remain alive and in remission at time of analysis (median FU 9 months). Conclusion: We have demonstrated the feasibility of ACOPP as a chemotherapy regimen which can be delivered in an outpatient setting to elderly patients with HL. We would highlight the median age of 81 years and significant co-morbidity burden of the patients in this pilot study. All patients achieved a negative interim PET and remain in remission at the time of analysis. Toxicity was mainly haematological but was manageable with only 1 episode of febrile neutropenia and no platelet transfusion required. The majority had hospital admissions during therapy, with only 4/7 managing to complete six cycles of treatment. Definitive conclusions regarding efficacy and safety cannot be drawn from this small number of patients but the high rates of metabolic response are encouraging and we feel the regimen merits further, prospective assessment in a large clinical trial. Disclosures Travers: Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. McKay:Janssen: Honoraria, Speakers Bureau; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leach:Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria.

Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity and outcomes in the modern era

One-in-five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT). Given bleomycin-omission data with negative interim-PET, we assessed changes in BPT statistics. We retrospectively evaluated 126 ABVD-treated HL patients for overall survival (OS), progression-free survival (PFS), BPT factors, and management. Forty-seven patients developed BPT with 17% BPT-mortality. In univariable analysis, OS was negatively impacted by BPT (HR = 3.6, 95%CI = 1.2–10.6), but not bleomycin-omission (HR = 1.3, 95%CI = 0.5–3.7). In multivariable analysis, BPT was not associated with OS (HR = 3.0, 95%CI = 0.9–9.9). BPT patients were older (46 y vs 33 years) and received less bleomycin (107 vs 215 units) compared to non-BPT patients. BPT was managed primarily with bleomycin-omission. “Recent Era” patients had lower BPT rates (28% vs 48%), mortality (10% vs 21%), and bleomycin doses (7 vs 12 doses), yet higher bleomycin-omission in the absence of the BPT (59% vs 8%) compared to “Early Era”. Our data suggest BPT continually impacts OS in ABVD-treated HL patients, however management is changing.

CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET

AbstractA negative interim positron emission tomography/computerized tomography (PET/CT) after 1 to 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, nonbulky stage I or II Hodgkin lymphoma (HL) predicts a low relapse rate. This phase 2 trial was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without radiation therapy (RT) on the basis of a negative interim PET/CT, thereby limiting the risks of treatment. Between 15 May 2010 and 21 February 2013, 164 previously untreated patients with nonbulky stage I/II HL were enrolled, and 149 were included in the final analysis. Patients received 2 cycles of ABVD followed by PET. Deauville scores 1 to 3 were negative (≤ liver uptake) based on central review. PET− patients received 2 more cycles of ABVD, and PET+ patients received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus 3060-cGy involved-field RT. The primary objective was to determine 3-year progression-free survival (PFS) for the PET− group. One hundred thirty-five patients (91%) were interim PET−, and 14 patients (9%) were PET+. With median follow-up time of 3.8 years, the estimated 3-year PFS was 91% for the PET− group and 66% for the PET+ group (hazard ratio, 3.84; 95% confidence interval, 1.50-9.84; P = .011). There was 1 death as a result of suicide. Four cycles of ABVD resulted in durable remissions for a majority of patients with early-stage nonbulky HL and a negative interim PET. This trial was registered at www.clinicaltrials.gov as #NCT01132807.

Interim PET-CT may predict PFS and OS in T-ALL/LBL adult patients.

T lymphoblastic leukemia/lymphoma (T-ALL/LBL) is highly aggressive. Although intensive chemotherapies such as ALL-type regimens are commonly used, about half adult patients eventually relapse and die of T-ALL/LBL. Overwhelming evidences have confirmed that interim PET can predict survival outcomes and guide subsequent treatments in Hodgkin lymphoma. However, whether interim PET-CT can predict survival outcomes or not in T-ALL/LBL patients remains unclear. 47 adult patients of T-ALL/LBL were retrospectively reviewed. Interim PET-CT was done after induction therapy and evaluated according to the International Harmonization Project criteria. After induction therapy, interim PET-CT was positive in 19 patients (40.4%). After a median follow up time of 34 months, the 2-year and 3-year progression free survival (PFS) rate were 39% and 30%, respectively, and the 2-year and 3-year overall survival (OS) rate were 54% and 45%, respectively. Using Kaplan-Meier survival analysis, it was found that interim PET-CT positivity correlated with significantly inferior PFS and OS (2-year PFS rate for patients with positive or negative interim PET were 21.1% or 56.0%, respectively, p = 0.002; 2-year OS rate for patients with positive or negative interim PET were 31.6% or 63.7%, respectively, p = 0.010). However, there was no significant relationship between PFS, OS and bone marrow infiltration, lactate dehydrogenase level, and stages (p > 0.05). Interim PET-CT may predict PFS and OS in adult patients of T-ALL/LBL, which needs to be validated in prospective clinical trials. The optimal criteria for interim PET-CT evaluation and risk-adapted treatment strategy determined by interim PET-CT should be investigated in future clinical practice.

Response-adapted frontline therapy for Hodgkin lymphoma: are we there yet?

Treating Hodgkin lymphoma by using chemotherapy with or without radiotherapy is highly successful, with substantially fewer deaths from lymphoma than from other causes in recent studies of both early-stage and advanced-stage disease. Long-term toxicity is a major consideration in this context, and recent trials have used functional imaging with [18F]fluorodeoxyglucose (FDG) positron emission tomography early in the course of treatment (interim PET) to assess response and modulate subsequent therapy. In early-stage disease, this has allowed omission of consolidation radiotherapy after a good response to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, and trials have shown that this can be done without detriment to overall survival, despite a small increase in rates of recurrence of ∼5%. Conversely, escalation to more intensive chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) for those with positive interim PET scans seems to be an effective strategy with improved disease control. In advanced-stage disease, several groups have elected to start treatment with ABVD and escalate to BEACOPP or myeloablative therapy for patients who remain PET positive after 2 cycles, which gives rates of disease control of ∼65%. De-escalation by omission of bleomycin and consolidation radiotherapy after a negative interim PET scan seems safe with no increase in recurrence rate, but the performance of interim PET after ABVD is suboptimal, especially for those with very advanced disease at presentation; recurrence rates after a negative scan are ∼15%. The negative predictive value of PET is higher after escalated BEACOPP chemotherapy, and the approach of initially treating with BEACOPP and de-escalating to ABVD for those with negative interim PET scans shows promising early results. Response-adapted therapy has yielded important results for patients with Hodgkin lymphoma and is becoming established as a standard approach.

High-risk interim PET negative patients in Hodgkin's lymphoma

Interim FDG-PET/CT done as early as after the first or second cycle of first line chemotherapy is now recognised as a good predictor of outcome in classic Hodgkin's lymphoma. This scan has been successfully used as a guide to escalate or de-escalate therapy in several important trials. 1 Radford J Illidge T Barrington S PET-directed therapy for Hodgkin's lymphoma. N Engl J Med. 2015; 373: 392 Crossref PubMed Scopus (4) Google Scholar Interim PET negative scans have a high negative predictive value, the abrupt decrease of the fluorodeoxyglucose signal expression during therapy is explained by the switch-off of activity of the microenvironmental cells recruited by chemokines that are produced by the Hodgkin Reed-Sternberg cells. 2 Gallamini A Positron emission tomography scanning: a new paradigm for the management of Hodgkin's lymphoma. Haematologica. 2010; 95: 1046-1068 Crossref PubMed Scopus (31) Google Scholar Indeed, the intense fluorodeoxyglucose uptake observed in Hodgkin's lymphoma at staging of the disease is explained mainly by the activity of the GLUT3 receptors on the microenvironmental cells, which account for 99% of cells in the Hodgkin's lymphoma tumour. However, 10–15% of patients with a negative interim PET scan still had disease progression or relapsed. 3 Johnson P Federico M Kirkwood A et al. Adapted treatment guided by interim PET-CT Scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016; 374: 2419-2429 Crossref PubMed Scopus (488) Google Scholar In a prospective study, 3 Johnson P Federico M Kirkwood A et al. Adapted treatment guided by interim PET-CT Scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016; 374: 2419-2429 Crossref PubMed Scopus (488) Google Scholar the 3 year progression-free survival rate of patients who were PET negative after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) was 86% (95% CI 82·1–88·6). No diagnostic tool has been proposed yet for better identification of PET negative patients who relapse these patients. The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin's lymphoma: a retrospective, European, multicentre cohort studyThe CART algorithm correctly predicted the response to treatment in more than a half of patients who had a relapse or disease progression despite a negative PET-2 scan, thus increasing the negative predictive value of PET-2. In keeping with preliminary results from interim PET response adapted clinical trials of patients with advanced Hodgkin's lymphoma, there might be a non-negligible proportion of treatment failures in the interim PET negative group treated with standard ABVD. Full-Text PDF

Hodgkin lymphoma: a negative interim-PET cannot circumvent the need for end-of-treatment-PET evaluation.

We examined the outcome of a cohort of patients with Hodgkin lymphoma (HL) in order to assess if fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) at the end of treatment (end-PET) can be omitted when the interim PET (int-PET) is negative. Seventy-six ABVD(adriamycin, bleomycin, vinblastine, dacarbazine)-treated patients were retrospectively included. No change in treatment was made on the basis of int-PET results. Suspicious foci on end-PET received biopsy confirmation whenever possible. Median follow-up was 58·9months. Uptake on int-PET higher than liver (scores 4-5) was rated positive according to the Lugano classification, while a positive end-PET corresponded to scores 3, 4 and 5. Fifteen patients had treatment failure. Sensitivity, specificity, positive predictive value (PPV), negative predictive value and accuracy of int-PET were 46·7%, 85·2%, 43·8%, 86·7% and 77·6%, respectively. For end-PET the figures were: 80%, 93·4%, 75%, 95% and 90·8%. Eight patients with negative int-PET had treatment failure; six of them were identified as non-responders with end-PET. The 5-year progression-free survival (PFS) was 87% for patients with negative int-PET versus 56% with positive int-PET. The 5-year PFS was 96% with negative end-PET versus 23% with positive end-PET. The prognostic information from int-PET as regards PFS (log-rank test P=0·0048) was lower than that provided by end-PET (P<0·0001). Int-PET predicted only half of the failures. When used in clinical routine, a negative int-PET study cannot obviate the need for end-PET examination.