Complete Metabolic Remission Research Articles

Exceptional sustained long-term complete response to Tepotinib in a MET-amplified advanced intrahepatic biliary tract cancer failing Durvalumab plusCisplatin and Gemcitabine.

Biliary tract cancers (BTCs) are a diverse group of malignancies with varied genetic backgrounds. The prevalence of intrahepatic cholangiocarcinoma (iCC) is increasing, particularly in Western countries. Despite advancements in treatments, the prognosis for BTC remains poor. Recent molecular profiling has revealed that up to 40% of iCC cases have targetable genetic alterations. MET amplification, although rare, presents a significant target for therapy. A 25-year-old female with a history of ulcerative colitis presented with shoulder pain and a positron emission tomography-computed tomography (PET-CT) scan revealed an enlarged liver and multiple metastases. Histopathological analysis diagnosed poorly differentiated adenocarcinoma. First-line therapy with Cisplatin, Gemcitabine, and Durvalumab resulted in disease progression. Molecular profiling identified a TP53 mutation and MET amplification. Based on these findings, Tepotinib was initiated. Tepotinib treatment led to a significant reduction in tumor size and normalization of CA 19-9 levels within 2 months, achieving a complete metabolic remission lasting up to 17 months. The treatment was well tolerated with minimal side effects. MET-amplified BTCs are exceedingly rare, and evidence for targeted treatment is limited. This case demonstrates the efficacy of Tepotinib in a young patient with MET-amplified iCC, showing a long-term response and suggesting a potential new standard treatment option for this molecularly defined entity. This case also highlights the aggressive nature of MET-amplified tumors and the need for targeted second-line therapies. Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.

Complete metabolic remission of widespread blastic plasmacytoid dendritic cell neoplasm after treatment

Complete metabolic remission of widespread blastic plasmacytoid dendritic cell neoplasm after treatment

How I Follow Hodgkin Lymphoma in First Complete (Metabolic) Remission?

Hodgkin lymphoma is characterized by a high cure rate in the modern era of medicine regardless of stage, but patients suffer from a high risk of comorbidity associated with the administered therapy. The main aim of this review article is to assess and analyze the various comorbidities associated with Hodgkin lymphoma and address the survivorship of patients, including fertility, secondary cancers due to cardiovascular toxicity, and quality of life. Furthermore, this review explores the optimal strategy for detecting relapse. The treatment paradigm of Hodgkin lymphoma has shifted, with a paradigm shift toward achieving a high cure rate and low toxicity as a standard of care in this patient population. Checkpoint inhibitors, especially nivolumab, in combination with chemotherapy are increasingly being studied in the first line of therapy. However, their long-term toxicity remains to be assessed in longer follow-up. In conclusion, Hodgkin lymphoma survivors, regardless of their treatment, should be followed up individually by a multidisciplinary survivorship team in order to detect and properly treat the long-term side effects of therapy.

Development of Diffuse Large B-cell Lymphoma Serendipitously Led to Life-Saving Treatment in a Patient with Refractory Classical Hodgkin Lymphoma.

A 65-year-old man with generalized lymphadenopathy was diagnosed with classical Hodgkin lymphoma-Mixed cellularity via left cervical lymph node biopsy. Initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine led to complete metabolic remission (CMR); however, recurrence developed after 6 months. Brentuximab vedotin induced partial remission followed by systemic relapse after 10 months. Nivolumab led to a second CMR, but disease progression persisted over nearly 4 years, despite treatment adjustments and local radiotherapy. Eventually, the patient was diagnosed with diffuse large B-cell lymphoma during routine esophagogastroduodenoscopy. Four courses of rituximab-CHOP therapy led to a CMR. This case highlights the importance of performing re-biopsies to detect the recurrence or progression of lymphoma.

Development and Clinical Validation of an Ultra-Fast CAR-T Manufacturing Platform Enabling Production of CAR-T Cells in Less Than 1 Day

Recently, the use of CAR-T cells has made a major impact on the therapy for a subset of hematologic malignancies including non-Hodgkin lymphoma (NHL) and multiple myeloma. In relapsed/refractory NHL where historically most patients did not respond to chemotherapy, CAR-T cell therapy can lead to initial remission rates >50%. Despite promising outcomes, there are major unmet needs to develop rapid, cost-effective, and scalable CAR-T manufacturing platforms that lead to efficacious and affordable autologous CAR-T cell products. Major barriers to widespread access to CAR-T cell therapy include weeks to months long delays from time of prescription to infusion that leads to disease progression in a significant subset of patients, very elevated costs that preclude access for a majority of patients world-wide, and high relapse rates (~estimated 30-60% within one year) in patients who initially achieve remission. To help address these barriers, we developed an ultra-fast CAR-T manufacturing platform (UF-CAR) that allows production of highly cost-effective CAR-T product in less than 24 hours. The manufacturing workflow was specifically designed to be simple, low cost and rapid to enable its formulation in healthcare facilities without sophisticated equipment or personnel expertise. In addition, we hypothesized that this manufacturing workflow would generate a product that demonstrates dramatically improved efficacy and CAR-T expansion in vivo. Using a BCMA CAR we manufactured CAR-T cell product using both our ultra-fast manufacturing workflow and a traditional 9-day CAR-T cell manufacture workflow. Both workflows led to nearly identical levels of CAR surface expression on the T cells (67% and 66% CAR expression on the UF-BCMA product and 9-day product respectively). To compare the activity of the products, we injected immunodeficient mice intravenously with luciferase labelled MM1.s cells followed by a single intravenous injection of CAR-T cells on day 0. As seen in figure 1A, both products demonstrated efficacy, but the UF-BCMA product induced durable disease control while disease progression started to occur with the 9-day product on day 29 after CAR-T injection. Consistent with the improved efficacy, circulating levels of the UF-BCMA CAR-T cells in the mouse blood were found to be up to 100x higher than the levels of the 9-day BCMA CAR-T product (Figure 1B). Similar increased potency and marked increases in circulating CAR-T cells were observed in a mouse model of human lymphoma when comparing a CD19 CAR manufactured using the UF-CAR workflow as compared to a standard CAR-T manufacturing process. To assess the safety and clinical potential of CAR-T products manufactured with the UF-CAR platform, a phase 1 trial was recently initiated using a CD19 CAR-T product (UF-Kure19). This trial that is open to patients with relapsed/refractory NHL completed treatment of its first patient who had relapsed mantle cell lymphoma. UF-Kure19 product was manufactured successfully in less than 1 day and demonstrated CAR expression of 41%. The product passed all release criteria for infusion and was administered to the patient after lymphodepletion with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 daily for 3 days. UF-Kure19 cells expanded robustly in the patient and peaked around day 10 (23% of circulating CD3) with a strong skewing of CD4/CD8 cells (93% CD8+ T cells on day 10). The patient was found to be in complete metabolic remission by day 28 and ongoing remission was confirmed on day 60. We have developed an ultra-fast CAR-T cell manufacturing platform that enables low-cost production in less than one day. In vitro and animal data suggest this fast-manufacturing platform leads to potent CAR-T cells. Early human testing indicates CAR-T cells generated using this novel system have clinical activity against hematologic malignancies.

Pet-2 Positive during Frontline Therapy: An Early Unfavorable Predictor for Subsequent Salvage High-Dose Chemotherapy (HD-CT) and Autologous Stem Cell Transplant in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: Interim PET (PET-2), performed after two cycles of chemotherapy (CT), is widely adopted to select patients (pt) with classical Hodgkin lymphoma (cHL), who might benefit from omitting radiotherapy (RT) or reducing the number of CT cycles in early stages, as well as intensifying or de-escalating first-line therapy in advanced stages. Furthermore, PET-2 has prognostic value in the front-line and in the salvage treatment. In a retrospective multicenter Italian study on patients experiencing failure of first-line treatment, we recently observed that PET-2 seems to be an early unfavorable predictor for subsequent salvage high-dose (HD) CT and autologous stem cell transplant (ASCT). Aims of Study and Methods: To evaluate the impact of the prognostic factor PET-2, we performed a retrospective observational multicenter study on individual data of 184 pt with relapsed or refractory (R/R) cHL after first-line CT given according to a PET-adapted strategy. R/R pt were treated at 11 Italian centers with one or more lines of salvage CT followed by HD-CT and ASCT from 2009 to 2021. We compared characteristics and outcomes of 125 PET-2 negative with those of 59 PET-2 positive (PET-2+) R/R pt. Study endpoints included Progression-free survival (PFS) (defined as the time from the date of ASCT to progression or death after ASCT, whichever occurred first), Overall Survival (OS) (defined as the time from the date of ASCT to death from any cause or the last date for which information was available), and factors associated with ASCT outcome evaluated by univariate and multivariate analysis. Results Main pt characteristics at relapse or progression among 125 PET-2 negative and 59 PET-2+ pt were as follows: median age 34 vs 32 years, M/F 64/61 vs 28/31, refractory disease 38% vs 76%, early relapse (within 12 months from end of first-line CT) 27% vs 19%, late relapse 35% vs 5%, stage III or IV 43% vs 44%, B symptoms 24% vs 27%, extranodal involvement 26% vs 24% bulky disease 12% each, anemia 9% vs 22%, ECOG PS >1 11% vs 8%. First salvage treatment regimen was BeGEV in 34% vs 14%, IGEV in 34% each, Brentuximab Vedotin +/- Bendamustine in 6% vs 24%, DHAP or DHAOX in 17% vs 24% and other regimens in 10% vs 5% of pt, respectively. Before ASCT, 95 (76%) in the PET-2 negative and 32 (54%) in the PET-2+ group achieved a complete metabolic remission (mCR). After a median follow-up of 36 months, the 3-year PFS and OS were 73.8% (95% CI: 66.2-80.0%) and 89.3% (95% CI: 83.0-93.3%), respectively. Figure 1 shows PFS by PET-2 status. A total of 99 patients underwent ASCT after one line of salvage therapy. At 3 years PFS and OS in patients who underwent ASCT after one line of salvage therapy were 80.6% (95% CI: 68.9-88.3) and 92.2% (95% CI: 82.2-96.7) in the PET-2 negative group, and 56.2% (95% CI: 33.6-73.7) and 90.9% (95% CI: 68.1-97.6) in the PET-2+ group. Thirty-six patients required two and 14 more than two lines of salvage therapy in the PET-2 negative group; the same figures in the PET-2+ group were 21 and 14. There was no significant difference in PFS or OS by type of salvage therapy received in the two groups. In univariate analysis PET-2+ during frontline treatment (HR 2.68, P=0.001), anemia (HR 2.18, P=0.038), >2 lines of salvage therapy to enter a response (HR 3.68, P<0.001), achieving less than mCR prior to ASCT (HR 3.19, P<0.001) and RT performed before ASCT (HR 3.11, P=0.017) were associated with inferior PFS. Achieving less than mCR prior to ASCT (HR 2.86, P= 0.026), >2 lines of salvage therapy needed to enter a response prior to ASCT (HR 4.93, P=0.002), anemia (HR 2.96, P=0.040) and checkpoint inhibitors before ASCT (HR=5.10, P=0.032) were adverse prognostic factors for OS, whereas transplant performed after 2012 was associated with improved OS (HR 0.20, P<0.001). Cox regression multivariable analysis led to the identification of more than two lines of salvage therapy needed before ASCT (HR 3.14, P=0.008) as an independent adverse prognostic factor for PFS. PET-2+ at front-line treatment (HR 1.94, P=0.052), anemia at relapse or progression (HR 2.07, P=0.080) and RT before ASCT (HR=2.52, P=0.086) were associated with increased risk of failing ASCT, although they did not reach statistical significance Conclusions: PET-2+ during frontline CT may represent an early marker of chemo-refractoriness. Nevertheless, PET-2+ patients experiencing failure of a PET-guided treatment intensification can benefit from a prolonged OS after HDCT and ASCT.

Novel Targeted Agents in Combination with R-ICE (R-ICE-X) Based on Genotyping in Relapsed/Refractory DLBCL

Background: Relapsed/refractory (R/R) DLBCL constitutes 40% of all DLBCL cases. Coventional salvage regimens, such as R-ICE, R-GDP, and R-DHAP, have an overall response rate (ORR) of 60% and a complete response rate (CR) of 30-40%. For patients who have achieved complete metabolic remission as determined by PET-CT evaluation after salvage therapy, undergoing autologous transplantation is crucial in order to achieve durable long-term survival. The outcomes of these R/R DLBCL remain to be improved. Aims: This prospective study aims to investigate whether adding novel agents to R-ICE (R-ICE-X) based on genetic subtypes could improve clinical efficacy in R/R DLBCL. This trial is registered at clinicaltrials.gov (NCT05348213). Method:In this study, patients with R/R DLBCL aged 18 -75 years were enrolled. All patients were assigned and stratified by genetic subtype and received different targeted agents combined with R-ICE. The efficacy was evaluated after 3 courses of R-ICE-X (every 21 days). Patients with CR/PR were subsequently treated with autologous hematopoietic stem cell transplantation or 3 courses of R-ICE-X consolidation and lenalidomide maintenance for up to 12 months. See the detail in the figure. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were the 2-year progression-free survival (PFS) rate, 2-year overall survival (OS) rate, and safety evaluation. Results: At the time of data cut-off, a total of 66 patients were enrolled, with a median age of 61(20-75) years. In the patients with R-ICE-zanubrutinib group (n=28), the ORR was 84.0%, with 15 patients (15/25, 60.0%) achieved CR and 6 patients (6/25, 24.0%) achieved PR. The 1-year PFS rate and OS rate were 68.2% and 90.5%, respectively. In the patients with lenalidomide combined with R-ICE (n=28), 16 patients (16/26, 61.5%) achieved CR, 4 patients (4/26, 15.4%) achieved PR, and the ORR was 76.9%. The 1-year PFS and OS rates were 78.5% and 100.0%, respectively. In the patients with the R-ICE-decitabine group (n=7), the ORR was 66.7%, with 4 patients (4/6, 66.7%) achieving CR. The 1-year PFS rate and OS rate were 50.0% and 60.0%, respectively. The number of other groups needs to be further updated. Among 66 patients, 17 patients had autologous transplantation (ASCT) and 1-year PFS and OS of patients with ASCT were both 87.1%. The number of other groups will be further updated. Conclusion: Novel targeted agents in combination with R-ICE (R-ICE-X) regimen was well tolerated and efficacy in R/R DLBCL patients, meanwhile, it could be a promising bridging regimen for ASCT. The study is ongoing and further results will be continuously released.

Impact of Front-Line Treatment Interim PET/CT in Peripheral T-Cell Lymphoma Patients' Survival: Experience of a Single Center

Introduction: The introduction of PET/CT in the staging and response assessment to therapy has changed the clinical evaluation of most lymphomas, especially Hodgkin lymphoma and aggressive B-cell lymphomas. The use of PET/CT in the staging of peripheral T-cell lymphomas (PTCL) is already a standard of care in many centers, although its decisional role in course of chemotherapy or at the end of treatment remains unclear. Objective: The aim of this study is to evaluate the predictive role of interim PET/CT in newly diagnosed PTCL patients. Methods: We retrospectively analyzed the clinical data of adult patients diagnosed with PTCL and actively treated between 2014 and 2023 at our center. All patients were evaluated with PET/CT at different timepoints (baseline, interim and end of treatment). Results: We evaluated 49 patients, with a median age at diagnosis of 59 years (range: 18-83), and a slight predominance of females (54%) (table 1). Almost half of the patients were diagnosed of angioimmunoblastic/T-follicular helper lymphoma (AITL/TFHL) 23(47%), followed by anaplastic large cell lymphoma (ALCL) in 17 cases [9 ALK+ (18%) and 8 ALK- (17%))] and peripheral T-cell lymphoma NOS (PTCL-NOS) in 9 (18%). Seven (14%) patients had ECOG ≥ 2, 47 (90%) had stage III-IV disease, among them, 42 (84%) with extranodal involvement. Bone marrow was involved in 14 out of 36 (39%) evaluated patients. Twenty-seven (54%) patients had IPI score 3-5. Front-line treatment consisted in CHOP in 32 (65%) patients and brentuximab vedotin+CHP in 17 (35%). Interim evaluation was performed after 3 cycles in 32 (65%) and after 4 cycles in 16 (33%) patients. Only one patient was evaluated after 2 cycles due to suspected disease progression. At this time point, 31 (63%) patients were considered in complete metabolic response (CMR) with a Deauville Score (DS) 1-3, 12 (25%) in partial metabolic response (PMR) with a DS 4 and 6 (12%) patients with progressive disease (PD) with DS5. Among the latter's, 4 patients were treated with 2 nd line treatment, while 2 completed the planed 6 cycles due to significant tumor burden . Among 48 patients evaluated after 3 and 4 cycles of therapy, CMR was achieved in 18 (56%) and 13 (81%), respectively (p=0,088). Eleven (34%) and one (6%) pts were in PMR at iPET after 3 and 4 cycles, respectively. Forty-five (92%) patients completed front-line therapy and were evaluated with EOT PET/. CMR (DS1-3) was reported in 32 (71%) patients, PMR in 8 (18%) and PD in 5 (%). Among patients with CMR at iPET, 25 (81%) maintained CMR, 5 (16%) converted to PMR and only 1 (3%) progressed. Among patients with PMR at iPET, 5 (42%) converted to CMR, 4 (33%) maintained PMR and 3 (25%) progressed. Eighteen (37%) patients were consolidated with autologous stem cell transplantation, all in CMR at EOT, except for 1 patient with PMR DS4. With a median follow-up of 28 months (range: 2-107 months), 25 (51%) patients relapsed or progressed. Median progression-free survival (PFS) of the entire population was 24 months. According to interim response, median PFS of DS1-3, DS4 and DS5 were 28, 10 and 2 months, respectively (Figure 1). In univariate analysis, along traditional prognostic factors as advance stage (p=0.0324), increased LDH (0.0211), IPI ≥ 3 (0.0198) and bone marrow infiltration (0.0475), interim PET/CT (iPET) impacted on PFS (DS1-3 vs DS4 vs DS5, p=0.004; DS1-3 vs DS4-5, p=0.0233). When considering the exact timing, iPET after 4 cycles seemed to relate better with PFS (DS1-3 vs DS4 vs DS5, p=0.0009) than after 3 cycles (DS1-3 vs DS4 vs DS5, p=0.32). In the multivariate analysis, iPET/CT response maintained its prognostic significance (for DS1-3 vs DS4 vs DS5: HR 2.37, 95% CI 1,44-3,89, p=0,). Median OS was not reached. The estimated 2-year OS for the entire population was 75% (95% CI, 58-86). According to iPET, the estimated 2-year OS for DS1-3, DS4 and DS5 were 85% (60-95), 64% (30-85) and 63% (14-90), respectively. No impact of iPET was documented on . Conclusion: Our study highlights the potential role of interim PET/CT in the management of PTCL. Reaching an early metabolic complete remission seems to be associated with longer PFS. Patients with a DS4 at interim evaluation remain challenging for clinicians, since also in our study half of them converted to CMR at the end of . Further radiomics analysis may help to better identify patients at higher risk of progression and offer a more tailored treatment.

Survival Patterns of Non-Randomized Patients in the IELSG37 Study: Deauville Score 4 Is Not Necessarily Associated with Poor Outcome in Primary Mediastinal Lymphoma

Background:Primary mediastinal B-cell lymphoma (PMBCL) is clinically and biologically distinct from other types of aggressive lymphoma, it is characterized by a bulky mediastinal mass and most commonly occurs in women between 30 and 40 years of age. Although consolidation radiotherapy (RT) has yielded extremely positive outcomes in PMBCL, it carries a higher risk of long-term complications. Consequently, there has been an ongoing debate regarding the necessity of RT in patients responding to frontline immunochemotherapy. Methods:In the IELSG37 study, PMBCL 530 patients were treated with rituximab- and doxorubicin-containing regimens; 98% had stage I-II. Their response was assessed by positron emission computed tomography (PET/CT); 268 achieved a complete metabolic remission (CMR) defined as Deauville score (DS) 1 to 3 according to the Lugano classification and were randomly allocated to observation or mediastinal RT. The primary analysis [Zucca et al. J Clin Oncol 2023; 41 (suppl 17): abs. LBA7505] has shown that patients in CMR can safely forgo RT. The 3-year overall survival (OS) rate was 99% irrespective of irradiation. RT provided only minimal benefit on progression-free survival (PFS), which was over 96% at 3 years in both arms. Here we present the outcome of the 262 patients who were not randomized and were managed according to the preference of their treating physician. Results:Median follow-up was 64 months (interquartile range [IQR], 49-69). Besides 230 patients failing frontline treatment (174 DS4 and 56 DS5), the non-randomized cohort also included 1 patient with DS2 (who refused randomization and received RT) and 31 patients with DS3 who were initially considered as partial responders before a protocol amendment that changed the definition of CMR from DS 1-2 to DS 1-3. Among these non-randomized patients with DS3, 27 had RT consolidation, 1 was only observed, 2 had salvage chemotherapy ± RT, and 1 had missing data due to consent withdrawal; their 3-year PFS was very close to the one of the randomized patients with DS3 (90 vs 92%, p=0.99). In the DS4 group, 12 patients were observed, 149 had only RT, and 13 had second-line chemotherapy, with (12) or without (1) autologous stem cell rescue, 8 of 13 also had RT. Among the patients with DS5, only 2 were observed, 32 had only RT, and 22 had second-line chemotherapy, with (15) or without (7) autologous stem cell rescue; 12 of them also had RT. The outcome of patients with DS4 was overlapping the one of the patients achieving a CMR, with 3-year PFS of 97.1% (95%CI 93-99) and 97.4% (95%CI 95-99), respectively, while patients with DS5 had a significantly poorer 3-year PFS (62.4%, 95%CI 48-74) [Figure1A]. The 3-year OS showed a similar trend (98% in patients with DS4, 99% in those randomized, and 78% in the DS5 group). Notably, compared to patients receiving consolidation RT alone or only observed, the residual lesions on post-immunochemotherapy PET/CT scans of patients with DS4 and DS5 who were treated more aggressively (with salvage chemotherapy ± autologous transplant and/or RT) displayed significantly higher tracer maximum standardized uptake value (SUVmax, median: 8.2, IQR 4.6-16.5 vs. 3.8, IQR 3.1-4.9; p<0.0001) and larger residual metabolic tumor volume (MTV, median: 18 ml, IQR 3-95 vs. 3.6, ml, IQR 1-10; p<0.0001). These patients had significantly worse outcomes compared to those who received consolidation RT or were observed only [Figure 1B]. Conclusions:Patients with DS4 had outcomes similar to those of patients achieving a CMR, indicating that this group may either include a significant number of “false-positive” cases with inflammatory uptake or that their residual disease is limited and can potentially be cured with consolidation RT. Patients with DS5 had a significantly poorer outcome, although nearly half of them did well with RT alone. It seems plausible that clinical condition of the patient and/or imaging features of the residual disease have influenced treatment choices in patients without CMR after frontline immunochemotherapy. Further studies are needed to investigate whether PET metrics and/or liquid biopsies can aid in personalizing treatment and identifying patients who could potentially avoid irradiation.

High Progression Free Survival Rates in Patients with Multiply Relapsed/Refractory Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant after Checkpoint Inhibitors: Results from Grupo Argentino De Trasplante De Medula Osea y Terapia Celular (GATMO-TC)

CONCLUSIONS Consolidation with autologous stem cell transplant (ASCT) in Hodgkin lymphoma (HL) was traditionally reserved for patients with chemosensitive disease. In 2021 a retrospective study showed encouraging results with ASCT consolidation after checkpoint inhibitors (CPI) in pts with relapsed/refractory (R/R) HL. Subsequently, several prospective studies with CPI +/- chemotherapy in 2nd line were published showing 1-year progression free survival (1-y PFS) rates of 90% but with increased incidence of engrafment syndrome. We aimed to evaluate survival outcomes of consolidation with ASCT after CPI in our cohort of patients with R/R HL and the incidence of engrafment syndrome. Patients with R/R HL who received consolidation with ASCT between 01/2016 and 5/2023 after treatment with CPI were included in this retrospective multicentric study. Descriptive statistics were used to summarize variables of interest. Progression free (PFS) and overall survival (OS) were estimated with Kaplan-Meier and variables were compared with log-rank test. Forty-one patients from 15 transplant centers in Argentina were analyzed. The median age at ASCT was 31 years (19-60). High risk features were present in three quarters of patients, 23 (56%) with primary refractory disease and 8 (19.5%) with early relapse. Eighteen patients (43.9%) had ≥3 of the 5 pre-ASCT modified AETHERA high-risk factors. Patients received a median of 4 (2-6) systemic therapies before ASCT, including 27 patients previously treated with Brentuximab Vedotin (BV) to which 26 were refractory. Thirty-six patients (87.8%) received CPI monotherapy and 5 (12.2%) in combination with chemotherapy. Thirty-six (87.8%) underwent ASCT after CPI and 5 received additional treatment before transplant due to lack of response or progression. Patients received a median of 7 cycles (2-34) of CPI before ASCT. Complete metabolic (CMR) and partial remission (PMR) pre ASCT was documented in 31 (75.6%) and 10 (24.4%) patients, respectively). The median time from last dose of a CPI to ASCT was 60 days (3-183). The most utilized conditioning regimens were BEAM (22%), BEC (22%), BeEAM (7.2%) and CBV (48.8%). Median time to neutrophil engrafment was 11 days (8-15). Engrafment syndrome was observed in 14 (34.1%) with 10 patients requiring treatment with corticosteroids. Seven patients (17.1%) received post ASCT consolidation with either CPI or BV. After a median post ASCT follow up of 12.3 months, only 2 patients relapsed and 3 patients died (one of progressive disease, one of transplant related mortality and the other of a late infectious complication). Estimated 1-y PFS was 92.6% for the whole cohort, 93.5% and 90% for patients undergoing ASCT in CMR and in PMR, respectively, p: 0.92 (Figure 1). Patients requiring additional treatment after CPI had an estimated 1-y PFS of 80% vs. 94.4% in those undergoing ASCT straight after CPI, p: 0.38. ASCT consolidation after CPI in this cohort of patients with high risk R/R HL was associated with very promising results even in those proceeding to ASCT in PMR. A third of the patients developed engrafment syndrome so it is important to be alert to the appearance of symptoms and evaluate early use of corticosteroids. Our findings are similar to the results of other studies and support ASCT consolidation in high-risk R/R HL patients receiving CPI.

Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms

AbstractLangerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by the accumulation of clonal mononuclear phagocyte system cells expressing CD1a and CD207. In the past decade, molecular profiling of LCH as well as other histiocytic neoplasms demonstrated that these diseases are driven by MAPK activating alterations, with somatic BRAFV600E mutations in >50% of patients with LCH, and clinical inhibition of MAPK signaling has demonstrated remarkable clinical efficacy. At the same time, activating alterations in kinase-encoding genes, such as PIK3CA, ALK, RET, and CSF1R, which can activate mitogenic pathways independent from the MAPK pathway, have been reported in a subset of histiocytic neoplasms with anecdotal evidence of successful targeted treatment of histiocytoses harboring driver alterations in RET, ALK, and CSF1R. However, evidence supporting the biological consequences of expression of PIK3CA mutations in hematopoietic cells has been lacking, and whether targeted inhibition of PI3K is clinically efficacious in histiocytic neoplasms is unknown. Here, we provide evidence that activating mutations in PIK3CA can drive histiocytic neoplasms in vivo using a conditional knockin mouse expressing mutant PIK3CAH1047R in monocyte/dendritic cell progenitors. In parallel, we demonstrate successful treatment of PIK3CA-mutated, multisystemic LCH using alpelisib, an inhibitor of the alpha catalytic subunit of PI3K. Alpelisib demonstrated a tolerable safety profile at a dose of 750 mg per week and clinical and metabolic complete remission in a patient with PIK3CA-mutated LCH. These data demonstrate PIK3CA as a targetable noncanonical driver of LCH and underscore the importance of mutational analysis–based personalized treatment in histiocytic neoplasms.

HIGH RATE OF METABOLIC COMPLETE RESPONSE AFTER LOW DOSE RADIOTHERAPY AND OBINUTUZUMAB IN EARLY STAGE FOLLICULAR LYMPHOMA: INITIAL RESULTS OF THE GAZAI STUDY (GLA 2018‐3)

Introduction: The FORT trial demonstrated a higher complete remission (CR) rate using 12 × 2 Gy compared to 2 × 2 Gy in Follicular Lymphoma (FL) (67% vs. 47%). This benefit resulted also in an improved progression free survival (PFS). The TROG 99.03 trial and the MIR study showed an improved PFS with the addition of Rituximab to radiation therapy of 30–40 Gy in early stage FL. Preclinical data suggest that the anti-CD20 antibody may act synergistic with radiation therapy and therefore enhance the radiation effect of low dose radiotherapy. The prospective, multicentric phase II GAZAI study of the German Lymphoma Alliance (GLA) investigated the efficacy of low dose radiation therapy (2 × 2 Gy) in combination with the anti-CD20 antibody Obinutuzumab in early stage nodal FL. The primary endpoint was the metabolic complete remission at the end of therapy. Methods: Patients with early stage FL grade 1/2 were recruited in 11 German centers. Ann Arbor stage I or II was confirmed by FDG-PET/CT. Patients received 1000 mg Obinutuzumab flat dose intravenously in weeks 1, 2, 3, 4, 8, 12 and 16. An interim CT scan was performed in week 7 for response evaluation and subsequent treatment planning. Radiation therapy was applied to the initial involved sites (site of diagnostic surgical intervention and PET positive sites) in week 9. The radiation dose was 2 x 2 Gy on two succeeding days. A FDG-PET/CT was performed at the end of therapy in week 18 for evaluation of the metabolic and morphologic response. Minimal detectable/residual disease (MRD) in peripheral blood was monitored at baseline and at week 18 by allel-specific RQ PCR targeting t(14;18) translocations and clonal immunoglobulin heavy chain (IGH) rearrangements. Results: Of 89 patients included in the study, 54 entered the treatment phase showing FDG-PET-positive lymph nodes qualifying for the primary endpoint. At week 18, metabolic CR (Deauville score (DS) <3) was seen in 46/53 patients (87%; one patient only had a CT without FDG-PET). Partial metabolic remission with a DS 3 was seen in 3 patients (6%) and 3 patients showed a DS 4. Morphologic (CT based) CR/CRu according to Cheson 1999 criteria was seen in 21/54 patients (39%) at week 7 and in 49/54 patients (91%) at week 18. Morphologic PR was seen in 17 patients (32%) at week 7 and in 4 patients (7%) at week 18; one patient (2%) showed progressive disease (metabolic and morphologic) outside of the radiation field. 13/54 patients (24%) were initially MRD positive. All but one patient converted to MRD negativity at week 18. Conclusions: Low dose radiation therapy using 2 × 2 Gy in combination with Obinutuzumab is highly effective in early stage FL. Longer follow-up is necessary to investigate if this effectivity also results in a prolonged PFS. Currently, the FORTplus trial is looking for non-inferiority of this regimen in comparison to a conventional radiation dose (12 × 2 Gy) combined with Rituximab. The research was funded by: Roche Pharma Keywords: combination therapies, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract K. Herfarth Research funding: Roche Pharma Educational grants: Roche Pharma C. W. Scholz Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma K. Hübel Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speaker Honoraria Roche Pharma Research funding: Roche Pharma C. Buske Consultant or advisory role: Roche Pharma Honoraria: Roche Pharma Research funding: Roche Pharma J. Dürig Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma G. Lenz Consultant or advisory role: Advisory board Roche Pharma Honoraria: Speakers honoraria Roche Pharma Research funding: Roche Pharma C. Pott Research funding: Roche Pharma M. Dreyling Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Research funding: Roche Pharma

SINGLE AGENT BRENTUXIMAB VEDOTIN AS BRIDGE TO ALLOGENEIC STEM CELL TRANSPLANT IN ADOLESCENTS WITH RELAPSED ANAPLASTIC LARGE CELL LYMPHOMA (ALCL): THE UCLH EXPERIENCE

Introduction: Optimal treatment for relapsed ALCL in children and adolescents is still subject of debate. We present here the results of our salvage strategy in the TYA Unit at UCLH, using single agent brentuximab vedotin (BV) as bridge to allogeneic stem cell transplant (alloHSCT). Methods: Between 2011 and 2021 we treated 7 patients with relapsed ALCL; all patients had received first line treatment according to ALCL99 guidelines. All relapses were biopsy proven and centrally reviewed if not performed at UCLH. Brentuximab Vedotin was given at the standard dose of 1.8mg/kg intravenously every 3 weeks. Results: All 7 patients were male; median age at diagnosis was 16 (range 13–19). Baseline characteristics were as follows: 7/7 were CD30+, 3/7 were CD3+, 6/7 biopsies were ALK positive, and 3/7 presented with a small cell/lymphohistiocitic (SC/LH) pattern. Six/7 patients had stage IV disease, 4/7 had skin involvement, bone marrow involvement was seen in 3/7 cases (infiltrate between 2 and 10%); 1/7 patients had bulky disease. Of the 7 patients, 3 had primary progressive disease, while 4/7 patients initially achieved a complete metabolic response (CMR), but had a very early relapse, between 2 and 3 months after completion of treatment. 6/7 patients received BV as first line of salvage treatment, 1 as second salvage, after failing ICM (ifosfamide, carboplatin, mitoxantrone), which was still our standard of care in 2011. Median number of doses of BV received was 3 (range 2–5); 6/7 (86%) patients obtained a complete metabolic remission, after a median of 3 doses (range 3–5). One patient progressed on BV; after failing crizotinib he achieved CMR with vinblastine-dexamethasone, then proceeded to transplant and is in long term remission. All 6 patients who achieved a complete remission after BV proceeded to alloHSCT, 1/6 from fully matched sibling donor, 3/6 from haploidentical donors, 2/6 from matched unrelated donors. Conditioning regimen was myeloablative for 5/6 patients, using Cyclophosphamide/total body irradiation +/- Campath depending on donor source; one patient received intermediate intensity conditioning with BEAM (BCNU, etoposide, cytarabine, melphalan)-Campath. With a median follow up of 55 months (range 4–133), all 6 patients are alive and 5/6 (83%) remain in remission with no need for further treatment; 1/6 patients relapsed 8 months post-transplant. This patient was re-challenged with BV, with the addition of donor lymphocytes infusions (DLI) and achieved a complete remission. Conclusions: Salvage treatment with single agent BV followed by alloHSCT is effective in adolescents with relapsed ALCL and lead to durable responses in a cohort of patients with high prevalence of high-risk features (advanced stage, SC/LH pattern, CD3+, early relapse after first line treatment). Interestingly, in one patient who relapsed after alloHSCT, BV and DLI were successful in inducing another complete remission. Keywords: Molecular Targeted Therapies, Non-Hodgkin (Pediatric, Adolescent, and Young Adult), Stem Cell Transplant No conflicts of interests pertinent to the abstract.

A non-randomized risk-adjusted comparison of lenalidomide + R-CHOP versus R-CHOP for MYC-rearranged DLBCL patients

Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.

First-Line Therapy for Nodal T-cell Non-Hodgkin Lymphomas: an Unmet Need in Hematology.

The main aim of this review is to summarize first-line therapy of nodal T-cell non-Hodgkin lymphoma. Current treatment with CHOP chemotherapy results in poor outcomes in the majority of patients. However, there are advances within the field. First breakthrough is the ECHELON-2 trial which showed that the addition of brentuximab vedotin improves outcomes in anaplastic large cell lymphoma. However, other types of peripheral T-cell non-Hodgkin lymphoma were underrepresented with optimal treatment not known. Second breakthrough is an increase of autologous stem cell transplantation usage in the first complete metabolic remission, except in ALK + anaplastic large cell lymphoma, offering better disease control. Despite advances in the field, CHOP remains the standard treatment for the majority of these lymphomas, but multiple trials are underway with the aim to improve this unmet need in hematology and, hopefully, leading us to a new era in the treatment of peripheral T-cell lymphomas.

Sexual dysfunction is highly prevalent in male survivors of malignant lymphoma.

With improved survival in patients with lymphoma, long-term toxicity and quality of life (QoL), including sexual health, have become increasingly important. We aimed to (1) determine the prevalence of erectile dysfunction (ED) in adult male lymphoma survivors; (2) determine whether testosterone deficiency, comorbidities, or lifestyle factors were associated; and (3) evaluate their impact on QoL. A cross-sectional study including 172 male survivors of Hodgkin lymphoma or diffuse large B cell lymphoma diagnosed in adulthood between 2008 and 2018 was performed. Patients were in complete metabolic remission after first-line treatment and remained in remission at follow-up (3-13years after diagnosis). Participants completed 3 questionnaires measuring sexual health and general QoL. Serum concentrations of total testosterone were measured and thorough medical history and sociodemographic factors were obtained. The Danish SEXUS Project, European Male Ageing Study, and European Organization of Research and Treatment of Cancer (EORTC) Reference Manual were used as reference values of the general population. Patient reported outcome measures including the 5-item International Index of Erectile Function, EORTC C30, and EORTC 22-item Sexual Health Questionnaire. ED was reported by 55.2%, which was higher than in an age-matched Danish population cohort (17.5%). Erectile function score (5-item International Index of Erectile Function) was negatively associated with comorbidity, body mass index, smoking, and age and positively with the number of children conceived before treatment and serum concentration of total testosterone. Overt testosterone deficiency in combination with ED was detected in 10 (5.7%) of 176 survivors, including excluded survivors in hormonal treatment, which is higher than for the general population (0.1%-3.2% for men <70years of age). Mean EORTC C30 global health score for survivors with ED was lower (67.7) than for survivors without ED (80.1) but was comparable to the general population (71.2). Furthermore, a positive association was seen between sexual function and both sexual and general QoL. Sexual health is important for QoL and related to comorbidities. The focus on improving QoL requires that both sexual health and comorbidities are addressed in the follow-up of lymphoma patients. Despite the relatively high number of included survivors, the cross-sectional design of this study warrants longitudinal studies to clarify the specific underlying causes of sexual dysfunction. ED was highly prevalent and associated with comorbidity in lymphoma survivors, and more focus on sexual health and treatment related comorbidity is needed to improve sexual and general QoL.

Surgical Management and Denosumab for Aneurysmal Bone Cysts of the Spine in an Australian Tertiary Paediatric Centre.

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70mg/m2 was given 4-weekly for at least 6months, followed by 2 doses of zoledronate 0.025mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.

Role of Post-Treatment 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients Receiving Definitive Chemoradiation for Locally Advanced Head and Neck Squamous Cell Carcinomas

Background and Objectives &lt;sup&gt;18&lt;/sup&gt;F-fluorodeoxyglucose PET/CT scans can be a useful method to detect recurrence. However, its role in locally advanced head and neck squamous cell carcinomas (HNSCCs) patients after definitive chemoradiotherapy (CRT) has not yet been determined. The current study was performed to identify the role of therapeutic response evaluation using PET/CT after definitive CRT.Subjects and Method We conducted a retrospective review of patients with locally advanced HNSCCs, and who have undergone definitive CRT from 2009 to 2017 at a single institution. The patients were divided into two groups according to their responses to the treatment (metabolic complete remission [mCR] group or non-mCR group), assessed by PET/CT scans after definitive CRT.Results Twenty-eight patients were consecutively enrolled. The most common primary site of cancer was the oropharynx, followed by the oral cavity, hypopharynx, and nasal cavity. The therapeutic response assessed by PET/CT scans was mCR in 14 patients. The median progression- free survival (PFS) was not reached in the mCR group but was 13.3 months for the non-mCR group (&lt;i&gt;p&lt;/i&gt;=0.001). The median overall survival was significantly longer for the mCR group (52.5 months) than for the non-mCR group (15.2 months, &lt;i&gt;p&lt;/i&gt;=0.002). A multivariate analysis showed PET/CT response and high-sensitivity C-reactive protein (hsCRP) as independent prognostic factors for PFS (mCR: &lt;i&gt;p&lt;/i&gt;=0.027; hsCRP: &lt;i&gt;p&lt;/i&gt;=0.042) and for the overall survival (mCR: &lt;i&gt;p&lt;/i&gt;=0.006; hsCRP: &lt;i&gt;p&lt;/i&gt;=0.020).Conclusion PET/CT scans after definitive CRT predicted the prognosis in patients with locally advanced HNSCCs. CRP was a prognostic factor affecting the outcomes of treatments.

A Multicenter, Single-Arm, Prospective Phase II Study of Orelabrutinib Combined with High-Dose Methotrexate and Rituximab Sequential Autologous Hematopoietic Stem Cell Transplantation in Newly-Dignosed Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is primarily large B-cell lymphoma (accounting for nearly 95% of central lymphomas). Current treatments, including surgery, chemotherapy, and whole-brain radiotherapy, often fail to achieve satisfactory results, especially in the elderly. High-dose methotrexate (MTX) based treatment is the current standard treatment, but the long-term survival rate of young patients is still less than 50% even after autologous transplantation. Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been tested in multiple clinical trials for PCNSL, as a single drug achieved an objective response rate (ORR) of 50-70% and a CRR of 20%-40% in relapsed and refractory PCNSL, while combination therapy can achieve an ORR of 80% and a CRR of 50%. However, ibrutinib efficacy is less than half a year and has poor selectivity. Owing to its off-target inhibition effect, the incidence of serious adverse reactions such as bleeding and atrial fibrillation in patients increases, leading to dose reduction or drug withdrawal, which makes patients unable to continue treatment. Orelabrutinib is a new-generation BTK inhibitor, that has been rationally optimized in molecular structure, which makes its binding with BTK more durable, more stable, more specific, less off-target effect, and higher BBB pass rate and better safety. In addition, a retrospective article published recently showed that obrutinib monotherapy was more effective and well-tolerated in patients with r/r PCNSL. Herein, we combined rituximab, MTX, and ibrutinib for induction therapy, finally through autologous hematopoietic stem cells consolidation therapy or lenalidomide or obrutinib maintenance treatment, to evaluate toxicity and to improve efficacy. This study is registered with Chictr.org.cn, number ChiCTR2200061485. Methods: The study is a multicenter, single-arm, prospective phase II study, conducted at Shengli Oilfield Central Hospital and Shandong Cancer Hospital. Patients diagnosed with Newly Diagnosed PCNSL by biopsy of brain lesion, systemic immunology, bone marrow, and a CSF examination, et al, and be suitable for the immunochemotherapy, were enrolled in the clinical trial. The Orelabrutinib -based ROM regimen consists of rituximab 375mg / m 2 on day 0. MTX 3.5g/m 2 on day1, and Orelabrutinib 150mg once daily on day1 to day 28. Every 28 days is a cycle of treatment. After 4-cycles of ROM induction therapy, patients who achieved CR/CRu/PR received autologous peripheral blood hematopoietic stem cell transplantation (HSCT) or the extra 2 cycles of ROM regimen as consolidation therapy. Orelabrutinib or lenalidomide monotherapy was prescribed as maintenance therapy, according to the willingness of patients until the disease progresses. The primary endpoint was the safety and efficacy of this regimen in newly diagnosed with PCNSL. Results: There were a real of 10 patients enrolled in this clinical trial, between July 2021 and May 2022. All the patients were pathologically DLBCL, including 7 non-GCB subtypes and 3 GCB subtypes. The median follow-up time was 6.5 (1-12) months up to June 30, 2022. After 4 cycles of ROM induction therapy, complete metabolic remission (CMR) was achieved in 5 patients (50%), partial response (PR) in 5 patients (50%), and the overall response rate (ORR) of induction therapy was 100% (Figure 1). Among responders, 3 (33%) received HSCT, 1 (10%) received RT and 5 (50%) received extra 2 cycles of ROM regimen as consolidation therapy. After the consolidation therapy, 90% of patients (9/10) received maintenance therapy, including 5 who received lenalidomide and 4 who received ibrutinib. The median progression-free survival (PFS) and overall survival (OS) were not achieved. The safety of Orelabrutinib -based regimens have also been evaluated. No grade 4 adverse events were observed. Grade 3 hematologic toxicity included lymphopenia in 1 case and neutropenia in 3 cases. Conclusions: Our data preliminaries indicate that ROM is efficacious and well-tolerated as a first-line regimen in newly diagnosed PCNSL and might effectively improve the survival of these patients. These combined therapies offer a potential new therapeutic strategy. More patients and longer follow-ups are necessary to confirm our conclusion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Propensity Score-Adjusted Comparison of Lenalidomide + R-CHOP Versus R-CHOP for MYC-Rearranged DLBCL Patients

Introduction Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) generally have a poor prognosis following standard treatment with R-CHOP. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission (CMR) rates and survival as more intensive chemotherapy regimens such as DA-EPOCH-R [Chamuleau, Haematologica 2020]. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed DLBCL patients treated with R-CHOP in the Netherlands, including MYC-R patients who were not included in the interventional trial due to logistic reasons. These two cohorts enable to evaluate the added value of lenalidomide to R-CHOP in first-line treatment of newly diagnosed MYC-R DLBCL patients. Methods In the single-arm, phase-II HOVON-130 trial, MYC-R DLBCL patients ≥ 18 years were treated with R-CHOP21 plus lenalidomide 15 mg day 1-15 for 6 cycles [Chamuleau, Haematologica 2020]. Additional inclusion criteria were Ann-Arbor stage II-IV, WHO performance status 0-3, ≥ one lesion of ≥ 1.5 cm on contrast-enhanced CT scan and ≥ one FDG-positive lesion on PET-CT scan. In the observational screening study HOVON-900, MYC, BCL2 and BCL6 fluorescent in situ hybridization (FISH) diagnostics were advocated as part of routine procedures and reviewed by the HOVON Pathology Facility. As a control group, we selected MYC-R patients from this observational cohort who met the inclusion criteria for the interventional trial but were not included, and who were treated with standard R-CHOP. Clinical information at presentation and treatment and outcome data were retrieved from the Netherlands Cancer Registry. We explored three statistical methods that account for baseline imbalances. First, we used multivariable regression, with baseline variables as covariates in the model. Second, we performed one-to-one matching on the IPI risk (low, intermediate, or high). Third, we performed inverse probability of treatment weighting (IPTW) using a propensity score. We calculated a propensity score for being included in the HOVON-130 trial based on the separate components of the IPI score (i.e., age, Ann Arbor stage, WHO performance score, extra-nodal localizations, serum LDH level), sex and rearrangement status. To allow for some degree of misspecification of the model for the propensity score, we used a doubly-robust estimator. Subgroup analyses were performed in single hit (SH: only MYC rearrangement), versus double hit and triple hit (DH/TH: MYC rearrangement with BCL2 and/or BCL6 rearrangement). Results Patients from the interventional trial treated with R2CHOP (n=77) were younger than patients in the control cohort (n=56) treated with R-CHOP (median age 63 versus 70 years, p=0.018) and they were more likely to have a lower WHO performance score (p=0.013). Ann Arbor stage, LDH level, number of extranodal localizations and median days before treatment (15 and 19 in the R-CHOP and R2CHOP group, respectively) did not significantly differ between the groups. Complete remission rates were 69.8% and 80.5% in the R-CHOP and R2CHOP group, respectively (p=0.209). Multivariable analysis, 1:1 matching and weighting using the propensity score consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.53, and 0.59 (Figure 1A), respectively, for OS, and 0.59, 0.53, and 0.60 for PFS (Figure 1B). In the subgroups determined by rearrangement status, we performed unadjusted OS and PFS analysis only, because we were not able to adjust for baseline imbalances because of the low number of events within the subgroups. Both SH patients and DH/TH patients tended to have a longer OS when treated with R2CHOP with HRs of 0.34 and 0.57, respectively. Similarly, for PFS the HRs were 0.66 in the SH subgroup and 0.48 in the DH/TH subgroup. Conclusion In conclusion, this propensity score-adjusted comparison study supports the addition of lenalidomide to R-CHOP as a valuable treatment option for MYC-R DLBCL patients. R2CHOP can be administered on a full outpatient basis, with minimal hospitalization visits. Future studies will explore whether adding next-generation cereblon targeting antigens to R-CHOP can improve the observed effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal