Long-term Progression-free Survival Research Articles

Immunological markers for predicting the response to immunotherapy in non-small cell lung cancer

Itroduction. Immune checkpoint inhibitors have become the standard of care for patients with advanced non-small cell lung cancer. However, despite the determination of programmed death-ligand 1 expression in clinical practice, which determines the effectiveness of therapy, up to 80 % of patients with non-small cell lung cancer do not respond to treatment.The study objective – investigation of the prognostic role of clinical and immunological markers during immune checkpoint inhibitor monotherapy in ≥2 lines in patients with advanced non-small cell lung cancer.Materials and methods. The study included 45 patients with advanced non-small cell lung cancer receiving programmed cell death 1 / programmed death-ligand 1 inhibitors in monotherapy in 2 and subsequent lines (Group 1), as well as 30 patients with advanced non-small cell lung cancer receiving first-line chemotherapy (Group 2). All patients from 2 groups did not have autoimmune diseases before starting treatment. The determination of autoantibodies, β-2-microglobulin, neopterin, interleukin 6, interleukin 18 and the allelic variant of HLA-DRB1 in patients in the Group 1 was carried out 2 months after the start of therapy, and in the Group 2 – before the start of the next chemotherapy cycle.Results. In Group 1, the presence of EGFR / ALK mutations is an independent predictor of shorter progression-free survival (p = 0.018). Also, in the univariate analysis, neutrophil-lymphocyte ratio <5 before immune checkpoint inhibitors (p = 0.009) and the appearance of immune-related adverse events (p = 0.038) are associated with long-term progressionfree survival. In Group 1, β-2-microglobulin was lower in patients with a response duration of ≥6 months than with a progression <6 months: 1.7 mg / L and 2.9 mg / L, respectively (p <0.0001). Patients receiving immune checkpoint inhibitors with a β-2-microglobulin level ≥2.5 mg / L have a shorter progression-free survival than patients with a marker value <2.5 mg / L: 168 days and the value is not reached, respectively (p = 0.017). In response duration ≥6 months neopterin value was lower than in disease progression: 8.6 nmol / l and 13.4 nmol / L, respectively (p <0,0001). Progression-free survival was lower in patients with neopterin ≥12 nmol / L than patients with neopterin <12 nmol / L: median was 164 days and the value was not reached, respectively (p = 0.0007). Based on the results of multivariate analysis, β-2-microglobulin ≥2.5 mg / L (p = 0.006) and neopterin ≥12 nmol / L (p = 0.027) were independent predictors of shorter progression-free survival. Low levels of interleukin 6 and interleukin 18, as well as antibodies to thyroperoxidase, are associated with a response of ≥6 months. HLA-DRB1*03 was associated with a duration of response of ≥6 months, as well as a longer progression-free survival compared with other allelic variants. The levels of β-2-microglobulin, neopterin, interleukin 6, interleukin 18 were higher in patients in Group 1 than in patients in Group 2 (p <0.0001).Conclusion. Immunological markers can serve as promising prognosis markers in patients with advanced non-small cell lung cancer during immunotherapy.

Autologous hematopoietic stem cell transplantation in children with relapsed or refractory Hodgkin lymphoma

The majority of patients with Hodgkin lymphoma (HL) are cured, which represents one of the best cure rates in oncology. However, the prognosis is not as favorable in case of relapsed or refractory (RR) disease. Autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective way to consolidate remission in patients with RR HL. Despite the many years of experience and the availability of results of randomized trials confirming the efficacy of high-dose chemotherapy in adults, the role of auto-HSCT in children with HL has not been studied as extensively, and there are only a limited number of publications on the subject. As is the case with the majority of other pediatric tumors, RR HL is a rare entity, which is why it is so difficult to study it. Here we share the experience of the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation in auto-HSCT in children and adolescents with HL. The study was approved by an Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University. We included 54 patients with RR HL who had undergone auto-HSCT during the period from 2007 to 2021. Refractory disease (n = 29; 54 %) was diagnosed in case of HL progression either during first-line therapy or in the first 3 months after the completion of the treatment. Relapsed disease was diagnosed in 25 (46 %) children. Early HL relapse (< 12 months since the start of therapy) was evident in 18 (72 %) patients, while late HL relapse (≥ 12 months since the start of therapy) occurred in 7 (28 %) children. The median number of lines of therapy before auto-HSCT was 3 (1–6). The first line of treatment was chemotherapy in accordance with the GPOH-HD (n = 27; 50 %), BEACOPP (n = 19; 35 %), or other protocols (n = 8; 15 %); the second line involved the use of IEP/ABVD (n = 14; 27 %), DHAP (n = 12; 23%), ICE (n = 13; 25 %), or other combinations (n = 13; 25%); and third-line treatment consisted of DHAP (n = 9; 29 %), a combination of brentuximab vedotin and bendamustine (n = 8; 26%), immune checkpoint inhibitors (ICIs) (n = 7; 22.5 %) or other regimens (n = 7; 22.5 %). ICIs were used for remission induction prior to auto-HSCT in 14 (26 %) patients. Response was assessed using the Lugano classification. Status before transplantation: complete remission (CR) – 21 (39 %) patients, partial remission (PR) – 30 (56 %), disease stabilization – 2 (3.5 %), disease progression – 1 (1.5 %). The BEAM conditioning regimen was used in 17 (31 %) patients, and the BeEAM regimen – in 32 (59 %) patients. The 3-, 5- and 10-year overall survival (OS) was 88% (95 % confidence interval (CI) 74–95), 80% (95 % CI 62–90) and 63% (95 % CI 34–81) respectively. The 10-year progression-free survival (PFS) was 46% (95 % CI 24–65). The median follow-up was 3.3 (0.1–12.3) years. The long-term PFS in children with CR and PR was 72% (95 % CI 41–89) and 33 % (95 % CI 8–61) respectively (p = 0.067). A total of 9 (16.7 %) patients died during follow-up. The main cause of death was progressive HL (n = 6), while some patients died in the early post-transplant period due to infections (n = 3; 5.6 %). The median time to relapse or progression after auto-HSCT was 6 (1–77) months. Out of 17 (31 %) patients with relapsed or progressive HL after auto-HSCT, 9 (53 %) children are alive at a median follow-up of 2.3 (0.7–9) years. Considering that our study included patients who had been more extensively pre-treated (the median number of lines of therapy – 3) than patients in the majority of other studies (the median number of lines of therapy – 2), it can be assumed that our results are superior to historical data. The improvement of transplantation outcomes observed over time can be attributed to better supportive treatment and probably, to the use of immunotherapy. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), it is crucially important that long-term survival in children with RR HL be monitored closely since it can be drastically different from results obtained during the first years of follow-up - due to late relapses and complications of the received treatment. The 10-year survival rates show that the RR HL problem is yet to be resolved. With the help of auto-HSCT, approximately half of children and adolescents with RR HL can be cured. One of the most important favorable prognostic factors in these patients is the achievement of CR before transplantation. The use of immunotherapy for remission induction before auto-HSCT is also promising.

Modeling the effect of gut microbiome on therapeutic efficacy of immune checkpoint inhibitors against cancer

Immune checkpoint inhibitors have been shown to be highly successful against some solid metastatic malignancies, but only for a subset of patients who show durable clinical responses. The overall patient response rate is limited due to the interpatient heterogeneity. Preclinical and clinical studies have recently shown that the therapeutic responses can be improved through the modulation of gut microbiome. However, the underlying mechanisms are not fully understood. In this paper, we explored the effect of favorable and unfavorable gut bacteria on the therapeutic efficacy of anti-PD-1 against cancer by modeling the tumor-immune-gut microbiome interactions, and further examined the predictive markers of responders and non-responders to anti-PD-1. The dynamics of the gut bacteria was fitted to the clinical data of melanoma patients, and virtual patients data were generated based on the clinical patient survival data. Our simulation results show that low initial growth rate and low level of favorable bacteria at the initiation of anti-PD-1 therapy are predictive of non-responders, while high level of favorable bacteria at the initiation of anti-PD-1 therapy is predictive of responders. Simulation results also confirmed that it is possible to promote patients’ response rate to anti-PD-1 by manipulating the gut bacteria composition of non-responders, whereby achieving long-term progression-free survival.

P1091: FEASIBILITY OF ASCT AFTER ANTI-PD-1 THERAPY FOR R/R CLASSICAL HODGKIN LYMPHOMA

Background: Immunotherapy with checkpoint inhibitors (anti-PD-1) is highly effective in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) and leads to more than 70% overall response rate. However, long-term progression-free survival rate is not sufficient. Consolidation with ASCT after anti-PD-1 could be a very promising option even among previously chemorefractory patients. Nevertheless, there is not enough experience about the safety and feasibility of ASCT after anti-PD-1 in the context of possible immune-related adverse events (AE). Aims: to assess the safety and feasibility of ASCT after anti-PD-1 therapy in patients with R/R cHL. Methods: We retrospectively analysed patients with cHL who previously underwent ASCT from November 2018 until December 2021 after treatment with anti-PD-1. A median patient age was 34 years (range, 20-55), 22 patients were female, 21 - male. Patients received anti-PD-1 as monotherapy (n=17), combination of anti-PD-1 and chemotherapy (n=4), anti-PD-1 monotherapy followed by combination of anti-PD-1 and chemotherapy (n=14), anti-PD-1 monotherapy followed by salvage therapy (n=3) and other (n=2). A median number of anti-PD-1 cycles was 6 (range, 1-45). The median time from the last dose of anti-PD1 was 69 days (range, 14-365). Conditioning regimen for ASCT consisted of BeEAM (n=12), BeAC (n=30) and other (n=1). Safety assessment was performed by Common Terminology Criteria for Adverse Events (CTCAE) (v5.0). Results: Forty-three eligible patients were enrolled in this analysis. A median time to engraftment was 10.5 days (range, 9-26). A median time to platelet count > 20x109/L was 13.5 days (range, 7-43). A median use of G-CSF after high-dose chemotherapy followed by ASCT was 9 days (range, 0-26). PEG-G-CSF (empegfilgrastim 7.5 mg/ml once) was used in 10 patients (23.3%). Plerixafor was used in 6 patients (14%). Neutropenic fever was observed in 32 patients (74.4%). Documented infections were reported in 19 patients (44.2%) among which were 5 cases of clostridial colitis (11.6%). A median intravenous administration of antibiotics was 8 days (range, 0-23). Grade 3-4 mucositis and enteropathy was reported in 2 patients (4.6%) and 6 (14%), respectively. Other non-hematological toxicity was observed in 10 patients (23.4%): 8 patients (18.6%) developed engraftment syndrome (that was successfully treated with steroids), grade 4 autoimmune toxic myocarditis was reported in 1 patient (2.3%). One death due to grade 5 autoimmune myocarditis in combination with grade 5 autoimmune pneumonitis was reported (2.3%). A median duration of hospitalization was 25 days (range, 14-72). Transplant-related mortality (TRM) was reported in 2 patients (4.6%). Image:Summary/Conclusion: The obtained data on safety of ASCT after anti-PD-1 treatment generally correspond to the data of international studies. Toxicity profile tends to be very similar to the published data about ASCT without anti-PD-1 previous treatment, especially in terms of TRM. However, we observe a high incidence of engraftment syndrome that can lead to fulminant immune-related AE (myocarditis and pneumonitis) probably. Attention should be paid to the defining of optimal “wash-out” period after last dose of anti-PD-1 and early defining of possible life-threatening immune related AE (especially myocarditis and pneumonitis).

Cost effectiveness of polatuzumab vedotin in combination with chemoimmunotherapy (Pola-R-CHP) in previously untreated diffuse large B-cell lymphoma.

7568 Background: In patients with treatment naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study demonstrated a 6.5% improvement in the 2-year (yr) progression-free survival (PFS) with no difference in overall survival or safety using polatuzumab vedotin + R-CHP compared to standard RCHOP. We evaluated the cost effectiveness of pola-R-CHP for DLBCL. Methods: We modeled a hypothetical cohort of US adults (mean age, 58 yrs) with treatment naïve DLBCL by developing a Markov model with a 1-month cycle and 20-yr horizon. The cost-effectiveness of two strategies were directly compared (pola-R-CHP, RCHOP) using a range of plausible long-term outcomes. A patient with DLBCL in remission after treatment could develop subsequent progression or relapse, death, or alternative toxicity. Progression rates and overall survival were estimated from POLARIX study. Outcome measures were reported in incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-yr (QALY). Results: Assuming a 5-yr PFS of 69.6% with pola-R-CHP and 62.6% with RCHOP, pola-R-CHP was more effective (0.81 incremental QALYs) but more costly ($66,218) and was cost-effective at a WTP of 150,000 (ICER $82,220/QALY). Its cost effectiveness was highly dependent on the 5-yr PFS of pola-R-CHP with it no longer being cost effective if the 5-yr PFS was < 65%. One way sensitivity analysis demonstrated that pola-R-CHP is cost effective up to a cost of $270,506 at a WTP of $150,000. Probabilistic sensitivity analysis was derived from performing 10,000 Monte-Carlo model iterations and demonstrated that pola-R-CHP was the cost-effective strategy in 61.3% of iterations with RCHOP being cost-effective in 38.6% of iterations at a WTP of $150,000. Conclusions: If the absolute benefit in PFS is maintained over time, frontline pola-R-CHP for treatment of DLBCL would be cost effective at its current cost when compared to RCHOP at a WTP of $150,000/QALY. However, its cost effectiveness is highly sensitive to changes in long-term PFS and the cost of pola-R-CHP. If pola-R-CHP is adopted as frontline therapy for the 29,108 incident cases of DLBCL annually in the US, this will lead to an additional 1.8 billion dollars in healthcare expenditures. This highlights the importance of decreasing the cost of pola-R-CHP and identifying sub-populations that derive the highest benefit from it.[Table: see text]

First-line brentuximab vedotin plus chemotherapy to improve overall survival in patients with stage III/IV classical Hodgkin lymphoma: An updated analysis of ECHELON-1.

7503 Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval [CI] 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% CI 0.532–0.863]). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.

Veterans affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligorecurrent prostate cancer (VA STARPORT).

TPS5112 Background: Two diverging paradigms have been studied in recent years to improve the survival of men with recurrent metastatic prostate cancer (PCa). First, multiple recent phase II randomized trials have demonstrated improved long-term progression-free survival (PFS) with metastasis-directed therapy (MDT) in men with oligorecurrent PCa in the absence of systemic therapy. Yet, most patients receiving MDT for oligorecurrent PCa develop progression in new areas, arguing that systemic therapy is needed to treat occult metastases. The second approach that has recently been studied is whether escalating systemic therapy by adding novel androgen receptor axis targeted agents or chemotherapy improves outcomes in men with metastatic PCa. Multiple phase III randomized trials demonstrate that enhancing hormonal therapy with these therapeutic agents improves progression-free survival (PFS) and overall survival. Therefore, these agents have been integrated into today’s standard systemic therapy (SST) for metastatic recurrence, and SST is the current NCCN guidelines standard of care for recurrent metastatic PCa. The primary goal of our study is to determine if adding PET-directed local therapy (PDLT) to SST improves disease control compared to SST alone in Veterans with oligorecurrent PCa. Methods: VA STARPORT is a phase II/III randomized trial open at 16 VA medical centers comparing SST with or without PDLT in Veterans with oligorecurrent PCa. Key eligibility criteria include prior localized PCa with biochemical recurrence after initial curative-intent local therapy and workup including any FDA-approved PCa PET/CT that reveals oligorecurrence in 1-5 metastatic lesions. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered with an intent for indefinite SST using any NCCN guideline-concordant regimen in both arms. PDLT (Arm 2) consists of surgery or radiation to metastases and any present prostate/prostate bed local recurrence. Metastasis-directed radiation can consist of stereotactic body radiotherapy or elective nodal radiotherapy per clinician discretion from dose/fractionation options defined in the protocol. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Germline sequencing and tumor banking in a separate biorepository study is recommended. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 primary events (CRPC-free survival) by the end of the 48-month active study phase. The study began enrollment in August 2021. Clinical trial information: NCT04787744.

Long-term efficacy and safety of anlotinib in advanced sarcomas.

e23564 Background: Treatment of sarcomas has advanced in recent years partly because of the application of multitarget tyrosine kinase inhibitor (TKI) drugs. Anlotinib is an oral TKI with the dual effects of antiproliferation and antiangiogenesis, and it has a therapeutic effect with good tolerance and low side effects. In theory, physicians can gain long-term tumor control with anlotinib in certain advanced sarcomas. Methods: We conducted a retrospective analysis of patients with advanced sarcomas with measurable target lesions who had been treated in our ward since 2018. There were 22 patients who had taken anlotinib regularly for more than 12 months. Their general information, clinical efficacy, and toxicities were statistically analyzed. We used a swimmer plot to observe the efficacy and duration of the drugs and a waterfall plot to express the best treatment effect. Results: There were 14 male and 8 female patients, ranging in age from 14 to 75 (44.77 on average) years. The primary sarcomas were ASPS in five cases; synovial sarcoma (SS) in four cases; LMS in three cases; epithelioid sarcoma (ES) and UPS in two cases each; and clear cell sarcoma, RMS, angiosarcoma (AS), fibrosarcoma (FS), pleomorphic liposarcoma (LS), and osteosarcoma (OS) in one case each. The sites of metastasis were the lung in 15 cases, lymph nodes in 4 cases, and multiple sites in 3 cases. Therapies were as follows: first-line therapy (6 cases), second-line therapy (9 cases), third-line therapy (5 cases), and more than third-line therapy (2 cases). The current therapy protocols were nine cases with oral anlotinib alone, nine cases with combination chemotherapy, and four cases with combination immunotherapy (anti-PD1). The best clinical efficacy of this group was complete response (CR) in four cases (18.18%), partial response (PR) in five cases (22.73%), and stable disease in 13 cases (59.09%), with an overall response rate of 40.91% and the longest lasting time of 26, 16, 38 months in different response groups. The mean of progression-free survival (PFS) was 23.32 months. The main adverse effects included myelosuppression in seven cases (31.82%), hypertension in three cases (13.64%), and hand-foot syndrome and weakness in two cases (9.10%). Severe adverse effects included hypothyroidism with weakness in one case and wound ulceration with pneumothorax formation in another case. Conclusions: Anlotinib monotherapy or combination therapy can be an effective and safe choice for some advanced sarcomas with a longer maintenance time and acceptable side effects. Besides, anlotinib combined with anti-PD1 therapy has better therapeutic efficacy for specific diseases such as ASPS and ES. Anlotinib combined with chemotherapy has therapeutic efficacy for SS, LMS, FS, and RMS. Clinical efficacy such as CR and PR may be a prediction of long-term PFS in some advanced sarcomas.

Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings

BackgroundImmune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. Patients and MethodsThis was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. ResultsThe PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. ConclusionsThe 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

Long-term progression-free survival achieved in the skull base metastasis of gastrointestinal stromal tumor with introduction of tyrosine kinase inhibitor: illustrative case.

BACKGROUNDGastrointestinal stromal tumors (GISTs) are common subepithelial tumors that rarely metastasize to the intracranial space. Because the standard treatment for metastatic intracranial GISTs has not been established, multimodal therapies are needed, especially in the case of skull base metastasis. However, its outcome has not always been favorable. The authors report the longest known surviving case of skull base metastasis of GIST treated with imatinib only.OBSERVATIONSA 52-year-old male with a history of GIST presented with left facial swelling and numbness. Examinations revealed a 70-mm tumor occupying the left middle cranial fossa and the orbit. The authors performed transnasal endoscopic tumor biopsy for definitive diagnosis and reintroduced imatinib treatment. The tumor significantly decreased in size early after the introduction of imatinib, and symptoms completely disappeared within several weeks. The lesion has remained shrunk radiologically for 63 months, and the patient is continuously being followed up under imatinib treatment.LESSONSThe authors reported a rare case of skull base metastasis of GIST successfully treated solely with systemic therapy with a tyrosine kinase inhibitor, achieving tumor control for over 5 years. This case suggests that tyrosine kinase inhibitors might play a key role in the multidisciplinary treatment for skull base metastases of GIST.

Stereotactic radiosurgery in the management of petroclival meningiomas: a systematic review and meta-analysis of treatment outcomes of primary and adjuvant radiosurgery.

To summarize the clinical features and outcomes of petroclival meningioma patients treated with stereotactic radiosurgery (SRS) as either a primary or an adjuvant modality. Relevant articles were retrieved from PubMed, Scopus, Web of Science, and Cochrane. A systematic review and meta-analysis of treatment outcomes comparing primary and adjuvant SRS was conducted. Seven articles comprising 722 cases were included. The mean tumor marginal dose was 13.5Gy. After SRS, symptoms improved in 28.7%, remained unchanged in 61.3%, and worsened in 10.0% of the cohort. Tumor control was achieved in 94.8% of patients. The mean tumor volume change was -6.4 cm3. The 5-year and 10-year progression-free survival (PFS) rates were 91-100% and 69.6-89.9%, respectively. Overall, 61.9% of patients underwent primary radiosurgery, and 38.1% had adjuvant radiosurgery. Patients who had primary SRS reported higher rates of tumor control (94.3% vs. 88.2%) and fewer SRS-related complications (3.7% vs. 10.3%) than those who received adjuvant SRS (not accounting for microsurgical complications). The functional status of patients who had primary SRS was more likely to improve or remain unchanged, with an effect size of 1.12 (95% CI 1.1-1.25; I2 = 0). Neither group displayed superiority in worsening functional outcomes or tumor control rate. SRS of petroclival meningiomas was associated with excellent long-term PFS and local tumor control rates. Primary SRS was highly effective for patients with smaller volume lesions without clinically symptomatic mass effect. In patients who warrant initial resection, adjuvant radiosurgery remains an important modality to prevent regrowth while maintaining postresection function.

Contemporary Radiotherapy for Fisch-Classified Jugulotympanic Paragangliomas - Does Tumor Category Matter? Outcomes From a 13-Year Experience

<h3>Purpose/Objective(s)</h3> Jugulotympanic paragangliomas (JTPGs), recognized as slow-growing tumors, represent a treatment challenge because of their known vascular nature, tendency to be locally invasive, location near many vital structures, and their potential to cause very disabling symptoms. This study aimed to examine the outcomes of patients with Fisch-classified JTPGs treated with conventional radiotherapy including stereotactic radiosurgery. <h3>Materials/Methods</h3> Twenty-four consecutive patients with head and neck paragangliomas diagnosed between November 2003 and May 2017 were identified from the radiation oncology and radiosurgery databases and lists of patients presented for discussion at the weekly Department of Otolaryngology-Head and Neck Surgery multidisciplinary conference. After excluding individuals with carotid body glomus tumors or missing clinical and radiological follow-up information, 13 patients (with a mean age of 61.8 years; 6 glomus tympanicum and 7 glomus jugulare PGs; 10 women and 3 men;) composed the JTPG study participants. Non-invasive stereotactic radiosurgery or external beam radiotherapy was used to treat JTPGs in 11 patients and 2 patients, respectively. The investigation endpoints included subjective and objective responses to treatment (i.e., exhibited symptoms and signs of disease and the tumor) and observed toxicity. <h3>Results</h3> With regard to the risk designation of JTPGs, seven (54%) belonged to the Fisch A-B categories and six (46%) to C-D categories. During a median follow-up of 36 months (range 7-204) after-therapy, subjective responses consisted of eight patients (62%) who were symptom-free, and five individuals (38%) who did not improve. At a median radioimaging follow-up of 34 months (range 6-204), eight (62%) treated neoplasms were stable, two (15%) showed continued tumor growth, and three (23%) were smaller following radiation treatment. One participant (8%) experienced transient otalgia and tinnitus after external beam irradiation; no patient developed radiation oncogenesis. Long-term follow-up (from 75 to 204 months) was documented in six people (46%). Characterization and effects of treatment were not significantly different between the compared Fisch categorized groups of JTPGs. <h3>Conclusion</h3> The observed rates of tumor control (85%) and treatment-related toxicity (8%), and the long-term disease progression-free survival of some patients suggest that contemporary radiotherapy is efficacious and safe when applied for Fisch-classified JTPGs.

Frontline chemotherapy-free induction for mantle cell lymphoma.

Standard treatment for young patients with mantle cell lymphoma involves intensive regimens (rituximab–anthracycline–cytarabine-based) with or without autologous haematopoietic stem cell transplantation (HSCT) and rituximab maintenance and yields high complete response rates (61–89%). 1 Romaguera JE Fayad L Rodriguez MA et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005; 23: 7013-7023 Crossref PubMed Scopus (459) Google Scholar , 2 Geisler CH Kolstad A Laurell A et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112: 2687-2693 Crossref PubMed Scopus (487) Google Scholar , 3 Eskelund CW Kolstad A Jerkeman M et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016; 175: 410-418 Crossref PubMed Scopus (112) Google Scholar , 4 Hermine O Hoster E Walewski J et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016; 388: 565-575 Summary Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 5 Le Gouill S Thieblemont C Oberic L et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017; 377: 1250-1260 Crossref PubMed Scopus (185) Google Scholar However, relapses still occur, with 3-year progression-free survival rates of 60–85%, and such treatment regimens are also associated with non-negligible adverse events. 1 Romaguera JE Fayad L Rodriguez MA et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005; 23: 7013-7023 Crossref PubMed Scopus (459) Google Scholar , 2 Geisler CH Kolstad A Laurell A et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112: 2687-2693 Crossref PubMed Scopus (487) Google Scholar , 3 Eskelund CW Kolstad A Jerkeman M et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016; 175: 410-418 Crossref PubMed Scopus (112) Google Scholar , 4 Hermine O Hoster E Walewski J et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016; 388: 565-575 Summary Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 5 Le Gouill S Thieblemont C Oberic L et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017; 377: 1250-1260 Crossref PubMed Scopus (185) Google Scholar Ibrutinib–rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trialInduction with ibrutinib–rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. Full-Text PDF

Veterans affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligorecurrent prostate cancer (VA STARPORT).

TPS203 Background: Two diverging paradigms have been studied in recent years to improve the survival of men with recurrent metastatic prostate cancer (PCa). First, multiple recent phase II randomized trials have demonstrated improved long-term progression-free survival (PFS) with metastasis-directed therapy (MDT) in men with oligorecurrent PCa in the absence of systemic therapy. Yet, most patients receiving MDT for oligorecurrent PCa develop progression in new areas, arguing that systemic therapy is needed to treat occult metastases. The second approach that has recently been studied is whether escalating systemic therapy by adding novel androgen receptor axis targeted agents or chemotherapy improves outcomes in men with metastatic PCa. Multiple phase III randomized trials demonstrate that enhancing hormonal therapy with these therapeutic agents improves progression-free survival (PFS) and overall survival. Therefore, these agents have been integrated into today’s standard systemic therapy (SST) for metastatic recurrence, and SST is the current NCCN guidelines standard of care for recurrent metastatic PCa. The primary goal of our study is to determine if adding PET-directed local therapy (PDLT) to SST improves disease control compared to SST alone in Veterans with oligorecurrent PCa. Methods: VA STARPORT is a phase II/III randomized trial open at 16 VA medical centers comparing SST with or without PDLT in Veterans with oligorecurrent PCa. Key eligibility criteria include prior localized PCa with biochemical recurrence after initial curative-intent local therapy and workup including any FDA-approved PCa PET/CT that reveals oligorecurrence in 1-5 metastatic lesions. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered with an intent for indefinite SST using any NCCN guideline-concordant regimen in both arms. PDLT (Arm 2) consists of surgery or radiation to metastases and any present prostate/prostate bed local recurrence. Metastasis-directed radiation can consist of stereotactic body radiotherapy or elective nodal radiotherapy per clinician discretion from dose/fractionation options defined in the protocol. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Germline sequencing and tumor banking in a separate biorepository study is recommended. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 primary events (CRPC-free survival) by the end of the 48-month active study phase. The study began enrollment in August 2021. Clinical trial information: NCT04787744.

Rituximab Concentration Varies in Patients With Different Lymphoma Subtypes and Correlates With Clinical Outcome.

Individual variations in concentrations of rituximab in different B cell non-Hodgkin’s lymphoma subtypes and their relevance to efficacy were still unclear. From 2016 to 2021, a prospective clinical trial was conducted, and 510 samples with 6 uncommon subtypes of B-cell lymphoma were enrolled to examine the pharmacokinetic behaviour of rituximab and its impact on clinical outcomes, including complete response (CR), progression-free survival (PFS) and overall survival (OS). Considerable variability was observed in the rituximab trough concentration in the first cycle (C1-trough, 1.16–55.52 μg/ml) in patients with different lymphoma subtypes. Patients with “double-hit” lymphoma (4.01 ± 0.77 μg/ml) or mantle cell lymphoma (MCL; 15.65 ± 16.45 μg/ml) had much lower C1-trough and worse outcomes. Great individual variation in the C1-trough existed among patients with mucosa-associated lymphoma (MALT), and the high C1-trough observed in patients treated with the RB regimen was associated with a better response than was obtained with R-CHOP (38.41 ± 14.13 μg/ml vs 15.49 ± 8.80 μg/ml, p = 0.0029). Despite the high aggressiveness of the cancer, Burkitt lymphoma patients receiving intensive chemotherapy had the highest C1-trough (28.85 ± 9.35 μg/ml) and maintained long-term PFS. The C1-trough in patients with mixed, unclassifiable B-cell lymphoma was close to 20 μg/ml, and these patients had acceptable outcomes. Overall, a low rituximab C1-trough was associated with adverse consequences, including persistent progression, early recurrence and a short OS, however, some high-risk factors appeared to be balanced by the presence of a high C1-trough. Basal levels of circulating CD19+ lymphocytes differed between and within patients with diverse lymphoma subtypes and were negatively correlated with C1-trough. Therefore, the traditional doses of rituximab are inadequate for patients with “double-hit” lymphoma and MCL. Increasing the initial rituximab dose according to the disease, high-risk factors and even the baseline CD19+ lymphocyte count will be new methods to optimize therapeutic regimens for patients with different lymphoma subtypes.

How to choose first salvage therapy in Hodgkin lymphoma: traditional chemotherapy vs novel agents.

Approximately 10% to 30% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (R/R) disease. Of those patients, 50% to 60% show long-term progression-free survival after standard salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). In the past decade, novel therapies have been developed, such as the CD30-directed antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors, which have greatly extended the treatment possibilities for patients with R/R cHL. Several phase 1/2 clinical trials have shown promising results of these new drugs as monotherapy or in combination with chemotherapy, but unfortunately, very few randomized phase 3 trials have been performed in this setting, making it difficult to give evidence-based recommendations for optimal treatment sequencing. Two important goals for the improvement in the treatment of R/R cHL can be identified: (1) increasing long-term progression-free and overall survival by optimizing risk-adapted treatment and (2) decreasing toxicity in patients with a low risk of relapse of disease by evaluating the need for HDCT/ASCT in these patients. In this review, we discuss treatment options for patients with R/R cHL in different settings: patients with a first relapse, primary refractory disease, and in patients who are ineligible or unfit for ASCT. Results of clinical trials investigating novel therapies or strategies published over the past 5 years are summarized.

Risk Stratification and Treatment Algorithm of Metastatic Renal Cell Carcinoma.

Systemic therapy for metastatic renal cell carcinoma has continuously evolved over the last two decades. Significant improvements in overall survival and quality of life of patients with advanced disease have been observed. With the approval of combination therapies with PD(L)-1 immune checkpoint inhibitors (ICI) as first-line therapy in 2019, the previous standard VEGFR-TKI monotherapy has been replaced as the primary treatment option. In addition to immunotherapy with nivolumab and ipilimumab, three VEGFR-TKI/ICI combinations are now approved. Therapy selection should be preceded by risk stratification using defined criteria from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Clinical parameters, as well as detailed patient counseling on differences in the efficacy profile (response rate, long-term progression-free survival), potential side effects, and impact on quality of life, are of key importance in the individual treatment decision.

Are Novel Therapies Worth the Cost for Young Patients?: A Cost-Effectiveness Analysis of Frontline Therapies with or without Radiation for Early-Stage Unfavourable Hodgkin Lymphoma

Background: A variety of frontline treatment regimens exist for early-stage unfavourable Hodgkin lymphoma (HL), offering personalization of risk versus benefit in this primarily young population of patients. While radiation therapy has been a mainstay of treatment due to improved progression-free survival (PFS), recent studies have challenged this paradigm, using a PET-driven approach (HD17) or incorporating novel agents (nivolumab-AVD (N-AVD), brentuximab-AVD (A-AVD)). Long term risks of radiation and chemotherapy include secondary breast and other cancers, and heart failure; however novel regimens are more costly with uncertainty surrounding long-term efficacy.Methods: A cost-effectiveness and cost-utility analysis was conducted to compare five published frontline approaches for early-stage unfavourable HL: HD17, two H10 approaches, N-AVD, and A-AVD without radiation (Table 1). A Markov model was constructed with a lifetime horizon using TreeAge Pro 2021 (Figure 1). The base case was a 20-year-old female with a mediastinal mass who would require chest field radiation. Baseline estimates in the model were derived from the literature, including risk of relapse after each line of therapy, risk of late complications (breast cancer, secondary cancer, and/or heart failure), risk of death (from complications, lymphoma, and background mortality), and health state utilities. A Canadian public health care payer's perspective was taken, and costs are estimated in 2021 Canadian dollars. Global discounting of 3% was used.Results: Probabilistic sensitivity analyses were performed (10,000 simulations). First, we evaluated the uncertainty of long-term PFS using novel regimens (N-AVD or A-AVD); at a willingness-to-pay of $50,000/QALY, N-AVD was the most cost-effective regimen when 5-year PFS was at least 92% (Table 2). If 5-year PFS with N-AVD was <92%, HD17 became the most cost-effective approach. There was no PFS threshold at which A-AVD was the most cost-effective regimen. Holding the 5-year PFS of novel regimens at 92%, the model remained robust to multiple deterministic sensitivity analyses testing key variables including health state utilities (of relapse post-transplant, breast cancer, second malignancy, heart failure), costs (of radiation, autologous stem cell transplant, breast cancer, second malignancy, heart failure), and risks (of breast cancer after radiation, cardiovascular disease after radiation and/or chemotherapy,). However, if the risk of developing second cancer was less than 2% after 5 years with HD17 approach (current estimates 1% at 48 months in HD17 to 2% at 43 months in HD14 (which used a similar regimen)), or if the median overall survival after secondary cancer was over 9 years, HD17 became the most cost-effective regimen. The threshold cost for brentuximab to make A-AVD the most cost-effective regimen was <$5000 per dose (current price $14,520 CAD).Conclusions: If the long term PFS of nivolumab-AVD is greater than 92%, it could be the most cost-effective regimen when treating a young female patient with early-stage unfavourable Hodgkin lymphoma. This model accounts for increased costs with nivolumab added to chemotherapy, due to potential reduced incidence of late effects. However, there remain uncertainties in efficacy and risk regarding novel therapies as only non-randomized Phase II studies with short follow-up durations have been published; further trials of these approaches are being planned. HD17 remains the most cost-effective approach among published Phase III regimens. Long term follow-up of HD17 will also be meaningful to understand the risk of second cancer with this approach, which may impact its cost-effectiveness. [Display omitted] DisclosuresCrump: Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

Classical Hodgkin Lymphoma; Real-World Observations from Physicians, Patients, and Caregivers on the Disease and Its Treatment (CONNECT): Physician First-Line Treatment Preferences for Stage III or IV Classical Hodgkin Lymphoma

BackgroundMainstay therapies for patients with stage III or IV classical Hodgkin lymphoma (cHL) include several multiagent chemotherapy regimens. A combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is commonly administered in the first-line (1L) setting; however, ~30% of patients with stage III or IV cHL will be refractory to or relapse following ABVD treatment. Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD), a novel targeted therapy in combination with a standard chemotherapy regimen, is another option for 1L treatment of stage III or IV cHL. In the 5-year update of the ECHELON-1 trial (Straus, 2021), patients with stage III or IV cHL randomized to 1L A+AVD compared with ABVD continued to demonstrate progression-free survival (PFS) improvement with a 32% reduction in the risk of progression or death (HR=0.681, nominal P=0.002). To understand the decision-making process when selecting a 1L cHL treatment regimen for stage III or IV cHL, we surveyed physicians to gain insights into their preferred regimens and factors that influence their treatment choices as part of CONNECT, the first real-world observational survey in cHL that includes physicians, patients, and caregivers.MethodsPhysicians in the United States who treat patients with cHL were recruited to participate in an Institutional Review Board-approved, online anonymous survey from October 19, 2020-November 16, 2020. Eligible participants were medical oncologists, hematologist/oncologists, or hematologists with ≥2 years medical practice experience who, within the past 12 months, had treated ≥1 adult (aged ≥18 years) with stage III or IV cHL and ≥1 adult in the 1L setting.ResultsOf participating physicians (N=301), 62% were community-based and 80% identified themselves as a hematologist/oncologist, reporting a median of 15 years of experience. Participants saw a median (interquartile range) of 16 (7-40) patients with active, newly diagnosed cHL and 15 (8-40) cHL survivors in the 12 months preceding survey participation. The most important considerations (ranked 1 or 2) for cHL treatments were clinical trial efficacy and safety data (60%) and official guideline recommendations (58%). Specifically, efficacy attributes including overall survival (OS; 91%), long-term PFS (86%), curative potential (85%), and complete response (81%) were rated highest or as having the most essential impact. In contrast, patient personal goals (6%), treatment costs (4%), and patient financial support programs (4%) were endorsed by <10% of participants. When asked about acceptable long-term toxicity trade-offs for increased efficacy in patients with stage III or IV cHL, participants stated that an additional median of 8 months of OS and 6 months of PFS were worth the potential for downstream toxicity. Fifty percent of participants reported that disease stage was the most important patient characteristic to consider when deciding on 1L cHL treatment. In patients with newly diagnosed stage III or IV cHL, 37% to 50% of participants selected A+AVD as their first-choice regimen across various populations (Figure); no significant differences in preferences were noted between community and academic practice settings. Participants reported selecting intensive treatment regimens based on OS and PFS and less intensive regimens (e.g., AVD) based on age, comorbidities, and patient quality of life.ConclusionsEfficacy attributes, including OS and PFS; quality of life; and patient age were top reasons cited by surveyed participants for selecting a specific 1L treatment regimen in stage III or IV cHL. Treatment preferences for newly diagnosed stage III or IV cHL varied based on patient characteristics including presence of bulky mediastinal disease, disease stage, perceived risk of relapse, age, and comorbidities. [Display omitted] DisclosuresYu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Kumar: Seagen, Inc: Consultancy. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Flora: Seagen, Inc: Research Funding. Parsons: SeaGen: Consultancy.

A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients with Previously Untreated Double and Triple Hit Lymphoma

Background: Double hit lymphoma (DHL) accounts for approximately 10-14% of diffuse large B cell lymphoma (DLBCL) and is characterized by the presence of rearrangements affecting MYC and either BCL2 and/or BCL6 by FISH. The complete response (CR) rate with standard R-CHOP is very poor at 20%, with dismal long-term progression-free (PFS) and overall survival (OS). Aggressive chemotherapy regimens including R-EPOCH, R-HyperCVAD/MA, and R-CODOX-M/IVAC have been evaluated in retrospective studies and have demonstrated better PFS compared to R-CHOP. However, no OS benefit is noted. Moreover, these regimens are associated with significant toxicity and cannot be used in a substantial proportion of patients due to advanced age and comorbidities, and have not been evaluated in prospectively studies. Therefore, new therapeutic modalities, which are better tolerated, are indeed needed to improve outcomes in this high-risk population.Polatuzumab vedotin (PoV) is a CD79b-directed antibody-drug conjugate delivering monomethyl auristatin E (MMAE). PoV either as a single agent or with bendamustine and rituximab (BR) demonstrated encouraging activity in relapsed refractory DLBCL with an overall response rate (ORR) of approximately 50%. Given the promising activity, PoV has been combined with rituximab, cyclophosphamide, doxorubicin, prednisone (R-CHP) in a phase 1b/2 trial, and has shown a favorable safety and tolerability profile.Study design and Methods: This is a phase II, multicenter, open label study of PoV 1.8 mg/kg in combination with standard doses of R-CHP in patients with untreated double or triple hit lymphoma. One cycle of R-CHOP prior to enrollment is allowed. Key eligibility criteria include patients aged > 18 years with previously untreated double or triple hit lymphoma, ECOG PS 0 to 2, measurable FDG-avid disease. Key exclusion criteria are DLBCL NOS subtype, primary mediastinal or Burkitt's lymphoma, and CNS involvement. A total of 49 patients will be enrolled. All patients will receive PoV with R-CHP every 3 weeks for a total of 6 cycles with intrathecal methotrexate for CNS prophylaxis. The primary endpoint is CR rate. Key secondary endpoints are PFS, OS, ORR, duration of response, and safety and tolerability of the combination. Disease response will be assessed by the Lugano response criteria. The study is currently enrolling. ClinicalTrials.gov Identifier: NCT04479267. DisclosuresModi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Pregja: Janssen: Consultancy; Regeneron: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Intellia: Consultancy; Caelum: Consultancy; Alnylam: Consultancy; Eidos: Consultancy; BMS: Research Funding. Ramchandren: pharmacyclics: Consultancy, Research Funding; Trillium: Research Funding; curis: Research Funding; BMS: Consultancy; MERCK: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding.