The Outcomes of Nivolumab Fixed Dose 40 Mg Therapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma

Background Currently, the recommended dose of nivolumab for patients with relapsed or refractory classical Hodgkin lymphoma (r/r сHL) is 3 mg/kg. Nevertheless, published clinical cases indicate the possible efficacy of lower doses of nivolumab. Moreover, experimental studies provided the rationale for possible reduction of nivolumab dose in patients with solid tumors (Agrawal et al. 2016). The presented data creates prerequisites for studying the lower nivolumab doses efficacy and safety in the r/r cHL therapy. Patients and Methods This study included 42 patients (14 male/28 female) with r/r cHL who were treated with nivolumab 40 mg every 2 weeks. The median age of patients was 36 (22-53) years. The median number of prior therapy lines was 4 (2-7). Prior treatment contained high dose chemotherapy with ASCT in 9 pts (21%), brentuximab vedotin in 14 pts (33%) and allo-HSCT in 1 pt (2%). Four pts (9,5%) had the partial response (PR) and the remaining 38 pts (90,5%) had the disease progression (PD) at the moment of nivolumab initiation. B-symptoms were present in 23 pts (55%), ECOG status was grade 0-I in 25 pts (59,5%), grade II in 12 pts (29%), grade III in 4 pts (9,5%) and grade IV in 1 pt (2%). The primary endpoint was the overall response rate (ORR) determined by positron-emission tomography/computed tomography (PET/CT) using LYRIC criteria every 3 months. Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were evaluated according to CTCAE 4.03. The patient group characteristics were evaluated using descriptive statistics methods, the survival analysis was performed using Kaplan-Meyer method (SPSS Statistics v.17). Results The median number of nivolumab cycles was 24 (2-38). The response was evaluated in 41 out of 42 pts. The ORR was 66%. The best response included complete response (CR) in 39%, PR in 27%, stable disease in 5%, PD in 2%, indeterminate response (IR) in 27% of pts. With a median follow-up of 27,5 mo (11,3-34,5) 41 pts (97,6%) were alive, the median OS was not reached. The 2-year PFS was 44,5% (95% CI, 28,2-59,6) The nivolumab therapy was discontinued in 39 pts (93%) due to scheduled discontinuation in 14 pts (33%), PD in 13 pts (31%), grade 3-4 AE in 2 pts (5%), change of therapy because of insufficient response in 6 pts (14%) and other reasons in 4 pts (10%). The progression of disease during nivolumab therapy was present in 14 (33%) pts and after nivolumab discontinuation in 6 (14%) pts. After disease progression 30 pts (71%) were retreated with nivolumab monotherapy or in combination with chemotherapy. The median time to additional therapy was 14,5 mo (4,2 -32,9). The adverse events of any severity were observed in 30 pts (71%). Grade 3 or higher AE were present in 4 pts (9,5%), including grade 3 arthralgia, grade 3 anemia, grade 4 pneumonia and pneumonitis, grade 4 increased level of alanine aminotransferase and grade 5 MDS in 1 pt. A significant reduction of PD1+CD3+ cell population of peripheral blood lymphocytes was observed after first nivolumab cycle (median 0.7% (0-1.7) versus 33% (15.7-80.1) before therapy initiation, p = 0.02, Wilcoxon signed-rank test). Conclusion Our study demonstrated the efficacy and safety of nivolumab 40 mg therapy. The presented results are comparable to previously published data of nivolumab 3 mg/kg therapy in patients with r/r cHL. Thus, this creates a basis for further direct comparative study of nivolumab efficacy in different doses Disclosures No relevant conflicts of interest to declare.

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High-Dose Cytoxan, Etoposide, and Cisplatin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma: A 20-Year Single-Institutional Experience.

Blood ◽

10.1182/blood.v110.11.1913.1913 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1913-1913

Author(s):

Thomas R. Klumpp ◽

Moshe C. Chasky ◽

Robert V. Emmons ◽

Mary E. Martin ◽

James L. Gajewski ◽

...

Keyword(s):

Complete Remission ◽

Total Dose ◽

Hodgkin Lymphoma ◽

Pulmonary Toxicity ◽

Median Number ◽

High Dose ◽

Post Transplant ◽

Grade 3 ◽

Active Disease

Abstract Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.

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Real-Life Experience of Nivolumab in Heavily Pretreated Relapsed and Refractory Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood.v128.22.3008.3008 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3008-3008 ◽

Cited By ~ 2

Author(s):

Ohad Benjamini ◽

David Lavie ◽

Eldad J Dann ◽

Chava Perry ◽

Ory Rouvio ◽

...

Keyword(s):

Adverse Events ◽

Hodgkin Lymphoma ◽

Clinical Studies ◽

Life Experience ◽

Real Life ◽

Brentuximab Vedotin ◽

Efficacy And Safety ◽

Classical Hodgkin Lymphoma ◽

Post Transplantation ◽

Heavily Pretreated

Abstract Background: The fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has shown to be highly efficacious in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL). Initial results of a single-arm nivolumab monotherapy in heavily pretreated young adults with RR cHL, previously treated with autologous hematopoetic stem cell transplantation (autoSCT) and brentuximab vedotin are promising. However, demonstrating similar results in real-life experience in patients not on Pharma clinical studies are of major clinical importance. Aim: The aim of the current study was to evaluate the efficacy and safety of nivolumab in previously heavily pretreated patients with RR cHL not on Pharma clinical studies. Methods: The records of patients with RR cHL who were treated with nivolumab in seven medical centers were reviewed. The regimen consisted of nivolumab 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. Results: Between May 2015 and April 2016, 30 patients with RR cHL received nivolumab monotherapy. The median age was 35 years (range: 21 to 88). Patients were extremely heavily pretreated with median of 6 prior therapies (range: 3 to 11); 73% of them received ≥ 5 lines of therapy. Specifically, 29/30 (97%) received ABVD, 7/30 (23%) escBEACOPP, 20/30 (67%) gemcitabine based regimens, 30/30 (100%) brentuximab vedotin, 8/30 (27%) bendamustine, 3/30 (10%) lenalidomide, 28/30 (93%) other combinations of chemotherapy and 22/30 (73%) radiotherapy. Twenty patients (67%) previously underwent autoHSCT and 4/30 (13%) allogeneic transplantation (alloSCT), two before and two after receiving nivolumab. Median number of nivolumab doses received was 8 (range 1 to 29). Twenty three patients (77%) are still on treatment. Seven patients (23%) discontinued therapy due to disease progression 3/30 (10%), adverse events 2/30 (7%) and referral to alloSCT 2/30 (7%). Overall response rate among 25 evaluable patients was 76%, complete response (CR) - 7/25 (28%), partial response - 12/25 (48%), stable disease - 3/25 (12%) and only 3/25 (12%) progressed, one of them with cHL type of Richter's transformation. Two patients underwent alloSCT in remission following nivolumab treatment. One patient was transplanted from a matched sibling donor and the second patient from a T replete haploidentical donor with post transplantation cyclophosphamide as anti-graft versus host disease prophylaxis. Both patients are in CR, ten and three months post transplantation, respectively. The median overall survival (OS) and progression free survival (PFS) for the cohort were not reached (Figure 1). At 24 weeks the PFS was 74%. Adverse events reported in 9/30 patients (30%) were usually mild. Severe nivolumab related adverse events in 3/30 (10%) included immune related pneumonitis, myelitis and uveitis. No treatment related death occurred. Conclusions: The check point inhibitor nivolumab is a novel therapy for RR cHL patients, previously with unmet need following relapse or refractory to autoHSCT and brentuximab vedotin. Our real life experience confirms and highlights the efficacy and safety of nivolumab in very heavily pretreated young and elderly patients with cHL eligible as well as ineligible for autologous HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A Retrospective Analysis of Brentuximab Vedotin and Pembrolizumab Combination As Salvage Treatment for Patients with Relapsed or Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-137399 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Fulvio Massaro ◽

Nathalie Meuleman ◽

Dominique Bron ◽

Marie Maerevoet

Keyword(s):

High Risk ◽

Disease Progression ◽

Hodgkin Lymphoma ◽

Metabolic Response ◽

Conflicts Of Interest ◽

Phase 1 ◽

Brentuximab Vedotin ◽

Salvage Treatment ◽

Fixed Dose ◽

High Dose

Background:The standard treatment for Hodgkin lymphoma (HL) patients presenting a relapsed/refractory (R/R) disease is salvage chemotherapy followed by autologous stem cell transplantation (ASCT). However, with commonly used chemotherapy combinations (such as DHAP, ICE, BEGEV), 25-30% of these patients fail to achieve a complete metabolic response (CMR) and to proceed to ASCT, with subsequently poor outcomes. Single agents brentuximab vedotin (BV) and pembrolizumab have shown efficacy in heavily pretreated HL patients, as reported in previous studies. The combination of BV with nivolumab has been explored in a phase 1/2 study as first salvage treatment for HL patients, showing a CR rate of 61% (Herrera et al 2018). We explored the outcome of BV and pembrolizumab combination as salvage treatment in a series of R/R HL patients. Methods:We retrospectively collected data of seven HL patients presenting with a high-risk multi-refractory disease (two or more prior treatments) followed at Jules Bordet Institute between May 2019 and July 2020 and treated with a combination of BV and pembrolizumab. Patients were covered by special insurance conditions allowing treatment reimbursement. Treatment proposal was approved by a local multidisciplinary committee. Treatment consisted of 3-week cycles with a combination of BV (1.8 mg/kg IV) and pembrolizumab (200 mg IV fixed dose), an early PET-CT evaluation followed by high-dose chemotherapy and ASCT consolidation for those achieving a Deauville score ≤4. After ASCT, patients received BV as maintenance for a total of 16 administration (including pre-ASCT cycles). Results:We included 7 patients, 6 male and 1 female, with a mean age of 27.4 (20.6-36.3) years. All patients presented with an advanced-stage disease, with a mean number of 2.56 (2-3) prior treatments. The median follow-up time was 9.7 months, while the average number of received cycles of treatment was 4.2 (range 2-7). Table 1 shows additional patients' characteristics. The overall response rate (ORR) was 87% and particularly a CR was achieved in five patients (72%), with a median time to response of two cycles. One partial response and one disease progression were also observed. Six patients proceeded to ASCT (86%) and subsequent BV maintenance, with one early disease progression. One patient, in complete molecular remission after 2 cycles, locally progressed after 6 cycles and received radiotherapy before ASCT. Table 2 summarizes the outcome for each patient included in the series. Conclusions:The BV and pembrolizumab combination is a very effective bridge treatment to ASCT for high-risk R/R HL patients. Disclosures No relevant conflicts of interest to declare.

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Retrospective Analysis of the Efficacy and Safety of Modified Bortezomib-Lenalidomide-Dexamethasonelite (modified RVD-lite) Therapy for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112294 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1961-1961

Author(s):

Kiyoshi Okazuka ◽

Tadao Ishida ◽

Junichiro Nashimoto ◽

Takao Yogo ◽

Kanji Miyazaki ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Staging System ◽

Median Number ◽

Al Amyloidosis ◽

Fish Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Grade 3

Abstract [Background] Thecombination therapy consisting of bortezomib, lenalidomide and dexamethasone (RVD) for newly diagnosed multiple myeloma has been one of the standard induction therapies in recent years. However, 9-23 % of patients discontinued treatments because of severe adverse events in the previous reports (SWOG S077, IFM2009). Thus, it has not been clarified ifthe dosing schedule of RVD is appropriate. Here, we investigated the efficacy and safety of modified RVD-lite for 45 transplant eligible patients with newly diagnosed multiple myeloma (NDMM). [Patients and methods] We retrospectively analyzed 45 transplant eligible patients with NDMM who received modified RVD-lite for induction therapy between February 2016 and March 2018. The median age was 58 years old (range 36~66), and 6 (13.3%) patients were AL amyloidosisassociated with multiple myeloma. Patients received bortezomib 1.3 mg/m2once weekly subcutaneous (SC) on days 1, 8, 15, 22, lenalidomide 15 mg/day on days 2-7, 9-14, 16-21 and dexamethasone 40mg on days 1, 8, 15, 22. The Revised International Staging System (R-ISS) wereI in 13 (28.9%), II in 30 (66.7%) and III in 2 (4.4%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 5 (11.1%) patients. After 4 cycles of modifiedVRd-lite, we evaluated the efficacy and adverse events. [Results] The overall response rate (ORR) after four 28-day cycles of modifiedRVD-lite was obtained in 41 (91.1%), including sCR in 6 (13.3%) and CR in 5 (11.1%). SD and PD were observed in 2 patients (4.4%) and 1 patient (2.2%), respectively. One patient was not evaluated efficacy, because a patient changed modifiedRVD-lite to ixazomib, lenalidomideand dexamethasone therapy for grade 3 peripheral neuropathy. Thirty-eight of 45 patients (84.4%) received autologous stem cell transplantation (ASCT) after at least 4 courses of modifiedVRd-lite. The median number of CD34+cells/kg collected was 4.83 x 106(range, 1.1-11.9). All patients received melphalan at doses of 200 mg/m2. In these patients, response after ASCT were sCR in 15(41.7%), CR in 2 (5.6%), VGPR in 8 (22.2%) and PR in 8 (22.2%). Three of seven patients who did not received ASCT will receive ASCT ina few months. Among other 4 patients who did not receive ASCT, 2 patients chose other therapies without ASCT, and 2 patients could not receiveASCT because they showed no improvement in cardiac AL amyloidosis. Grade 3 or higher adverse events (AEs) were observed in 17 (37.8%). Most frequent grade 3 or higher AE was neutropenia (grade 3:17.8%, grade 4:6.7%). Only one patient (2.2 %) discontinued modifiedRVD-lite because of grade 3 peripheral neuropathy. [Conclusions] The ORR after 4 cycles ofmodifiedRVD-lite was high (91.1%). These results might be related to low rate of discontinuation of treatment. Also, the ORR after ASCT was comparable to the results previously published (N Engl J Med .2017 Apr 6:376(14):1311). AEs in modified RVD-lite were feasible and manageable in most patients. Our results suggest that modifiedRVD-lite is very feasible and effective treatment for patients with transplant eligible NDMM. Disclosures Suzuki: Sanofi Aventis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment.

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Outcomes and safety analysis of a phase IB trial of stereotactic body radiotherapy (SBRT) to all sites of oligometastatic non-small cell lung cancer combined with durvalumab and tremelimumab.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21212 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21212-e21212

Author(s):

Michael Frederick Bassetti ◽

Nan Sethakorn ◽

Joshua Michael Lang ◽

Jennifer L. Schehr ◽

Zachery Schultz ◽

...

Keyword(s):

Adverse Events ◽

Disease Progression ◽

Performance Status ◽

Cohort Analysis ◽

Median Number ◽

Ecog Performance Status ◽

Phase Ib ◽

Grade 3 ◽

Metastatic Sites

e21212 Background: Combining local ablative and systemic therapies in patients with oligometastatic NSCLC leads to improved overall survival (OS) and progression-free survival (PFS). The potential immunostimulatory effects of ablating all visible disease with SBRT in combination with dual immune checkpoint inhibition has prompted interest, but the toxicity and benefit are unknown. Methods: We conducted a phase Ib study to investigate the safety of SBRT, with doses between 30 and 50 Gy in five fractions to all sites of disease, followed by durvalumab 1500 mg IV in combination with tremelimumab 75 mg IV every 4 weeks x 4 cycles, followed by durvalumab maintenance until progression. Eligible patients had 1-6 extracranial metastatic sites, allowing multiple metastases per location, with all lesions suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy. The primary endpoint was safety of this combination. Secondary endpoints include PFS and OS. Dose-limiting toxicities (DLTs) (any Grade ≥ 3 toxicity) were evaluated from the first administration of SBRT until 28 days post start of durvalumab and tremelimumab. Baseline tumor mutational burden, PD-L1 expression on post-SBRT biopsy and circulating tumor cells will be correlated with outcomes. In this first cohort analysis, we assess the safety and outcomes of the first 17 patients. Results: From 2/2018-2/2021, the first 17 pts were enrolled. Characteristics of those enrolled included: median age 68 years, female/male 4/13, squamous/non-squamous 2/15, median number of non-central nervous system (CNS) metastatic sites 2 (1-5), median number of non-CNS metastatic lesions 2 (1-9), CNS involvement 6/17 (35.3%), previous treatment 4/17 (23.5%). DLTs were seen in 2/17 (11.8%) patients; DLTs were autoimmune hepatitis and autoimmune pancreatitis. Most treatment-related adverse events (TRAEs) were grade (G) 1/2. TRAEs included: all TRAEs n = 188, 88.2% (of patients); G 3 n = 17, 29.4%; G 4 n = 1, 5.8%. There were no treatment-related deaths. Five patients discontinued treatment due to grade 3/4 immune related adverse events (IRAE). At a median follow up of 20 months 11/17 (64.7%) patients are alive with 10/17 (58.8%) with no evidence of disease (NED). Six of 17 (35.2%) patients experienced disease progression and 4/17 (23.5%) patients died of disease progression. Median PFS and OS are not yet reached. Conclusions: There were no unexpected safety signals in the cohort of patients enrolled. The incidence of grade ≥ 3 IRAEs is similar to the treatment of advanced NSCLC and no additional toxicity was observed with the addition of SBRT. Clinical outcomes look promising with median OS and PFS not yet reached at 20 months median follow up. The study continues to enroll a second cohort and results will be updated. Clinical trial information: NCT03275597.

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Open Label Non-Randomized Phase II Study Exploring «Chemo-Free » Treatment Association with Idelalisib + Obinutuzumab in Patients with Relapsed/Refractory (R/R) Waldenstrom's Macroglobulinemia (MW), a Filo Trial: Results of the Intermediary Analysis of the Induction Phase

Blood ◽

10.1182/blood-2019-122826 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 346-346 ◽

Cited By ~ 1

Author(s):

Cecile Tomowiak ◽

Kristell Desseaux ◽

Stéphanie Poulain ◽

Charles Herbaux ◽

Aurore Perrot ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Fixed Dose ◽

Induction Phase ◽

Efficacy And Safety ◽

Advisory Committees ◽

Grade 3

Background The treatment algorithm is still limited in WM as very few drugs were approved based on studies dedicated to WM patients. In 2015, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib became the first drug approved to treat WM (Treon et al, 2015). However, a subset of patients (pts) relapses due to acquired resistance. Therefore there is a great medical need to develop chemo-free approaches based on a better understanding of the biology of the disease to increase all survival endpoints. MYD88L265P also promotes activation of the phosphatidylinositol-3-kinase (PI3K) pathway Gopal et al. reported 80% ORR in 10 patients with WM, refractory to anti-CD20 and alkylating agents, treated with idelalisib (a PI3K inhibitor) (NEJM, 2014). A previous study was stopped because of high incidence of hepatotoxicity (Castillo, Leuk lymphoma, 2017). So we design our trial with a Bayesian analysis of adverse events. Aims We initiated a prospective, single-arm phase II study to evaluate efficacy and safety of idelalisib in combination with obinutuzumab in pts with R/R WM in need of treatment. (NCT02962401). Methods During the induction phase, idelalisib was given continuously 150 mg BID PO in association with IV obinutuzumab 100mg day 1, 900mg day 2 then 1000mg fixed dose day 8, 15 of cycle 1 and every day 1 of cycles 2 to 6 (28-days cycle). Then during the maintenance phase, idelalisib was given alone for a maximum of 2 years. Pts were closely monitored for infusion related reactions (IRR). Adverse events were graded per CTCAE v.4.0. Response was assessed based on IWWM6 criteria. The analyses of PFS, primary endpoint of this study, were based on the intent-to-treat population. The safety analysis was designed according to Bayesian estimation of the probability of grade 3 or more adverse events. Roche and Gilead provide drugs and funding. Results Fifty pts were enrolled between February 2017 and July 2018 but 49 pts were analyzed (1 screen failure). We present the results of early efficacy and safety, assessed after the induction phase. At time of analysis, median follow-up was 18.3 months (range 14.9-23 months). Median age was 71 years (range 50-83 years) and 36 pts (73%) were men. MYD88 mutation was present in 47 pts (96%). Indications to treat were anemia (31%), anemia + thombocytopenia (11%), constitutional symptoms (11%), rapid evolution of monoclonal component (11%), hyperviscosity syndrome (9%), thrombocytopenia (6%), extramedullary disease (8%) and neuropathy (6%) (data not available for 2 pts). Median number of previous lines of therapy was 1 (range 1-3), and only 1 patient was previously exposed to BTK inhibitors. At baseline, median serum IgM was 2.193 mg/dl (range 0.19-9.2), median bone marrow involvement was 55% (range 10-90, n=25) and median hemoglobin was 10 g/dl (range 6.5-13.8). Thirty-four pts responded, 13 after 3 cycles and 21 after 6 cycles. The overall response rate (ORR) was 90% and the major response rate (MRR) was 76% (no CR, VGPR: 8%, PR: 68%, MR: 14%, SD: 8%, and progression: 3%). The correlation between responses and genomic status using ultra deep next generation sequencing will be communicated later. Median PFS was 25.2 months. The1-year and 2-year PFS were 90% [IC95%: 80; 100] and 70% [IC95%: 53; 93] respectively. The1-year and 2-year OS were 98% [IC95%: 94; 100] and 85% [IC95%: 69; 100] respectively. Three pts died (1 before starting treatment, 1 from macrophage activation syndrome, 1 after stopping treatment). Median duration of response was 21.8 months. No flare, no IRR grade ≥ 2, no tumor lysis syndrome were observed. Thirty-five pts experienced at least one grade ≥ 3 adverse events (AE) or serious adverse events (SAE), with an estimated probability of 72.5% (95% credibility interval, 59.5-83.9) and a probability of 1 that more than 30% of pts experience at least 1 grade 3 AE. Events that occurred most frequently included hepatotoxicity (23 AE, 5 SAE, 20%), diarrhea (4 AE, 10 SAE; 10%), skin (3 AE, 3 SAE, 4%), infections (0 AE, 5 SAE, 4%), neutropenia (41 AE, 29%), anemia (7 AE, 5%), thrombopenia (6 AE, 4%). This trial is ongoing with 29 pts who started idelalisib maintenance. Conclusion This is the first study evaluating combination with idelalisib + obinutuzumab and the first chemo-free fixed-duration association in R/R WM pts. The combination has clinical activity with 90% ORR and 76% MRR. Median PFS was 25 months. Most of grade ≥ 3 AE or SAE are hepatotoxicity, diarrhea and neutropenia as expected with idelalisib. Figure Disclosures Tomowiak: Abbvie: Honoraria; Janssen: Honoraria. Perrot:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria; takeda: Honoraria; jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

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Efficacy and Safety of Low-Dose Decitabine in Low- or Intermediate 1-Risk MDS

Blood ◽

10.1182/blood-2018-99-118683 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4377-4377

Author(s):

Zhijian Cao ◽

Jun Ma

Keyword(s):

Adverse Events ◽

Median Time ◽

Low Dose ◽

Conflicts Of Interest ◽

Performance Status ◽

Median Number ◽

Neutropenic Fever ◽

Efficacy And Safety ◽

Ecog Performance Status ◽

Grade 3

Abstract OBJECTIVES: Decitabine has been approved in China for treatment with high-risk Myelodysplastic syndromes (MDS) patients (pts) in 2008. However data of decitabine on efficacy and safety of low-dose decitabine in low- or intermediate 1-risk MDS was absence. Herein,3 years datas in our centre of low- or intermediate 1-risk MDS treated with decitabine were analysed to evaluate the efficacy and safety in two subgroups. METHODS: Inclusion Criteria:Patients of age > 18; Patients with low-or intermediate 1-risk MDS. The IPSS is used to classify patients with MDS across disease subgroups. ECOG performance status ≤ 2. And normal hepatic,renal and cardiac function. Study Design: Decitabine 20mg/m2 intravenously (IV) over the course of one hour daily for 3 days. Courses were repeated every 28 days when possible. Dose reductions for grade 3 and 4 toxicities were allowed for decitabine (to 10 mg/m2 or 15 mg/m2). The primary endpoint was overall response rate (ORR). RESULTS: In total, 37 patients were enrolled and treated from September 2014 to October 2017 in our center. The median follow-up was 26 months (range, 4-49 months). The median time from diagnosis to therapy with decitabine was 3 weeks (range, 1-52 weeks). Their F/M ratio was 16/21 and the median age of the enrolled population was 58 years (range, 40-71 years). More than 70% of patients had 2 to 3 cytopenias, and 43% were transfusion dependent at enrollment. Most patients had intermediate 1-risk MDS by IPSS (n=29). Next-generation sequencing was performed in 35 patients (90%). The most frequently detected mutations included TET2 (n=15; 41%), SF3B1 (n=7; 19%), ASXL1 (n=5, 13%), RUNX1 (n= 5, 13%), and SRSF2 (n=3, 8%). The ORR after 2 cycles of decitabine was 65% (24/37),with 35% of patients (13/35) achieving a CR. Hematologic improvement was seen in 19%(7/37). The median time to best response was 3 months (range, 1-12 months). The median number of cycles received was 5 (range, 1-13 cycles). 19% of patients (7/37) became transfusion independent. The EFS and OS were 68% and 78% respectively in 1 year. The treatment was well-tolerated, with most adverse events being of grade 1 to 2, Nausea (24%), Fatigue (14%), Infection/Neutropenic fever (19%), Constipation (6%), Diarrhea (6%). Grade 3 and higher nonhematologic adverse events were rare. Grade 3 adverse events were Infection/Neutropenic fever (6%), but rare, and no grade 4 adverse events were observed. CONCLUSIONS: These data confirm that decitabine is a feasible and effective agent for low- or intermediate 1-risk MDS pts, and its need longer time to response (more than 2 cycles). Safety profile was acceptable and the most adverse events were Nausea, Fatigue, and Infection/Neutropenic fever. Disclosures No relevant conflicts of interest to declare.

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Low-Dose Nivolumab Plus Brentuximab Vedotin As a Bridge to Stem Cell Transplantation in Relapsed/Refractory Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood-2021-153267 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4534-4534

Author(s):

Perla R. R. Colunga-Pedraza ◽

Edgar Ulises Coronado-Alejandro ◽

Fernando De La Garza ◽

Eliezer Tomas Gomez Gomez ◽

Andres Gomez-De Leon ◽

...

Keyword(s):

Adverse Events ◽

Hodgkin Lymphoma ◽

Low Dose ◽

Progression Free Survival ◽

Brentuximab Vedotin ◽

New Drugs ◽

Fixed Dose ◽

Classical Hodgkin Lymphoma ◽

Median Dose ◽

Low Middle Income Countries

Abstract Background: Up to one-third of patients with Hodgkin lymphoma (HL) are not responsive to first-line therapy or eventually relapse. New drugs, including anti-PDL1 (i.e., nivolumab) and monoclonal antibodies (i.e., brentuximab vedotin (BV)), have changed the landscape in the treatment of HL. However, the financial toxicity associated with these new drugs is worrisome and are practically inaccessible to most patients living in low-middle income countries. The approved dose of nivolumab in refractory classical Hodgkin Lymphoma (HL) is 3 mg/kg, but lower doses have demonstrated efficacy. Objective: To assess the efficacy of low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg in combination with BV 1.8 mg/kg every three weeks in patients with relapsed or refractory (R/R) HL. Methods: We conducted a retrospective analysis of adults with R/R HL who received BV at 1.8 mg/kg and low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg IV every three weeks. Patients were routinely offered the highest dose possible that could be afforded for at least 4 cycles, as treatment costs were covered out of pocket. We calculated treatment responses, and overall survival (OS), and progression-free survival (PFS) with the Kaplan-Meier method. Results: A total of 10 patients (50% male, median of age 26.5 years (15-50)) with R/R HL were included; n=7 relapsed and n=3 refractory patients. Median follow-up was 11.5 months (range, 5-18) (antes o después del BV/nivo?). The median previous lines of treatment were three (range, 1-4) and regimens were ESHAP (2, 20%), IGEV (3, 30%)), CGEV (1, 10%), ICE (3, 30%), and allogenic transplantation (1, 10%). Six patients (60%) had received radiotherapy (median dose: 21.5 Gy, range: 20-25). Five patients (50%) received 40 mg of nivolumab, n=3 100 mg (30%) and n=2 140mg (20%). The median dose per cycle was 0.93 mg/kg (range, 0.48-1.9 mg/kg). After a median of 4 (range, 4-8) cycles of low-dose nivolumab + BV the overall response rate was 80% (n=8); five obtained a complete response (CR) (50%) and n=3 a partial response (30%) . One patient (10%) had stable disease, and the other progressed (10%). Grade 1 or 2 adverse events occurred in n=6 patients (60%), including neuropathy (n=2), grade 1 leucopenia (n=3), fever (n=1), and myalgia (n=1). No grade III or IV adverse events were reported. One-year OS and PFS was 83.3%. Transplant consolidation was conducted in six cases (60%) (three autologous and three haploidentical), three are awaiting transplantation and one relapsed after achieving CR before transplant conditioning. One patient died on day +21 after haploidentical transplantation in the context of progressive disease. Conclusion: A short course of low-dose nivolumab and BV showed remarkable efficacy, achieving response in most patients with minimal toxicity and allowed patients with R/R HL who could not afford standard doses to undergo transplantation. The real-world safety and efficacy of low-dose nivolumab and BV should be further addressed in more extensive prospective studies. Figure 1 Figure 1. Disclosures Gomez-De Leon: ASH: Research Funding; Sanofi: Honoraria; Novartis: Honoraria; Abbvie: Honoraria. Gomez-Almaguer: Janssen: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau.

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Brentuximab Vedotin Plus ESHAP (BRESHAP) Is a Highly Effective Combination for Inducing Remission in Refractory and Relapsed Hodgkin Lymphoma Patients Prior to Autologous Stem Cell Transplant: A Trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)

Blood ◽

10.1182/blood.v128.22.1109.1109 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1109-1109 ◽

Cited By ~ 16

Author(s):

Ramon Garcia-Sanz ◽

Anna Sureda ◽

Ana Pilar Gonzalez ◽

Fatima De la Cruz ◽

Blanca Sanchez-Gonzalez ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Hodgkin Lymphoma ◽

Abdominal Sepsis ◽

Brentuximab Vedotin ◽

High Dose ◽

Line Therapy ◽

Grade 3 ◽

One Year

Abstract Introduction: 30% of Hodgkin Lymphoma (HL) patients are refractory or relapse (RR) after first line therapy. Salvage chemotherapy followed by high-dose chemotherapy and with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) can cure many patients, but those who are transplanted with active disease detectable by PET-CT have a very poor prognosis. Therefore, the current challenge in HL is to improve the results of the pre-transplant chemotherapy. We and others have demonstrated that the addition of Brentuximab Vedotin (BV) to chemotherapy can produce very good results. Objectives: We conducted a phase II trial to assess response rate with combined Brentuximab vedotin and ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436). Methods: Primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. A prior phase I step was carried out to establish the appropriate dosis. Final treatment consisted of Brentuximab Vedotin (1.8 mg/m2/day IV, D1), Etoposide (40 mg/m2/day IV, D1-4), Solumedrol (250 mg/day IV, D1-4), High dose AraC (2 g/m2 IV, D5) and cisPlatin (25 mg/m2/day IV, D1-4). Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. 66 patients were included in the trial. There were 35 females and 31 males, with a median age of 36 years (18-66). At inclusion, 40 patients were considered primary refractory, 16 as early relapses (complete remission -CR- shorter than 1 year) and 10 as late relapses. Currently, all patients have completed the pre-transplant therapy. During that period, there were 22 Severe Adverse Events (SAEs) reported in 15 patients: Fever in 13 occasions (neutropenic in seven, and non-neutropenic in six), hypomagnesemia and gastrointestinal alterations (n=2) and pneumothorax, skin lesions, left ventricular function reduction and pulmonary embolism [PE](n=1). There were 2 deaths: non-neutropenic abdominal sepsis and PE. Grade 3-4 hematologic toxicity presented in 22 cases: neutropenia (n=18), thrombocytopenia (n=12), and anemia (n=5). Grade 3-4 extrahematologic adverse events present in ≥5% of cases were non-neutropenic fever (n=8) and hypomagnesemia (n=3). All patients except three underwent stem cell mobilization after the 1st (n=15), 2nd (n=36) or 3rd (n=12) cycle using subcutaneous G-CSF 5 mcg/Kg/12 h. for 5 days. All patients collected >2·10e6/Kg peripheral blood CD34+ cells in all cases (median 5.75, range 2.12-33.4). The number of harvesting procedures was one in 47 patients, two in 13, three in 2 and four in 1. The transplant has been done in 61 patients, with data are available from 47: all engrafted with a median of 9&10 days for neutrophil and platelet recovery, respectively. No major events were registered during transplant period, except for one patient who died at day +110 due to pneumonia. Overall pre-transplant response was 96%, including a 70% and 26% complete and partial remission rates, respectively. Of these forty-seven patients, 37 (80%) were in metabolic CR after transplant and 3 (7%) in PR; six patients were considered as non-responders (13%) and went out of the trial. At a mean follow-up of 11 months, 7 patients have progressed, rendering a projected progression free survival of 87% at one year. Six patients have already died: three due to progression, and the three already mentioned above (PE, abdominal sepsis and pneumonia). With a mean follow-up of 11 months, the projected overall survival was 90% at one year (cause specific, 96%). Conclusions: BRESHAP is a highly effective regimen for remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma. The addition of BV to the conventional chemotherapy did not resulted in a higher toxicity for the pre- and post-transplant periods and it did not hamper the collection of PBSC. Disclosures No relevant conflicts of interest to declare.

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Safety of switching between rituximab biosimilars in onco-hematology

Scientific Reports ◽

10.1038/s41598-021-85563-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Silvana A. M. Urru ◽

Stefania Spila Alegiani ◽

Anna Guella ◽

Giuseppe Traversa ◽

Annalisa Campomori

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Adverse Events ◽

Prospective Observational Study ◽

Randomized Trials ◽

Lymphocytic Leukemia ◽

Safety Signal ◽

Efficacy And Safety ◽

Clinical Safety ◽

Study Population ◽

Grade 3

AbstractComparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin’s Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3–4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.

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