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

Blood ◽  
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.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Liudmila Fedorova ◽  
Kirill Lepik ◽  
Polina Kotselyabina ◽  
Elena Kondakova ◽  
Yuri Zalyalov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Median Number ◽  
Fixed Dose ◽  
Published Data ◽  
High Dose ◽  
Efficacy And Safety ◽  
Classical Hodgkin Lymphoma ◽  
Grade 3

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.

Brentuximab Vedotin in Combination with Donor Lymphocyte Infusion for Patients with Hodgkin Lymphoma Relapsing after Allogeneic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4361-4361
Author(s):  
Panagiotis Tsirigotis ◽  
Ronit Yerushalmi ◽  
Kostantinos Gkirkas ◽  
Noga Shentov ◽  
Ivetta Danylesko ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Allogeneic Stem Cell Transplantation ◽  
Low Dose ◽  
Brentuximab Vedotin ◽  
Donor Lymphocyte Infusion ◽  
Efficacy And Safety

Abstract Introduction Brentuximab Vedotin (BV) has recently received approval for treatment of Hodgkin lymphoma (HL) relapse after auto-SCT. Although BV is very effective in treating relapse of HL post auto-SCT, response is usually transient. In contrast, there is a paucity of data regarding the efficacy and safety of BV, combined or not with donor lymphocyte infusion (DLI), for the treatment of relapse occurring after allo-SCT. Methods Search for patients (pts) with relapsed HL post allo-SCT was performed in our transplant data set with the aim to evaluate the efficacy and safety of BV in combination with DLI for the treatment of relapsing HL post allo-SCT. Eight pts with relapsed HL after allo-SCT that were treated with BV were included in this report. Results Patients and treatment: There were 6 males and 2 females, with a median age of 31 years (range, 23 - 40), who had previously failed an auto-SCT. Five pts had previously received BV after auto-SCT and all but one responded to treatment. All pts had chemosensitive disease before allo-SCT and were transplanted in a state of partial remission (PR). The graft source was unmanipulated peripheral blood stem cells from a matched related or an unrelated donor in 5 and 2 pts, respectively, while 1 pt received a double umbilical cord blood graft (DUCB). Five pts achieved complete remission (CR) and one PR after allo-SCT, while 2 pts had progressive disease (PD). Disease progression occurred in a median of 11 months (range, 4 - 17) after allo-SCT. All pts received BV at a dose of 1.8mg/kg every 3 weeks for a maximum of 16 doses, till disease progression or toxicity. In two pts chemotherapy was administered before BV. A median of 4.5 (range, 3 -12) BV cycles was administered. DLI was co-administered in 5 out of 7 pts (excluding one patient who received DUCB). Decision for DLI was at the discretion of the treating physician. One pt received 4 DLIs at escalating doses (5x106, 107, 5x107, 108/kg), while another one received 2 escalating DLIs (107, 108/kg) at 3 months interval. Three pts received a single DLI (107/kg). Treatment outcome: Three and two pts achieved CR and PR respectively after treatment with BV in combination with DLI. None of the pts treated only with BV responded. Four out of 5 pts developed GVHD (3 chronic, 1 acute) post DLI administration, that resolved in all cases after a short course of low dose steroids. Disease progression was observed in 3 out of 5 responders in 4, 7 and 9 months, while 2 pts remain progression free with a median follow up of 14,5 (range, 4 - 22) months. Six out of 8 pts are alive, while 2 pts died from HL. BV/DLI treatment was well tolerated and no serious adverse effects were observed in any of the patients. Conclusions In our study, we observed that administration of BV with DLI for HL relapsing post allo-SCT in pts with prior failure to auto-SCT was effective while toxicity was minimal. Notably, re-administration of BV to pts previously treated for post auto-SCT relapse did not result in additional toxicity or resistance. Furthermore, BV combined with DLI, but not BV alone, yielded anti-tumor response in 5/7 of these very high risk pts suggesting a possible synergistic effect. Of notice is the observation that one pt who was refractory to BV post auto-SCT, had a PR after re-administration of BV post allo-SCT. Our observations are in accordance with the results of a previous report, showing that BV plus DLI after allo-SCT creates a vaccination like-effect against HL [1]. Finally, in our study we observed lower than expected frequency of GVHD post DLI that was of transient duration and easily manageable with low dose steroids. We assume that this may be due to an immune-modulating effect produced by BV. Indeed previous studies have shown that CD30 is expressed on the surface of activated T-cells present in inflammatory infiltrates of GVHD lesions [2]. Administration of BV plus DLI should be tested in larger group of patients at high risk of relapse after allo-SCT. References Theurich S, Malcher J, Wennhold K, et al. Brentuximab Vedotin Combined With Donor Lymphocyte Infusions for Early Relapse of Hodgkin Lymphoma After Allogeneic Stem-Cell Transplantation Induces Tumor-Specific Immunity and Sustained Clinical Remission. J Clin Oncol. 2013; 31: 59-63. Chen Y, McDonough S, Hasserjian R, et al. Expression of CD30 in patients with acute graft-versus-host disease. Blood. 2012; 120: 691-696. Disclosures Tsirigotis: CELLTRION, Inc.: Research Funding.

A Phase 1 Study of Total Marrow Irradiation Combined with High-Dose Melphalan for Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4646-4646
Author(s):  
Pritesh R. Patel ◽  
Annie L. Oh ◽  
Matthew Koshy ◽  
Bulent Aydogan ◽  
Karen Sweiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Significant Difference ◽  
Total Marrow Irradiation ◽  
High Dose Melphalan

Abstract High dose melphalan at 200mg/m2(Mel200) followed by autologous stem cell transplant (ASCT) prolongs the survival of patients with multiple myeloma (MM) although it does not prevent relapse. Enhancing the anti-myeloma effect of pre-transplant conditioning without increasing toxicity is an important goal. To this purpose, intensity modulated radiation therapy (IMRT) can be used to deliver radiation to the marrow (total marrow irradiation, TMI) while sparing other organs. Here we tested the safety of combining linear accelerator based TMI to Mel200 in a phase 1, 3+3 trial. Twelve patients with MM who relapsed after at least one line of therapy were enrolled in 3 dose cohorts (3Gy, 6Gy and 9Gy). Prior ASCT was permitted. All patients received Mel200 over 2 days. In addition, 1.5Gy TMI was administered twice daily for 1, 2 or 3 days depending on dose cohort. Dose-limiting toxicity was defined as the occurrence of any NCI-CTCAE grade 4/5 non-hematologic toxicity or failure to engraft prior to day 30 after ASCT. Quality of life (QoL) was assessed using the FACT-BMT scale at baseline and 90-100 days after ASCT. Three groups of patients were enrolled and received 3Gy (n=3), 6Gy (n=3) or 9Gy (n=6). Median age at time of transplant was 66 years (range 40-71). Three patients had high risk FISH/ karyotype as defined by IMWG criteria. Median lines of prior therapy was 2 (range 1-4). Five patients (42%) had undergone prior autologous transplant. Of eleven patients (92%) who received prior lenalidomide, 7 (58%) were considered lenalidomide refractory. Similarly, of 11 (92%) patients previously treated with bortezomib, 6 (50%) were considered refractory. Eleven patients had a pre-transplant PET scan performed with 8 (73%) having skeletal PET avidity. All patients received TMI as scheduled. The mean reduction in dose to organs at risk (lens, oral cavity, kidneys, liver, bowels, lung) ranged from 25-63%. Median time to neutrophil (greater than 0.5x109/L) and platelet (greater than 20x109/L) engraftment were 10 (range 9-15) and 13 (range 9-17) days respectively. There were no dose limiting toxicities. Five patients experienced a total of 7 NCI CTCAE grade 3 toxicities including: diarrhea, n=2; mucositis, n=3; and nausea, n=2. Four of 6 patients who received 9Gy did not experience any toxicity greater than grade 2. Using the FACT-BMT scale, we observed that there was no significant difference in QoL between baseline and day 90 assessments. At day 100 overall response rate was 82% with 5 patients (45%) achieving a complete response. Four of 6 patients in the 9Gy cohort achieved at least a very good partial response. With a median follow up of 314 days, all patients were alive and only 4 patients (33%) relapsed. In this phase 1 trial we showed that TMI at 9Gy can be safely added to Mel200 without an increase in transplant related toxicities. Initial promising clinical results, even in high risk MM patients, will be further tested in a phase 2 study. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anti-CD25 Radioimmunotherapy with BEAM Autologous Hematopoietic Cell Transplantation Conditioning in Hodgkin Lymphoma

2021 ◽  
Author(s):  
Alex F. Herrera ◽  
Joycelynne M. Palmer, PhD ◽  
Vikram Adhikarla ◽  
Dave M. Yamauchi ◽  
Erasmus Kofi Poku ◽  
...  
Keyword(s):  
High Risk ◽  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Brentuximab Vedotin ◽  
Hematopoietic Cell ◽  
Phase 2 ◽  
Autologous Hematopoietic Cell Transplantation

High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL and we hypothesized that the addition of 90Y-antiCD25 (aTac) to BEAM AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled onto this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution and a third developed an unrelated catheter-associated bacteremia; therefore 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed and 0.6mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive > 2500cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with 3 or more risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL and we are further evaluating the efficacy of this approach in a phase 2 trial. The clinical trial was registered at clinicaltrials.gov (NCT01476839).

Excellent Outcome for Pediatric Patients with High Risk Hodgkin Lymphoma with Brentuximab Vedotin and Risk Adapted Residual Node Radiation

2020 ◽  
Author(s):  
Monika Metzger ◽  
Michael P. Link ◽  
Amy L. Billett ◽  
Jamie Flerlage ◽  
John T. Lucas Jr. ◽  
...  
Keyword(s):  
High Risk ◽  
Hodgkin Lymphoma ◽  
Pediatric Patients ◽  
Brentuximab Vedotin ◽  
Excellent Outcome

scholarly journals Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes

2016 ◽  
Vol 27 (7) ◽  
pp. 1317-1323 ◽  
Author(s):  
C.Y. Cheah ◽  
D. Chihara ◽  
S. Horowitz ◽  
A. Sevin ◽  
Y. Oki ◽  
...  
Keyword(s):  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Brentuximab Vedotin ◽  
Classical Hodgkin Lymphoma ◽  
Poor Outcomes

scholarly journals Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5631-5631 ◽  
Author(s):  
Cassidy Brothers
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Severe Neutropenia ◽  
High Dose ◽  
Cell Transplant ◽  
Curative Intent ◽  
Hematopoietic Stem

Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.

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