Relapsed/refractory Hodgkin Lymphoma Research Articles

The Combination of Nivolumab and CC-486 Is Active in Hodgkin Lymphoma Refractory to PD-1 Blockade

Introduction: PD1 blockade is highly active in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL); however, most patients ultimately progress on therapy, and HL that is refractory to PD1 blockade remains an unmet need. Furthermore, as PD-1 directed therapies are being administered in earlier lines, it is anticipated that pts with RR HL will be increasingly refractory to PD-1 directed therapies. Hypomethylating agents (HMA) have been shown to increase T-cell infiltration and upregulate PD-1 and CTLA-4 expression in tumors, as well as suppress myeloid-derived suppressor cells. We hypothesized that HMA might restore the sentivity of HL to PD-1 directed therapies. Therefore, we conducted a phase I study evaluating the safety and efficacy of nivolumab and CC-486, an oral HMA, in pts with RR HL refractory to PD-1 blockade. Methods:Adult pts with RR HL who had progressed after at least 1 prior line of therapy and were refractory to PD-1 therapy were enrolled to receive oral CC-486 and nivolumab IV in 28-day cycles. PD-1 refractoriness was defined as progressive disease (PD) as best response, or PD while receiving or within 12 weeks of the last anti-PD-1 directed therapy. Pts were treated in a dose-finding cohort at 2 dose levels (DL) using a Rolling 6 design and then in a dose expansion cohort at the recommended phase 2 dose (RP2D). In DL1, CC-486 was administered at 200 mg PO daily on days 1-7, and in DL2 CC-486 was dosed at 300 mg PO daily on days 1-7; nivolumab 480 mg IV was given on day 8 in both DLs. Treatment could be continued for up to 2 years. Primary endpoints were determination of the RP2D and overall response rate (ORR) defined as the proportion of patients with a complete response (CR) or partial response (PR). Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification. Results: As of July 7, 2023, 21 pts have been enrolled including 3 at DL1 and 18 at DL2 (RP2D). At baseline, 57% were male with a median age of 40 years (range 25-71), 95% had stage III-IV disease, and 71% had primary refractory disease, defined as lack of a complete remission (CR) or relapse within 3 months of frontline treatment. The median number of prior therapies was 6 (range 2-14), and 90% had prior brentuximab vedotin (BV). 76% of pts had received pembrolizumab, 67% had received nivolumab, and 43% had received both agents previously. 52% had undergone autologous stem cell transplant and 5% had had prior allogeneic stem cell transplant. Baseline characteristics are shown in Table 1. The median number of cycles was 7 (range: 3-17). Among 19 pts evaluable for response (2 pending), ORR was 63% and CR rate was 10%. An additional 32% had SD as their best response; only one pt had PD as the best response. The median follow-up time was 9 months (range 2.8-16.3), and 71% of pts remain on treatment with an estimated median PFS of 11.3 months (95% CI: 7.1-N/A). 6 pts stopped therapy, including 4 for disease progression, 1 at treating physician's discretion and 1 due to patient preference. The most common adverse events (AEs), any grade (Gr), were nausea (86%), diarrhea (71%), vomiting (48%), headache (33%), fatigue (29%), neutropenia (19%), and anemia (19%). Only two Gr 3+ AEs were recorded: one patient experienced Gr 3 anemia and another Gr 4 hypercalcemia. Notably, the hypercalcemia fully resolved with supportive care and did not recur with subsequent cycles. The only immune-related AE was grade 1 hypophysitis in a single pt. Conclusions: Nivolumab combined with CC-486 is tolerable and elicits a high response rate in a PD-1 refractory cohort. At this time, the study has been amended to enroll 10 more patients at DL2 to provide a better estimation of the efficacy.

Effectiveness and Tolerability of ICE Combinations in Relapsed/Refractory Hodgkin's Lymphoma; A Systematic Review of Clinical Trials

Background: Hodgkin's Lymphoma (HL), especially classic (cHL) subtype has a favorable prognosis and frontline therapy in almost 70-80% reach a durable complete remission. However, 10-30 % of patients relapse after achieving response, and an additional almost 14-15% will never achieve complete remission and will have refractory disease. Both groups need a second line chemotherapy regimen and possible transplantation. Among 2 nd line chemotherapy regimens, a combination of ifosfamide (I), carboplatin (C), and etoposide (E) is preferred. The aim of this systematic review is to study the efficacy and safety of combinations of ICE with other drugs in relapsed/refractory (RR) HL patients. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Embase, and Clinicaltrials.gov with mesh terms, “Hodgkin Lymphoma” and “ICE” from the inception of data till 07/06/2023. We screened 1412 articles and included 2 phase II randomized clinical trials (N=43) and 4 nonrandomized clinical trials (N=109), measuring the efficacy and safety of combinations of ICE in RR HL. Data was extracted for overall response rate (ORR), complete response (CR), partial response (PR), overall survival (OS) and progression free survival (PFS). Results: In the included clinical trials (N=152), ICE was combined with Immune check point inhibitors (ICIs) in two clinical trials on Pembrolizumab (PEM) and Nivolumab (N) (N=46). Panobinostat (PAN) was combined with ICE in phase I and phase I/II trials (N=32). Bortezomib (B) (N=10) and Brentuximab Vedotin (BV) (N=42) were studied in randomized phase II and phase I in combination with ICE, respectively. In 2 clinical trials (N=46) on combinations of ICE with ICIs, ORR, CR, and PR was 97-100%, 86-89%, and 11%. Grade≥3 hematological toxicity was 52% and 22% in PEM-ICE and NICE, respectively. The 2-year PFS and OS were 72% (95% CI: 56-83) and 95% (95% CI: 82-99), respectively in NICE study. BV-ICE showed ORR, CR, and PR of 76%, 60% and 16%, respectively with a 3-year OS and PFS of 100% and 64%, respectively. Combined grade ≥3 adverse events were 83.3%. PAN-ICE showed ORR, CR, and PR of 82-86%, 71-82%, 15% in phase I and II clinical trials but at the cost of greater myelosuppression depicted by thrombocytopenia's in 80-100% of patients. On the other hand, ICE alone showed ORR, CR, and PR of 75%, 67%, and 8%, respectively without causing significant myelosuppression. BICE showed ORR, CR, and PR of 70%, 30%, and 40%, respectively in comparison to ICE ORR, CR, and PR of 60%, 10% and 50%, respectively. BICE group showed the OS and PFS of 70% and 30%, respectively in comparison to 89% and 60%, respectively in ICE alone at 24 months. Grade≥3 adverse effects were also higher i.e., 37% in the BICE group in comparison to 28% in ICE alone. Table.1 Conclusion: Concurrent treatment with ICE and ICIs was well tolerated and was associated with improved effectiveness. BV-ICE achieved a greater CR regardless of frontline treatment and toxicity was manageable. PAN-ICE combination also produced high CR rate but at the cost of greater bone marrow toxicity. Investigation of PAN with less myelosuppressive agent can be considered for future trials. Due to the lack of significant improvement in outcomes of BICE as compared to ICE, this trial was stopped. More randomized double-blind large-scale phase III studies for further evaluation are needed.

Real-World Treatment Patterns and Patient Outcomes in Relapsed/Refractory Hodgkin Lymphoma in the US

Introduction Brentuximab vedotin (BV), a CD30-directed monoclonal antibody, and programmed cell death-1 inhibitors (PD-1; e.g., nivolumab, pembrolizumab) are efficacious for the treatment of adult patients with Hodgkin lymphoma (HL) at high risk of relapse or progression post-autologous stem cell transplantation (ASCT). In this study, we investigated the real-world treatment patterns and outcomes of patients with relapsed/refractory HL (RRHL) who had received ≥1 line of therapy (LOT). Methods Patients ≥18 years old with evidence of RRHL in ≥1 inpatient or ≥2 outpatient physician medical notes or evidence of ≥1 autologous/allogeneic hematopoietic stem cell transplant (HSCT) procedure following evidence of HL in the Humedica Electronic Medical Record (EMR) database, were selected between October 1, 2016 and September 30, 2020. The earliest evidence of RRHL (medical note or HSCT procedure) was defined as the patient's index date. Patients were excluded if they had evidence of RRHL, non-Hodgkin's disease, other primary cancers, or metastatic disease in the 12 months prior to the index date (baseline period). Patient demographic and clinical characteristics were evaluated during the baseline period and the index date. Patients were followed from their index date until patient death or the end of recorded healthcare activity during which treatment patterns and outcomes were assessed. Results A total of 342 patients with ≥1 LOT post-RRHL during the follow-up period were included in the final study population. Mean age was 44.2 years, 56.7% were male, 75.7% were white, and 61.4% had commercial insurance; mean Charlson Comorbidity Index score was 3.2 (Table 1). Approximately one-third (34.5%) of patients were not eligible for HSCT based on available laboratory data and comorbidity diagnoses during the baseline period or the index date. Across the study population, the average follow-up duration was 25.6 months (median: 23.9 months). Among the overall study population, 90 (26.3%) patients received BV treatment, with most (~86%) receiving BV in LOTs 1 and 2 post-RRHL evidence (Table 2). The average time from index date to initiation of BV treatment was 2.5 months and mean duration of treatment (DOT) with BV was 4.3 months. Most patients treated with BV (n=68) had not received a HSCT. During the follow-up, among those who received BV but not a PD-1 (n=57), the progression-free survival (PFS) rate was 73.7% and overall survival (OS) was 82.5%. Among the overall study population, 56 (16.4%) patients received a PD-1, with most patients (~68%) receiving a PD-1 in LOTs 1 and 2 post-RRHL evidence. The average time from index date to initiation of PD-1 treatment was 5.5 months and mean DOT with a PD-1 was 5.3 months. Among those patients who received a PD-1 but not BV (n=23), the PFS rate was 56.5% and OS was 69.6%. One patient received post-HSCT BV+PD-1 combination maintenance therapy. Among the patients who received BV and/or a PD-1 prior- or post-HSCT, 12 (52.2%) received BV prior to the HSCT and 9 (39.1%) received BV after the HSCT. Among those who received BV and PD-1 treatments (i.e., not at the same time; n=33), the PFS rate was 60.6% and OS was 90.9%. Among the study population, a majority of patients (n=232; 67.8%) did not receive a HSCT during the follow-up period (including the index date). Of these patients without a HSCT, 68 (29.3%) received BV, 46 (19.8%) received a PD-1, and 25 (10.8%) received both BV and a PD-1 (i.e., not at the same time). Conclusions In this real-world evaluation of the treatment patterns and outcomes among patients in post-RRHL evidence setting, BV was administered more frequently in patients without HSCT. Increasing the use of BV in patients with ASCT at high risk for relapse or progression may lead to improved clinical outcomes. This study was based on EMRs from a single administrative database and has a limited sample size; these findings may not apply to all patient populations in post-RRHL evidence setting in the US.

Real Life Analysis of Brentuximab Vedotin (BV) Use As Consolidation Therapy in Patients with Hodgkin's Lymphoma (HL) with High Risk of Relapse after Autologous Stem Cell Transplantation (ASCT). a Retrospective Analysis of the EBMT Lymphoma Working Party

Introduction: The gold standard treatment for patients (pts) with classical HL who fail first-line treatment is ASCT. However, a significant number of pts with high-risk relapsed/refractory (RR) HL will relapse after transplant. Most patients who relapse do so within the first 1-3-years following ASCT, providing a rationale for post-transplant consolidation strategies to mitigate relapse risk. The AETHERA trial demonstrated that post-ASCT consolidation with brentuximab vedotin (BV) in high-risk HL pts improved progression-free survival (PFS) compared to placebo. Three previous studies have reported real-life results of BV consolidation with similar results. Here, we present the largest series so far. Methods: Information of pts older than 18y with HL who received BV as consolidation after first ASCT between May 2016 and January 2021 was downloaded from the EBMT database. The decision to use BV consolidation was made by the attending physician on an individual basis. Patients who received BV for disease relapse after ASCT were excluded from the study. The primary endpoint was 2 year PFS from ASCT. Results: 309 pts (female 48%/male 52%) with HL were identified meeting the inclusion criteria. Median age at ASCT was 31y (18-70). The median number of therapy lines before ASCT was 2 (1-6), and 43% pts required >1 salvage treatment to achieve disease response. At the time of ASCT, 200 (66%) pts were in complete remission (CR), 81 (27%) in partial remission (PR), and 21 (7%) had refractory disease. Most pts (73%) received BEAM as conditioning regimen. Median time from ASCT to BV initiation was 2.2 months (0.1-16.7). A total of 55 (19%) pts relapsed after a median time of 8 months after BV initiation, and 24 of them were treated with an allogeneic transplantation. After a median follow-up of 20 months, 2 and 5-year PFS were 73.2% (95% CI 67.3-79.6) and 70.3% (95% CI 63.9-77.4) (Figure 1), and overall survival 95.1% (95% CI 92.1-98.2) and 91.3% (95% CI 86.7-96.1), respectively. The prognostic was excellent and significantly better for pts in CR at transplant than for those in PR or with progression disease (2-y PFS 83.5% [95%CI 77.3-90.2] vs. 57.2% [95% CI 45.6-71.8] and 63.6% [95% CI 45.3-89.5], respectively, p=0.001). No differences in OS were observed according to the disease status at ASCT. In comparison to AETHERA trial, the proportion of pts requiring >1 salvage therapy lines before transplant was similar (43% in both studies); however, in contrast to that trial, pts treated with >1 salvage therapy line had similar PFS than those treated with only one line (69.6% [95%CI 60.4-80.2] vs. 75.8% [95%CI 68.5-84.0], respectively, p=0.2). In our study, the number of pts with chemosensitive disease at ASCT was higher than in the AETHERA (93% vs. 72% CR + PR, and 66% vs. 37% CR). This fact could justify that the PFS observed in this real-life series was higher than this of the AETHERA trial (70.3% vs. 59%) and more similar to that reported in other real-life series. Conclusions: This EBMT-registry study confirms the improved PFS of RR HL pts who underwent ASCT followed by BV consolidation compared to historical cohorts. The proportion of patients receiving ASCT in CR is higher than published in the AETHERA trial, which would suggest that more effective pre-transplant salvage schemes, possibly including BV, have been used. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Treatment of Hodgkin lymphoma relapse after autologous hematopoietic cell transplantation

Despite the high response rate to first-line treatment, approximately 10% of patients with Hodgkin lymphoma (HL) develop primary resistance to chemotherapy, and 10–30% of patients experience relapse. Today, salvage chemotherapy with subsequent autologous stem cell transplantation (ASCT) remains the standard of care for those patients with relapsed/refractory HL (RRHL). Treating patients with HL who relapse following ASCT continues to be a difficult clinical challenge. For many years, allogeneic hematopoietic stem cell transplantation was the only therapeutic option in this patient population. The last decade has brought new treatment options for RRHL patients with immunotherapy, including: brentuximab vedotin anti-CD30 monoclonal antibody, or the checkpoint inhibitors nivolumab and pembrolizumab, or advanced immune therapies such as bispecific antibodies, or chimeric antigen receptor T-cell therapy.

PET-Adapted Nivolumab or Nivolumab Plus ICE As First Salvage Therapy in Relapsed or Refractory Hodgkin Lymphoma

PET-Adapted Nivolumab or Nivolumab Plus ICE As First Salvage Therapy in Relapsed or Refractory Hodgkin Lymphoma

Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodgkin lymphoma patients (long-term results of a trial by the Spanish GELTAMO Group)

BackgroundIn this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as second-line therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before autologous stem-cell transplantation (ASCT). Patients and methodsThis was a multicenter, open-label, phase I–II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day ‒1 to 3 + 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT. ResultsA total of 66 patients were recruited (median age 36 years; range 18–66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n = 25, 35% neutropenic), including 3 deaths. Grade 3–4 hematological toxicity presented in 28 cases: neutropenia (n = 21), thrombocytopenia (n = 14), and anemia (n = 7). Grade ≥3–4 extrahematological adverse events (≥5%) were non-neutropenic fever (n = 13) and hypomagnesaemia (n = 3). Sixty-four patients underwent stem-cell mobilization; all collected >2×10e6/kg CD34+ cells (median 5.75; range 2.12–33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%). ConclusionBRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.

BEAM Versus Single Agent High Dose Melphalan (HDM) Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplant (ASCT): A Retrospective Matched Analysis in Relapse/Refractory Hodgkin Lymphoma

Background The ideal conditioning regimen still remains a challenge in the autologous stem cell transplantation (ASCT) setting for relapsed/refractory Hodgkin Lymphoma (RR-HL). BEAM is the most popular preparative regimen but single agent high dose Melphalan (HDM) has also been used. However, the experience and data comparing BEAM vs. HDM are limited. Methods After the Institutional Review Board approval, we retrospectively evaluated the clinical course of 112 RR-HL patients, autografted from November 2008 till May 2017 in two different institutions. Twenty eight conditioned with HDM and compared in a matched paired analysis (1:3) with a cohort of 84 patients who received BEAM. The study groups had similar median age (30ys) and sex (M:F 1.7:1 vs. 1.8:1) and were matched for disease status before salvage (late relapse: 36 vs. 12, early relapse/primary refractory: 48 vs. 16 and disease status pre ASCT [complete remission (CR): 39 vs. 13 and partial remission (PR): 45 vs. 15]. BEAM regimen was given in the standard doses over 6 days, while HDM (200mg/m2) was given in a single day infusion. All patients received prophylaxis against microbial, fungal and viral infections; GCSF was routinely administered at the dose of 5mcg/kg at +1 day (BEAM group) and at +5 day (HDM group). The T-test and Kaplan-Meier method were used for the statistical analyses. Results The engraftment was successful; the median day for neutrophils >1000/mm3 was +11 for both groups while for platelets >20000/mm3 a faster recovery was noticed for HDM group: +13 vs. +22 days (p The 100 days non relapse mortality was acceptable for both groups: 2/84 (2.3%) in the BEAM group vs. 1/28 (3.5%) in the HDM group. Conclusion In this study, though retrospective, demonstrated that for RR-HL patients, the conditioning regimen consisting of HDM, offered at least comparable efficacy to the BEAM regimen. The earlier platelets recovery, and the shorter duration of chemotherapy administration (6 days for BEAM vs. 1 day for HDM), resulted in less hospitalization days, which along with the shorter period of GCSF administration post ASCT, may contribute to a better cost effectiveness for the HDM regimen. Nevertheless, prospective studies with larger series of patients and longer follow-up, including also a meticulous cost analysis, are warranted to determine the accurate role of single agent HDM as preparative regimen for ASCT in HL patients.

Potential Benefit of Involved-Field Radiotherapy for Patients With Relapsed-Refractory Hodgkin's Lymphoma With Incomplete Response Before Autologous Stem Cell Transplantation.

We investigated for a possible role for peritransplantation involved-field radiotherapy (IFRT) by comparing patients who received IFRT before after autologous stem cell transplantation (ASCT) and patients who received salvage chemotherapy (CT) alone. We retrospectively evaluated 73 consecutive patients with Hodgkin lymphoma treated with ASCT between 2003 and 2014. Twenty-one patients (28.8%) received peritransplantation radiotherapy. A Cox regression analysis (multivariate analysis; MVA) was performed to evaluate the prognostic role of any risk factor. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of ASCT. Response to CT and ASCT were evaluated with positron emission tomography (PET) scan. Median follow-up was 41 months (range, 1-136 months). Overall, no significant difference appeared between patients who received IFRT and patients treated with CT alone; however, patients who were treated with IFRT had worse prognostic factors. In the MVA, advanced stage at relapse and persistent disease before ASCT (evident on PET scan [PET+]) were related to worse PFS and OS. In patients with limited stage disease at relapse and PET+, peritransplantation radiotherapy showed higher 3-year OS rates (91.7% vs. 62.3%) and PFS rates (67.5% vs. 50%) compared with patients treated with CT alone, although this difference was not significant (P= .14 and P= .22, respectively). IFRT used before or after ASCT might partially compensate for worse prognostic factors among the overall population; subgroup analysis showed a trend for survival benefit at 3 years in patients with limited stage disease at relapse and PET+ before ASCT.

Outcomes in patients with relapsed/refractory Hodgkin lymphoma (RR-HL) with progression after autologous stem cell transplantation in the current era of novel therapeutics.

2543Background: Patients (pts) with RR-HL who progress or relapse following autologous stem cell transplantation (ASCT) have a poor prognosis, with a historical median overall survival (OS) of 27 m...

Metabolic Tumor Volume Influences Response to Brentuximab-Vedotin in Relapsed Refractory Hodgkin Lymphoma

Purpose: The total metabolic tumor volume at baseline (T-MTV0) computed on PET has been proposed as a prognostic factor at staging in Hodgkin lymphoma (HL) and diffused large B cell lymphoma (DLBCL). It has also been described to play a role in non-HL treatment by monoclonal antibodies since it could influence antibody exposure and efficacy in a murine model (Dayde D, et al. Blood 2009) that has been confirmed in DLBCL patients study (Casasnovas O, et al. Abstract Lugano 2015). We hypothesized the metabolic tumor burden could influence the efficacy of a monoclonal antibody-drug conjugated (ADC) such as monotherapy based anti-CD30 ADC brentuximab-vedotin (BV). In the present study, we assessed the pre-treatment baseline total metabolic tumor volume based on PET evaluation in the response to BV treatment as a single agent in patients with RR-HL, as well as its prognostic value.Methods: A retrospective multi-center study was built from January 2011 to June 2015. Forty-one consecutive heavily pre-treated patients with a diagnosis of relapsed refractory HL (RR-HL) were included. PET was performed at baseline (PET0) and after 4-6 cycles of BV defining two groups of responders, good responder group achieving a complete metabolic response (CMR group, 23 patients), and non-responder group (no-CMR group, 18 patients), using the revised Lugano classification with the 5-point scale visual analysis PET/CT. T-MTV0 was measured with a semiautomatic method using a 41%-SUVmax-threshold. SUVmax at PET0 (SUVmaxPET0) was measured in each patient and represented the hottest lesion independently from the site. To assess the influence of the T-MTV0 on BV efficacy, we compared the baseline metabolic tumor volume between the two groups. The ROC curve was established to determine the optimal cut-off of T-MTV0 to predict treatment failure.Results: T-MTV0 ranged from 14 cm3 to 213 cm3 in the 41 patients (median 62 cm3; 25th - 75th percentiles 25 - 94 cm3) and SUVmaxPET0 ranged from 4,1 to 19,3 (median 10,4; 25th-75th percentiles 7,8 - 13,7). T-MTV0 was significantly higher in the no-CMR group as compared with the CMR group (median 96 and 30 cm3; 25th-75th percentiles 90 - 139 cm3 and 18 - 38 cm3, respectively; p< 0.01). Considering metabolic sites, the nodal metabolic tumor volume (N-MTV0) represented the main component of T-MTV0 and was significantly higher than the extra nodal metabolic tumor volume (EN-MTV0) in the CMR group (p = 0.025). However, the EN-MTV0 dominated in the no-CMR group and was significantly higher than the N-MTV0 (p = 0.01). SUVmaxPET0 as well as clinical characteristics were not significantly different in the two groups. Furthermore the TMTV0 cut-off value was 62 ml and predictive of treatment failure.Conclusion: In the present study, we demonstrated that tumor metabolic burden and nodal or extra-nodal localizations influence response to BV as a single agent in RR-HL patients, offering some future research directions in the development of new schedules of antibodies administration in anticancer therapy such as the concept of the individual adjustment of treatment dose to tumor burden. This may guide clinicians in their choice of therapeutic strategy. DisclosuresThieblemont:St. Louis Hospital, Paris, France: Employment. Cartron:Sanofi: Honoraria; Gilead: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria; Celgene: Honoraria.

Allogeneic Stem Cell Transplantation in Hodgkin Lymphoma: The Timing of Relapse after Autologous Transplant and Primary Refractory Disease Do Not Impact the Survival Outcomes

The present study retrospectively analyzed a cohort of consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving allogeneic stem cell transplantation (alloSCT) in a single center with a thiotepa-based conditioning to understand whether the timing of relapse after autologous stem cell transplant (ASCT) or the primary refractory disease would change the survival.Of 247 patients with HL referred to our division from 2001 to 2014, 109 had RR-HL (64 primary refractory). After receiving salvage treatment, 62 patients (57%) underwent alloSCT with a thiotepa-based conditioning; 4 patients (4%) received fludarabine-melphalan conditioning in a phase II study, 43 patients (39%) did not receive alloSCT for progressive disease (31), advanced age (>65 years, 3 patients) or for achieving a complete response after a third-line chemotherapy consolidated by ASCT (9).This study analyzes the outcomes of the 62 consecutive patients allografted with thiotepa-based conditioning, which consisted of thiotepa, fludarabine, and cyclophosphamide (TFC) for patients with an HLA identical sibling donor, TFC plus anti-thymocyte globulin for matched unrelated (MUD) donors, TFC plus alemtuzumab and 2-Gray (Gy) total body irradiation (TBI) for T-deplete haploidentical alloSCT, or TFC plus 2-Gy TBI and post-transplant cyclophosphamide for T-replete haploidentical alloSCT. Multivariate analysis of alloSCT outcomes included as covariates the pre-transplant disease status (CR vs PR vs resistant), donor (HLA identical, MUD, or T-deplete or T-replete haploidentical), primary refractory disease (yes vs no) and timing of relapse after ASCT (<12 mos after ASCT vs >12 mos vs no ASCT).Patients had a median of 33 years at alloSCT, 76% of them had a primary refractory disease at diagnosis. 74% of patients relapsed <12 months after ASCT, 15% relapsed >12 months after ASCT, 11% underwent alloSCT without previous ASCT. At alloSCT, 25% had resistant disease whereas 75% were in partial (31%) or complete response (44%) after the last salvage treatment. Donors were HLA identical siblings (42%), MUD (29%), or haploidentical (21% T-deplete, 8% T-replete).Median follow-up was 5.4 years. Three- and 5-years OS was 61 and 59%, PFS and relapse incidence were 46% and 38% at both 3 and 5 years. Non-relapse mortality (NRM) was 10% at 100 days, 17% at 1 year and for the entire follow-up. In multivariate analysis, the timing of relapse after ASCT and primary refractory disease did not impact the transplant outcomes. OS was reduced by resistant disease at alloSCT (HR=4.01, CI95% 1.34-11.97, p=0.012) and by T-depleted haploidentical transplant (HR=3.81, CI 95% 1.36-10.66, p=0.010). PFS and relapse incidence were impacted only by resistant disease (HR=5.54, CI 95% 2.13-14.37, p<0.001, and HR=6.75, CI 95% 2.07-21.96, p=0.001, respectively). NRM was significantly impacted only by the use of T-depleted haploidentical grafts (HR=7.63, CI95% 1.07-54.31, p=0.042).In conclusion, the pre-transplant disease status and not the timing of relapse after ASCT or primary refractory disease, impacts OS, PFS and relapse of RR-HL patients allografted with thiotepa-based conditioning. An optimal response before alloSCT is critical to maximize the long-term benefit of alloSCT. In the era of novel agents this can be a realistic goal for the majority of patients. DisclosuresViviani:Takeda Italia SpA: Consultancy; Teva Italia SpA: Consultancy; Italfarmaco SpA: Consultancy; Takeda International: Consultancy.

13‐ICML Satellite symposia programs (updated on May 9, 2015)

13‐ICML Satellite symposia programs (updated on May 9, 2015)

Overall Survival Benefit for Patients with Relapsed Hodgkin Lymphoma Treated with Brentuximab Vedotin After Autologous Stem Cell Transplant

AbstractAbstract 3701 Background:Salvage chemotherapy and autologous stem cell transplantation (ASCT) in the management of relapsed or refractory Hodgkin's lymphoma (HL) results in prolonged disease-free survival in only around 50% of patients (pts). Median survival following relapse from ASCT is estimated at 2.4 years, with poor outcomes in those experiencing relapse or progressive disease within one year from ASCT (Horning 2008 et al). Recently, a pivotal multicenter Phase 2 trial investigated the efficacy of brentuximab vedotin (BV) in pts with recurrent HL following ASCT. The study demonstrated an overall response rate of 75% and median duration of response of 6.7 months. Furthermore, 34% of patients achieved a complete response (CR), with a median progression free survival of 29 months (mos). Whether treatment with BV renders an OS benefit in pts with relapsed or refractory disease after ASCT remains to be determined. Objective:1) To compare OS in pts with relapsed HL after receiving ASCT in a cohort of 102 HL pts treated with BV, with 756 pts from 6 international centers before the introduction of BV. 2) To evaluate predictors of durable CR in pts treated with BV. Methods:Kaplan-Meier method was used to depict time-to-event outcomes, including OS. The Chi-square test was used to evaluate the association between two categorical variables and log-rank test to compare time-to-event endpoints among pt groups. Based on the univariate proportional hazard model, we examined whether certain variables (sex, stage at diagnosis, number of prior treatments, and time to CR) were predictors of CR duration in pts receiving BV. Results:In the non-randomized comparison between those with relapsed-refractory HL following ASCT who received BV and those who did not, pts were well matched by age, with a relatively higher percentage of females treated on the pivotal study. Dates of progression from ASCT ranged from 1996–2009 in the BV group and 1981–2003 in the international cohort. Median follow-up after ASCT for the censored observations of pts who received BV and those in the international cohort was 49.4 and 58.8 mos. The difference in median OS was statistically significant (p<0.0001) between those receiving BV and those not exposed to the drug (91.49 vs. 27.99 mos). Improvement in OS was irrespective of time to relapse from ASCT, despite previous studies noting a higher risk of recurrence in pts relapsing within 12 mos of ASCT (Sureda 2005 et al). Neither age nor sex was found to impact OS. In the subgroup analysis of pts achieving a CR with BV, univariate analysis of duration of CR and PFS uncovered no significant factors, while only stage of disease at initial diagnosis had a significant effect on OS (P=0.0004). Disease status characterized as relapsed vs. refractory had borderline significance with a positive impact on OS (P=0.0581). No significant associations were noted between the variables and duration of response post BV stratified into periods of less or greater than 12 mos. However, among those pts who experienced a duration of CR greater than 12 mos, 81.8% (n=18) had an initial CR after receiving ≤ 4 doses of BV, compared with 58.3% entering CR after receiving > 4 doses. Conclusions:While the impact of BV on OS can only be determined through a randomized clinical trial, our analysis indicated that treatment with BV in pts with relapsed/refractory HL following ASCT is associated with prolonged OS when compared with historical control patients. Those who achieve a rapid CR with BV may also have a longer duration of response. A randomized clinical trial is ongoing to evaluate prospectively the efficacy of BV following ASCT.Table 1:Median OS post ASCT w/Univariate AnalysisNEventMedian OS Time in Mos (95%CI)OS Rate at 60 Mos (95%CI)OS Rate at 120 Mos (95%CI)P-valueAll patients85863433.44 (28.68, 38.44)0.3 (0.27, 0.34)0.16 (0.13, 0.2)BVNon-BV75659127.99 (24.05, 31.54)0.26 (0.23, 0.3)0.14 (0.11, 0.17)<0.0001BV1024391.49 (56.27, 177.2)0.58 (0.47, 0.71)0.33 (0.2, 0.56)Age<3038227234.2 (27.99, 40.05)0.32 (0.27, 0.37)0.17 (0.13, 0.23)0.6772>=3047636233.31 (28.09, 39.19)0.29 (0.25, 0.34)0.15 (0.12, 0.2)SexF35825928.88 (25.3, 38.11)0.31 (0.27, 0.37)0.18 (0.14, 0.24)0.8834M50037536.43 (29.73, 40.97)0.3 (0.26, 0.34)0.15 (0.11, 0.19) [Display omitted] [Display omitted] [Display omitted] Disclosures:Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ramchandren:Seattle Genetics, Inc.: Speakers Bureau. Forero-Torres:Seattle Genetics: Research Funding. Moskowitz:Seattle Genetics: Speakers Bureau. Connors:Seattle Genetics, Inc.: Research Funding. de Vos:Seattle Genetics: Speakers Bureau. Engert:Takeda: Honoraria, Research Funding; Millennium: Honoraria, Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Morschhauser:Takeda: Honoraria. Younes:Seattle Genetics: Honoraria.

A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (&gt;20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (&gt;1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.