Salvage Autologous Stem Cell Transplantation Research Articles

Anti-PD1 Consolidation in Patients with Hodgkin Lymphoma at High Risk of Relapse after Autologous Stem Cell Transplantation: A Multicenter Real-Life Study.

(1) Background: Consolidation therapy is an emerging strategy for patients with relapsed/refractory (RR) Hodgkin Lymphoma (HL) at high risk of failing salvage autologous stem cell transplantation (ASCT). (2) Objectives: To assess the safety and effectiveness of PD1-blockade consolidation for these high-risk patients. (3) Design: Multi-center retrospective analysis. (4) Methods: We identified 26 patients given anti-PD1 consolidation, from June 2016 to May 2020. (5) Results: Patients displayed the following risk factors: refractory disease (69%), relapse < 12 months from upfront therapy (15%), ≥2 lines of salvage therapy (73%), extranodal disease (65%). Nineteen patients (73%) had ≥3 of these factors. In addition, 16 patients (61%) also displayed PET-positive (Deauville ≥ 4) disease before ASCT. Treatment-related adverse events (TRAEs), never graded > 3, occurred in 12 patients (46.15%) and mainly included skin rashes (41.7%), transaminitis (33.3%), and thyroid hypofunction (25%). Patients completed a median of 13 courses (range 6−30). At a median follow-up of 25.8 months post-ASCT, the median progression-free (PFS) was 42.6 months, with a 2-year PFS and overall survival rates of 79% and 87%, respectively. (6) Conclusions: Post-ASCT consolidation with anti-PD1 is feasible and effective. Further studies are warranted to define the optimal treatment length and patients’ subsets more likely to benefit from this approach.

Impact of Maintenance Therapy after Salvage Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma

Background: Salvage autologous stem cell transplantations (ASCT) in the setting of relapsed multiple myeloma have historically been an important therapeutic option. There have not been any comparative studies looking at this approach in the era of novel therapeutic agents such as monoclonal antibodies and emerging immunotherapies. It is important to have a real world benchmark when understanding the landscape of potential treatments in this space. Maintenance therapy post frontline autologous stem cell transplantation has become standard of care due to the important improvement in progression free survival (PFS) as well as overall survival (OS). However, little is known about the impact of maintenance post-salvage transplant. The objectives of this study are to define PFS and OS for salvage transplants with or without maintenance and describe the outcomes by types of maintenance utilized in this setting. Secondly, to redefine the optimal duration of remission post-first transplant in the maintenance era that would justify a second autologous transplant. Historically, in the pre-maintenance era, 24 months was demonstrated as an optimal remission post first transplant to gain benefit from a second salvage transplant. Methods: This is a Canadian multicentre retrospective study utilizing the Canadian Myeloma Research Group Database, a national database with input from 16 Canadian centres hosting over 8700 patients. All patients included in the study had undergone a salvage ASCT between Jan 2012 to Dec 2021 at any line of treatment. Results: Three hundred and fifty-two patients met eligibility for inclusion in this analysis. Baseline characteristics are portrayed in table 1. The median PFS (mPFS) for patients undergoing salvage transplant with (n= 179) and without (n=173) maintenance were 42.1 (34.8-53.6) and 24.2 (20.7-28.1) months respectively. The mOS was 101m (97.6-NYR) in the maintenance group and NYR (53.7-NYR) in the no maintenance group. In patients who received any type of maintenance post ASCT1 (n=169) and had a duration of response greater than 36m to the first transplant, the salvage transplant without maintenance (n=54) provided a mPFS of 17.3m (15.2-35). In a similar group that had greater than 36m response and received maintenance after ASCT1 (n=92), the addition of maintenance after the salvage transplants significantly improved the mPFS to 34.8m (26.5-51, p=<0.01). Patients that received maintenance post ASCT1 and had less than 36m PFS represent a higher risk group. In these patients, a salvage transplant without post salvage maintenance (n=10), yielded a mPFS of 9.9m (8.5-NYR). The addition of post salvage maintenance, however, significantly improved outcomes for this group as well (n=13) to a mPFS of 29.1(14.6-NYR). The most common type of maintenance post-salvage was imid based (55.9%), followed by PI based (30.2%) and then PI+imid (7.8%). Overall response rates for salvage transplants with or without maintenance therapy were 94.1% and 89.9% respectively and > VGPR were 75.3% and 67.6% respectively. The mPFS based on type of maintenance therapy are portrayed in figure 1. There was no statistically significant difference in OS based on types of maintenance therapy. Further analyses are pending and will be presented. Conclusion: Salvage transplants followed by maintenance therapy in the first relapse space provide a meaningful duration of remission and this remains a good treatment option particularly in those with a long remission after their first ASCT. As novel immunotherapies such as CAR-T and bispecific antibodies move into earlier lines of treatment, this data could serve as an important real world benchmark when evaluating the landscape for these therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Limited Long-Term Benefit of Upfront Autologous Stem Cell Transplant on Survival in Severe Renal Impairment in Multiple Myeloma in Novel Drug Era, a Retrospective Multi-Center Study in China

Background Renal impairment (RI) is a common complication of multiple myeloma (MM) affecting approximately 20%-30% of the patients at diagnosis. The presence of severe RI is associated with an increased risk of early death and poor prognosis in myeloma. The impact of autologous stem cell transplant (ASCT) on outcome in severe RI patients remains controversial. Therefore, we performed a retrospective real-world analysis to clarify the effect of ASCT on the survival of MM patients with severe RI. Methods Clinical data of 337 MM patients with severe RI at diagnosis were collected from three centers in China from April 2004 to January 2020. Severe RI was defined as an increase creatinine ＞177 umol/L (or 2mg/L) or an estimated glomerular filtration rate ≤40 ml/min/1.73 m2 using the simplified modification of diet in renal disease (MDRD) formula. RI caused by other confirmed pathological diagnosis except for tubular nephropathy was excluded. We excluded patients underwent salvage ASCT (6 cases), patients older than 65 years (107 cases), and traditional introduction therapy (2 cases). At last, there were 232 cases for analysis, containing 59 cases received ASCT. All enrolled patients were treated with novel-agent introduction. Patients were divided into the ASCT group and the non-ASCT group. Hematological and renal response were assessed based on the International Myeloma Working Group (IMWG) criteria. Results The median age for all patients at diagnosis was 55 years old (range: 37-65 years old). 37% presented with free light chain myeloma. There were 4 patients underwent double-ASCT in the ASCT group. All dialysis patients in ASCT group were off dialysis after induction therapy. Baseline profiles between ASCT and non-ASCT group were matched in sex, M-protein isotype, ISS stage, and induction therapy. More patients were on dialysis at diagnosis in non-ASCT group (34.7% vs 19.3%, P=0.04). There were 59/159 patients presented unfavorable cytogenetic abnormality (del(17p), t(4;14), t(14;16)), including 40 cases (34.2%) in non-ASCT group and 19 cases (41.3%) in ASCT group (P=0.47). The 1q amplification presented 21.4% in non-ASCT group and 22.2% in ASCT group (P=0.56). In terms of hematological response, at least VGPR accounts for 88.1% in the ASCT group and 50.3% in the non-ASCT group (P<0.001). The overall renal response was significantly higher in the ASCT group than that in the non-ASCT group (94.9% vs 54.3%, P<0.001). There was the similar tendency for at least renal PR between ASCT and non-ASCT groups (88.1% vs 41.3%, P<0.001). The transplant-related mortality (within 3 months after ASCT) was 6.8%. Early mortality within 1 year was 6.7% in the ASCT group and 19.8% in the non-ASCT group (P=0.002). The median follow-up for all patients was 37.6 months (range: 1-157 months) and the median overall survival (OS) was 49.5 months (95% CI：42-57 months). In the ASCT group, the median OS was much longer than ASCT group (57.3 months vs 42.8 months, P =0.052). But there was no difference in PFS between the two groups (36.9 months vs 26.5 , p=0.348). As the log-rank test didn't hold the proportional hazards assumption, it would have low power. We use the two-stage landmark analysis to further determine the effect of ASCT on survival. In landmark analysis, 3-year PFS rate in ASCT group was significantly higher (54.0% vs 41.9%, P=0.024). Within 5-year follow-up, OS was significantly longer in the ASCT group than that in non-ASCT group (OR=0.61, 95%CI: 0.39-0.97, P=0.04). Beyond the 5-year time point, OS was similar between the two groups (OR=1.59, 95%CI: 0.60-4.20, P=0.35). In univariate analysis, at least renal MR, at least hematological VGPR, PLT＞100×109/L, and BMPC ≥60% were correlated with longer OS. In multivariate analysis, at least renal MR (HR=0.61, 95%CI: 0.39-0.96, P=0.031), at least hematological VGPR (HR=0.41, 95%CI: 0.27-0.63, P<0.001), and PLT＞100×109/L (HR=0.43, 95%CI: 0.28-0.66, P<0.001) were independent predictor of OS. Although upfront ASCT could remarkably prolong OS in severe RI myeloma, it was not confirmed in multivariate analysis. Conclusions In the novel agent era, role of upfront ASCT in myeloma with severe RI remains uncertain. In our analysis, it seems the benefit of the OS from novel-drug induction and upfront ASCT was observed in the first 5-year, but the long-term survival benefit was limited. Instead, deep hematological response and renal recovery was strong predictors for OS.

Impact of autologous stem cell transplantation on survival outcomes in patients with peripheral T cell lymphoma

Data about the timing of autologous stem cell transplantation (ASCT) in peripheral T cell lymphoma (PTCL) are conflicting. We aimed to investigate the impact of the sequence of ASCT on the survival outcomes in patients with PTCL. Analyzes were performed retrospectively in a total of 81 patients, 16 of whom underwent upfront ASCT and 12 received salvage ASCT. In univariate analysis, upfront ASCT reduced the risk of progression and death by 77% (Hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.09–0.60) (p = 0.003) and by 84% (HR: 0.16, 95% CI: 0.5–0.55) (p = 0.003), respectively. However, in multivariate analysis, only salvage ASCT predicted a more favorable progression-free and overall survival (HR: 0.17, 95% CI: 0.06–0.48, p = 0.001 and HR: 0.20, %95 GA: 0.06–0.62, p = 0.005, respectively). In conclusion, regardless of first-line therapy, patients have more favorable outcomes if they receive salvage ASCT. Upfront ASCT does not add clinically significant benefit to survival outcomes.

Progression-Free Survival at 24 Months as A Landmark After Autologous Stem Cell Transplant in Relapsed or Refractory Diffuse Large B-cell Lymphoma

Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve progression-free survival (PFS) at 24 months (PFS24) after immunochemotherapy (IC) have excellent overall survival (OS) comparable to that of the age- and sex-matched general population. However, a similar landmark has not been established for patients with relapsed or refractory (RR) DLBCL following frontline IC who are subsequently treated with salvage therapy followed by autologous stem cell transplantation (ASCT). To evaluate the role of PFS24 as a landmark after ASCT in patients with RR DLBCL, we identified patients with RR DLBCL after frontline R-CHOP or R-CHOP-like IC who underwent salvage therapy and ASCT at Mayo Clinic between July 2000 and December 2017 and University of Iowa between April 2003 and April 2020 from institutional lymphoma and transplantation databases. Clinical characteristics, treatment information, and outcome data were abstracted. PFS, OS, and post-ASCT relapse survival (PRS) were analyzed using Kaplan-Meier method, and cumulative incidences of relapse versus nonrelapse mortality and different causes of death were compared accounting for competing events. A total of 437 patients were identified. Median age at ASCT was 61 years (range 19-78), and 280 (64%) were male. After a median post-ASCT follow-up of 8.0 years (95% confidence interval [CI], 7.2-8.7), 215 patients had a relapse (or disease progression), 180 within 2 years and 35 after 2 years. For the entire cohort, the post-ASCT relapse rate was much higher than the nonrelapse mortality rate (48.1% versus 9.1% at 5 years). Median PFS and OS after ASCT was 2.7 and 5.4 years, respectively. Lymphoma was the primary cause of death after ASCT. In contrast, for patients who had achieved PFS24 (n = 220), rates of post-PFS24 relapse and nonrelapse mortality were similar (14.8% and 12.3% at 5 years). Median PFS and OS after achieving PFS24 was 10.0 and 11.5 years, respectively. Lymphoma-related and -unrelated death rates were similar after achieving PFS24. For all patients who had a post-ASCT relapse, median PRS was 0.7 (95% CI, 0.5-0.9) year, and late relapse (>2 versus ≤2 years after ASCT) was associated with better PRS (median 2.3 [1.7-4.8] versus 0.5 [0.3-0.7] years, P< .001). The study establishes PFS24 as an important landmark associated with post-ASCT outcomes in patients with RR DLBCL after frontline IC.

Sustained Hematopoietic Engraftment Potential after Prolonged Storage of Cryopreserved Hematopoietic Stem Cells Used in Salvage Autologous Stem Cell Transplantation

Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Peripheral blood stem cells (PBSCs), a source of hematopoietic stem cells (HSCs), are collected before the first transplantation, and adequate quantities of PBSCs can be collected and stored potentially for years to support at least 2 transplantations for eligible patients. To ensure the safety of salvage HSCT in the treatment of patients in subsequent relapse, PBSCs must retain the potential to engraft even after several years of cryopreservation. Although PBSC viability has been studied extensively using in vitro techniques, few publications describe the most rigorous functional potency measure, of patients receiving a myeloablative conditioning regimen. This study describes a large single-institution experience evaluating the engraftment kinetics of PBSCs used in salvage transplantation after multiple years of storage compared with first transplantation for the same patients in the treatment of MM. A retrospective chart review of patients with MM undergoing HSCT between 2000 and 2021 identified 89 patients who received salvage autologous PBSCs stored for >1 year after first HSCT. PBSCs were cryopreserved and stored in vapor-phase liquid nitrogen refrigerators at ≤-150°C. All patients received a PBSC product from the same collection cycle for both transplantations. Differences in CD34+ cell doses and days to engraftment between the first and salvage transplantations were tested using the paired 2-tailed t-test and Wilcoxon signed-rank test. Univariate and multivariable linear regressions were used to determine the association between storage time and days to engraftment, adjusting for CD34+ cell dose and conditioning regimen in the multivariable model. The median duration of storage between the day of initial collection and salvage transplant was 5.4 years (range, 1.0 to 19.7 years). Engraftment kinetics demonstrated a sustained neutrophil engraftment (absolute neutrophil count >0.5×109 cells/L) at a median of 11 days after both the first and salvage transplantations (range, 8 to 15 days and 8 to 19 days, respectively; P < .05). The median time to sustained platelet engraftment (>20×109 cells/L without transfusion support) was 13.5 days after the first HSCT and 14 days after salvage HSCT (range, 9 to 27 days and 10 to 56 days, respectively; P=.616). After adjusting for CD34+ cell doses and conditioning regimens, there was no association between the duration of cryopreservation and days to neutrophil engraftment (r=0.178, P=.130) or platelet engraftment (r=0.244, P=.100). Engraftment kinetics of the salvage HSCT are comparable to those of the first HSCT even when products are stored in vapor-phase nitrogen refrigerators for a median of 5.4 years. There is no association between the duration of storage and time to engraftment when controlling for CD34+ cell dose and conditioning regimen. Prolonged storage of cryopreserved HSC products is a safe practice for MM patients undergoing salvage autologous HSCT.

518 - Daratumumab-Based Maintenance in Patients with Relapsed Multiple Myeloma after Salvage Autologous Hemaptopoietic Stem Cell Transplantation

518 - Daratumumab-Based Maintenance in Patients with Relapsed Multiple Myeloma after Salvage Autologous Hemaptopoietic Stem Cell Transplantation

Prevalence, Patterns, and Predictors of Venous Thromboembolic Events in Patients Undergoing Salvage Chemotherapy and Autologous Stem Cell Transplantation for Relapsed Lymphomas.

Almost 25% of patients with lymphoma may have relapse or develop refractory disease, and a majority of such patients undergo salvage chemotherapy and autologous stem cell transplantation (ASCT). Data on venous thromboembolism (VTE) in this setting are scarce. This study aimed to investigate the prevalence and factors that may increase the risk of VTE in such patients. Adult patients who were diagnosed with lymphoma and received salvage chemotherapy and ASCT were included in the study, and the subgroup with radiologically confirmed VTE were identified. Correlations between different clinical and laboratory variables and VTE were evaluated. A total of 216 patients (median age, 31 [range, 19-60] years) were enrolled in the study. Most patients (n = 140, 64.8%) had Hodgkin's lymphoma, while 54 (25.0%) had diffuse large B-cell lymphoma. A total of 36 (16.7%) patients had VTE, mostly as upper extremity deep vein thrombosis (n = 28, 77.8%); 18 (50%) of the cases were related to central venous catheter insertion. Thrombosis rates were higher among patients with high lactate dehydrogenase (LDH) level (29.2% vs. 5.9%, p < 0.001), those with mediastinal involvement (25.9% vs. 11.5%, p = 0.025). and those with longer hospital stay (22.3% vs.9.5%, p = 0.036). In the multivariate analysis, high LDH level (odds ratio (OR), 6.53; p < 0.001), mediastinal involvement (OR, 2.70; p = 0.005) and hospital stay ≥24 days (OR, 2.71; p = 0.007) were all associated with significantly higher VTE rates. Patients with relapsed lymphoma undergoing salvage chemotherapy and ASCT are at higher risk for VTE, especially in those with high LDH level, mediastinal involvement, and prolonged hospital stay. If no contraindications exist, thromboprophylaxis might be considered in these settings.

Efficacy of high dose chemotherapy in adult patients with relapsed or refractory ewing sarcoma

Background: A rare condition in adults, Ewing sarcoma (EWS) has no standard treatment during the relapse–refractory period. In our study, we aimed to identify the treatment-related side effects of high-dose chemotherapy (HDC) and salvage autologous stem cell transplantation (ASCT) in adult patients with relapsed or refractory EWS and their survival rates. Materials and Methods: In a retrospective study, we recorded the clinical characteristics of patients with relapsed or refractory EWS treated with HDC in the hospital’s patient registry to determine their objective response rate (ORR), progression-free survival (PFS), 6-month PFS rate, overall survival (OS), 6-month OS rate, transplantation-related mortality (TRM) and treatment-related side effects. Results: In our sample of 29 patients (72.4% male), the mean age was 26.41 years (SD = 9.35). The most common primary tumour site was the lower extremities (31%), 69% of patients had lung metastases, and 48.1% had undergone surgical resection, adjuvant radiotherapy and chemotherapy. The ORR to HDC was 31%. Median PFS (IQR) was 5.35 (6.79) months (95% confidence interval = 4.23–8.28), whereas the 6-month PFS rate was 38.9%. Median OS (IQR) was 9.46 (14.45) months (95% confidence interval = 8.52–15.82), whereas the 6-month OS rate was 68.1%. Mortality from HDC or other causes occurred in five patients within the first 100 days after ASCT. Grade 3 febrile neutropenia and thrombocytopenia were present in all patients until engraftment following ASCT. Conclusion: Amongst adults with relapsed or refractory EWS, HDC has successful survival and response rates and a manageable side-effects profile.

Second Line Treatment Strategies in Multiple Myeloma: A Referral-Center Experience

Second Line Treatment Strategies in Multiple Myeloma: A Referral-Center Experience

Comparison of Salvage Autologous Hematopoietic Cell Transplantation with Outcomes Following Selinexor Combinations Among Double/Triple Refractory Myeloma Patients

Introduction: A vast majority of multiple myeloma (MM) patients requires subsequent lines of therapy following relapses. The choice of regimen following relapse is influenced by response, tolerance to prior therapies, as well as by disease and patient features. Treatment options are limited for those who develop triple-class refractory disease. In this setting, the role of a salvage autologous stem cell transplantation (sAHCT) is controversial. This unmet need has driven the development of new therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of nuclear export (SINE) compound, was recently approved by the FDA and EMA for use in heavily pretreated relapse refractory (RRMM) patients, including triple-class refractory RRMM and FDA has also approved the agent in patients with first relapse. In the absence of head-to-head studies, comparison of treatment options among triple-class treated patients is based on real world experience. Here we performed a retrospective comparison between outcomes following sAHCT versus Selinexor combinations administered among RRMMs.Patients & Methods: Between January 2015 and April 2021, 22 patients at our center underwent sAHCT for treatment of refractory relapse. A transplant was defined as salvage if the patient had already received one prior AHCT and underwent a further AHCT after evidence of disease progression not responding to second generation proteasome inhibitors (PI), İmmunomodulating agents (IMID) or antiCD38 monoclonal antibody. We compared the outcomes of these patients with 10 RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive Selinexor, dexamethasone in combination with either bortezomib (n=7) (XVd) or carfilzomib (n=3) (XCd) as a part of a Karyopharm Expanded Access Program (KEAP). Selinexor was administered 80-100 mg po weekly in combination. Response and disease progression were assessed according to the IMWG criteria.Results: Patients' characteristics and the outcome of treatments are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 6 prior lines of therapy (4-9) and 2 out of 10 carried high-risk cytogenetics in SVd group. Seven (31.8%) patients with high-risk cytogenetics underwent sAHCT. All patients were treated with or refractory to immunomodulators and proteasome inhibitors. Five patients responded to DCEP bridging therapy prior to sAHCT. Five patients received Selinexor after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In sAHCT group, 68.2% of patients relapsed within a median of 6.3 months (Figure-1). Figure-2 shows the impact of the prior lines of therapy and selinoxor on PFS.Adverse events on selinexor regimens included fatigue, nausea, thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. Two patients eventually transitioned to new therapies, while 4 still remain on SVd due to continued response.Conclusion: Our results based on a small number of patients, compared with outcomes post sAHCT reflects comparable duration of response and disease control rates with Selinexor-PI regimens among selected patients. Hospitalization and prolonged infusions are not required with the selinexor regimens, and prolonged treatment is possible with advance in lines of therapy duration of response lessens with any treatment modality. Despite of a DCEP bridging therapy prior to sAHCT, Selinexor combos have achieved similar PFS even among triple class refractory MM patients. For countries where CAR-T therapies are not accessible, sAHCT and Selinexor combinations may be considered as a valid clinical option after failing CD38 monoclonal antibodies, PI and IMIDs. These data support the use of selinexor-based regimens in the treatment of relapsed MM, and given the potency of the combinations, in earlier lines of therapy including in patients who have received anti-CD38 mAbs. [Display omitted] DisclosuresKashyap: Karyopharm: Current Employment. Niblock: Karyopharm: Current Employment. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. OffLabel Disclosure:Selinexor has not been approved for myeloma patients in Turkey. It could be used as a part of Karyopharm Expanded Access program (KEAP).

Real-World Patterns of Utilization and Outcome of Market Approved Lenalidomide-Based Triplet Combinations in First Relapsed Multiple Myeloma Patients: Evidence from a Propensity Score Matched Analysis

Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM.Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse.Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p<0.001), time from diagnosis was quite longer (3,5 vs 2,9 year in KRd, p=0.094), they received a lower rate of prior ASCT (56% vs 72% in KRd, p=0.008). After a median follow-up of 21.6 months (IQR: 9.6-32.4), response rate ≥PR were similar in both groups (92% in DaraRd vs 87,6% in KRd, IPTW analysis: OR=0.8, 95%CI: 0.4-1.5, p=0.422). No significant difference was found in terms of ≥VGPR (60% in DaraRd vs 62,9% in KRd, IPTW analysis: OR=0.7, 95%CI: 0,4-1,1 p=0.098) as well as of ≥CR (16,6% in DaraRd and 23,6% in KRd, IPTW analysis: OR=1,3, 95%CI: 0.8-2,2, p=0.340). The median number of administered cycles was higher for DaraRd (12 vs 10, IPTW analysis: β: 0.2, 95%CI: 0.1-0.4, p=0.025). Discontinuation rate was lower with DaraRd (28% vs 62% with KRd, IPTW analysis: OR: 0.3, 95%CI: 0.2-0.4, p<0.001). Most patients in both groups discontinued treatment for progression (55,3% with DaraRd and 59.3% with KRd), discontinuation for TEAE was reported respectively in 38,3% in DaraRd and 31,5% in KR; 6,4% of pts in DaraRd and 9,2% in KRd discontinued treatment for pts decision. Weighted analysis shows a similar outcome. In particular, the median PFS is 28 months for DaraRd vs 23 months for KRd, (HR=0.9, 95%CI: 0.6-1.2, p=0,420) (Figure 1). At left-truncation analysis, patients with ≥VGPR, had similar PFS when comparing DaraRd vs KRd (HR=1.0, 95%CI: 0.6-1.6, p=0.896) while in patients with ≤PR, DaraRd showed a longer PFS (HR=0.5, 95%CI: 0.3-0.9, p=0.012) (Figure 2). The median TTNT was 31 and 29 months in DaraRd and KRd, respectively (HR=0.8, 95%CI: 0.5-1,1 p=0,111). No difference was found in terms of OS (HR=1.2, 95%CI: 0.8-1.8, p=0.408)(Figure 3).Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice. [Display omitted] DisclosuresMangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.

Phase I Study of Oral Azacitidine (CC-486) Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

BackgroundA significant portion of diffuse large B-cell lymphoma (DLBCL) patients (35-40%) relapse or are refractory to frontline chemotherapy. The standard of care for relapsed/refractory (R/R) DLBCL patients has been salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) in eligible patients. Epigenetic alterations, such as aberrant DNA methylation patterns, have been linked to chemotherapy resistance in DLBCL. CC-486 is an oral hypomethylating inhibitor that inhibits DNA methyltransferase, and has provided evidence for chemotherapy sensitization in DLBCL (Clozel T, et al. Cancer Discovery, 2013). This provides rationale for addition of CC-486 to standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in R/R DLBCL patients who are candidates for ASCT. Here we report the results of the phase 1 trial investigating this combination.MethodsEligibility included age ≥ 18, a diagnosis of R/R DLBCL, follicular lymphoma grade 3B, or DLBCL transformed from indolent lymphoma who were candidates for salvage chemotherapy and ASCT consolidation. The study was conducted via standard 3+3 dose escalation of CC-486 at 200 mg (dose level (DL) 1), 300 mg (DL 2), and 150 mg (DL -1). A Dose limiting toxicity (DLT) was defined as grade ≥ 3 adverse event (AE) as defined by CTCAE v5 leading to ≥ 7 day delay in cycle (C) 1 or 2 of R-ICE chemotherapy as well as grade ≥ 2 vomiting/diarrhea, persisting 48 hours despite best supportive care. Patients received up to three 21-day cycles. CC-486 was given as a 7 day lead in prior to C1 and then on days 8-21 of C1 and C2 with doses held based on cytopenias/AE's per protocol. G-CSF was mandated with each cycle. The primary objective was to determine the recommended phase 2 dose (RP2D) of CC-486 in combination with R-ICE chemotherapy. Secondary objectives included overall response rate (ORR)/complete remission (CR) per 2014 IWG criteria, peripheral blood stem cell (PBSC) collection feasibility, and proportion of patients receiving ASCT consolidation. Biomarker objectives included assessment of locus specific and global methylation patterns in ctDNA at set time points.ResultsThe study has completed accrual with enrollment of nine patients from two institutions, all of which completed planned therapy. Eight (89%) of the patients had relapsed < 1 year from completion of frontline chemotherapy. Six patients were treated at the DL1 (200 mg), three patients were treated at DL2 (300 mg), and zero patients were treated at DL-1 (150 mg) with baseline characteristics described in table 1.The most common AE's (figure 1) included nausea (78%), thrombocytopenia (78%), anemia (56%), neutropenia (55.6%), fatigue (44%), and constipation (44%).Compared with DL1, DL2 was associated with greater incidence of grade ≥ 3 hematologic AE's/cycle including neutropenia (42% v 6%), anemia (29% v 11%), and thrombocytopenia (42% v 6%); higher incidence of neutropenic fever/cycle (28.5% vs 0%); more frequent delays in day 1 of C2 or C3 of R-ICE chemotherapy (80% vs 0%); and higher rate of CC-486 doses missed in C2 and C3 due to cytopenias (40% and 4%) respectively. One DLT occurred at DL2 in a patient with grade 5 neutropenic sepsis. A planned safety review of the three patients at DL2 established that no further patients would be enrolled at this dose. No DLTs were noted in the six patients enrolled at DL1.The ORR(CR) of the 8 evaluable patients was 50%(50%) and 4/9 patients proceeded to ASCT. With a median follow up of 9.5 months (range 1.2-25.1) the median PFS and OS were 4.0 months (95% CI 2.1-NR) and 10.7 months (95% CI 9.5-NR) respectively. All 4 patients successfully collected PBSCs (defined as ≥ 3.0 x 10^6 CD34 cells/kg) with median of 4.08 x 10^6 cells/kg. Biomarker studies are pending.DiscussionPatients enrolled at DL1 (200 mg) tolerated this combination well with expected hematologic AE's, no episodes of neutropenic fever, few missed doses of CC-486, no delays in R-ICE chemotherapy, and no DLTs. The CR rate was 50% and a high proportion of patients (89%) enrolled after relapsing < 1 year from completion of frontline therapy. Biomarker studies may provide information regarding DLBCL populations likely to benefit from combinations of chemotherapy and epigenetic priming. Biomarker studies related to locus specific and global methylation patterns in ctDNA will be presented at the ASH conference. [Display omitted] DisclosuresHess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Hill: Eli Lilly and Company: Ended employment in the past 24 months.

Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study

Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study

Time to Refractory Status Defines Subsets of Primary Refractory Diffuse Large B-Cell Lymphoma with Distinct Outcomes

Time to Refractory Status Defines Subsets of Primary Refractory Diffuse Large B-Cell Lymphoma with Distinct Outcomes

Risk Stratification for Relapsed/Refractory Classical Hodgkin Lymphoma Integrating Pretransplant Deauville Score and Residual Metabolic Tumor Volume

IntroductionPositron emission tomography (PET) positivity before autologous stem cell transplantation (ASCT) predicts poor prognosis in relapsed/refractory (rel/ref) classical Hodgkin lymphoma (cHL). However, there is limited data regarding the value of pre-ASCT residual metabolic tumor volume (rMTV) assessed by PET to predict post-ASCT outcomes. We aimed to evaluate the role of pre-ASCT Deauville score (DS) combined with rMTV in patients with rel/ref cHL who underwent salvage ASCT, and also to establish a risk model integrating pre-ASCT DS, rMTV, and other clinical risk factors.MethodsThis is a retrospective cohort study using clinical data of patients with rel/ref cHL identified from the lymphoma database and the ASCT database of the Princess Margaret Cancer Center, Toronto, Canada. Following criteria were required: (1) patients (≥18 yrs) with histologically confirmed rel/ref cHL between January 2014 to March 2019; (2) treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-equivalent regimens; (3) chemosensitive disease after salvage therapy; (4) restaging PET before ASCT clearance. Pre-ASCT PET scans were assessed using the Deauville 5-point scale, and rMTV was computed in the scans with DS 4 or 5 using the 41% maximum standardized uptake value threshold method. Receiver operating characteristics analysis was used to determine an optimal cutoff of rMTV 41% for event prediction. The primary endpoint was event-free survival (EFS), defined as time form ASCT to first documented disease progression, any new lymphoma therapy, death from any cause, or last follow-up.ResultsA total of 106 patients fulfilled the eligibility criteria and were included. Median age was 33.5 yrs (range, 18-70), and 72 (68%) were male. The cohort characteristics at time of progression were 55 (52%) patients with advanced stage, 28 (26%) with B symptoms, 39 (37%) with extranodal disease, and 39 (37%) with primary refractory disease, defined as achieving less than a complete response, disease progression during first-line therapy, or time to relapse (TTR) 3 months or less. All patients received gemcitabine, dexamethasone, cisplatin (GDP) regimen as salvage therapy. Based on the response to GDP therapy, 24 patients required second (N=20) or third (N=4) salvage regimens before ASCT (brentuximab vedotin [BV] alone or combination with bendamustine [N=16], pembrolizumab [N=9], and mini-BEAM [N=3]). 32 patients (30%) received planned pre- or post-ASCT involved field radiation for DS 4-5 lesions. 4 patients received post-ASCT BV consolidation.With a median follow-up of 26.2 months (interquartile range [IQR], 14.4-49.2), 2-year EFS and overall survival rates were 72.1% and 93.1%, respectively. Pre-ASCT DS was determined as 1-3 (N=63, 59%) and 4-5 (N=43, 41%). None of the patients with DS 5 had new lesions. Patients with pre-ASCT DS 1-3 had significantly better EFS than those with DS 4-5 (2-year; 80.8% vs 59.2%; P=0.002; Fig 1A).Median rMTV 41% of the 43 patients with DS 4-5 was 5.1 cm 3 (IQR, 2.0-24.7). The optimal cutoff of rMTV 41% was 4.4 cm 3. Patients with rMTV low (< 4.4cm 3, N=21) had better EFS than those with rMTV high (N=22; 2-year, 75.0% vs 45.4%; P=0.009), but had similar 2-year EFS when compared with patients with DS 1-3 (80.8%, P=0.280; Fig 1B)In the multivariable analysis for EFS, a combined assessment of pre-ASCT DS/rMTV 41% and rel/ref status at time of progression were independently associated with EFS (for DS 4-5/rMTV low, hazard ratio [HR] 1.58; for DS 4-5/rMTV high, HR 4.72; P<0.001: for primary refractory disease, HR 2.26; P=0.026). Based on these results, we stratified patients into 3 groups according to the post-ASCT outcomes: low-risk (relapsed disease [i.e., TTR > 3 months] and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=54), intermediate-risk (refractory disease and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=30), and high-risk (pre-ASCT DS 4-5/rMTV high irrespective of rel/ref status, N=22) groups. The risk model was significantly associated with EFS (intermediate vs low, HR 3.26, 95%CI 1.20-8.83, P=0.020; high vs low, HR 7.61, 95% CI 2.89-20.01, P<0.001; Fig 1C).ConclusionWe propose a risk stratification model integrating a combination of DS and rMTV 41% on pre-ASCT PET and rel/ref status at time of progression, which allow discrimination of post-ASCT outcomes in patients with rel/ref cHL. The model may serve as a tool to facilitate risk-stratified treatment decisions. [Display omitted] DisclosuresMetser: POINT Biopharm Inc: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Crump: Roche: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees. Kuruvilla: Seattle Genetics: Honoraria; Amgen: Honoraria; Antengene: Honoraria; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; BMS: Honoraria; Medison Ventures: Honoraria; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; Pfizer: Honoraria. Kridel: Gilead Sciences: Research Funding.

Maneuvering the Complex Web of Treatment Options for Relapsed/Refractory Multiple Myeloma

Numerous treatment options are available for patients with early relapsed multiple myeloma. Clinicians should consider using a monoclonal antibody for patients who have not yet received one, or changing either the immunomodulatory drug, the proteasome inhibitor, or both. Clinical trials are another option, or clinicians can refer transplant-naïve patients for autologous stem cell transplantation (ASCT). For patients with late relapse, a clinical trial is recommended, if possible, but many patients are ineligible due to poor blood cell counts or other factors. Additional treatment options include selinexor combinations, belantamab mafodotin-blmf, melflufen, or CAR T-cell therapy. Salvage ASCT should also be considered for this challenging population.

Pembrolizumab (Keytruda)

&#x0D; CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of adult and pediatric patients with refractory or relapsed classical Hodgkin lymphoma (cHL) if certain conditions are met.&#x0D; Keytruda should only be reimbursed to treat patients who have failed autologous stem cell transplant (ASCT) or who are not candidates for multi-agent salvage chemotherapy and ASCT.&#x0D; Keytruda should only be reimbursed as monotherapy and if the cost of pembrolizumab is reduced.&#x0D; &#x0D;

Tre-P-19 - Autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement: follow-up

Mycosis fungoides (MF) is a presentation of primary cutaneous T-cell lymphoma with adverse prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We reported a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization–European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a complete remission during a follow-up period of 32.5 months after autologous SCT. After that, the disease relapsed with simultaneous skin and cerebral lesions. Despite immediate intrathecal and subsequently intravenous administration of high-dose methotrexate and cytarabin, we observed further progressed and the patient deceased 3.5 months after this second fulminant recurrence and in total 36 months after autologous SCT transplantation.

Poster:ABCL-230 Prevalence, Patterns, and Predictors of Venous Thromboembolic Events in Patients Undergoing Salvage Chemotherapy and Autologous Stem Cell Transplant for Relapsed Lymphomas

Poster:ABCL-230 Prevalence, Patterns, and Predictors of Venous Thromboembolic Events in Patients Undergoing Salvage Chemotherapy and Autologous Stem Cell Transplant for Relapsed Lymphomas