Patients In First Relapse Research Articles

End-of-treatment 18[F]-FDG PET can predict early progression in patients receiving bendamustine-rituximab for follicular lymphoma in first relapse: a prospective West Japan hematology Study Group (W-JHS) NHL01 trial.

Response determined by 18[F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)-CT after induction therapy can predict progression-free survival (PFS) in follicular lymphoma (FL). However, little prospective research has examined the significance of PET after second-line therapy. We conducted a prospective multicenter phase II trial (W-JHS NHL01) of bendamustine plus rituximab (BR) without rituximab maintenance for FL in first relapse. This study aimed to evaluate the usefulness of end-of-treatment (EOT)-PET for predicting PFS in FL patients in first relapse. EOT-PET examinations were performed between 6 and 8weeks from the start of the last BR cycle. The primary endpoint was 1-year PFS. Key secondary endpoints were overall response rate (ORR), complete response rate (CRR), and 1-year overall survival (OS). Seventy-five patients were enrolled, and 8 were excluded from analysis. ORR was 86.6% and CRR was 59.7%. One-year PFS was 88.9% (95% confidence interval [CI] 80.7-94.3%) and 1-year OS in 75 patients was 97.3% (95% CI 89.6-99.3%). One-year PFS was significantly inferior in EOT-PET-positive patients (n = 9) compared with PET-negative patients (n = 58) (77.8% vs. 93.1%; p = 0.02). We confirmed that EOT-PET after second-line BR therapy could predict early progression in FL patients in first relapse.

Poor Outcome of Patients with Acute Myeloid Leukemia in First Relapse Underscores the Need for Effective Initial Treatment

Introduction: The incorporation of novel targeted agents into combination regimens used in the treatment of patients with acute myeloid leukemia (AML) has improved their outcomes. However, disease relapse is still challenging and associated with a poor response rate, limited therapeutic options and poor outcome. Predictors of outcome for patients in first relapse include the duration of first remission, cytogenetic risk at diagnosis, age and whether they underwent an allogeneic stem cell transplantation (alloSCT) in first remission. The incorporation of genetic aberrations detectable at diagnosis has been useful in further stratifying prognosis, but their predictive value at the time of relapse is not well established. Herein we analyze a large cohort of frontline-treated AML patients, focusing on the outcomes of patients presenting a first disease relapse. Methods: This is a retrospective single-center study including patients diagnosed with AML from April 2017 to October 2022. Risk assessment and response to treatment were defined according to the ELN 2022 guidelines. Mutations were assessed using an 81-gene NGS panel. Survival analyses were estimated with the Kaplan-Meier method, using the log-rank test for comparison. Univariate and multivariate analysis were performed using Cox proportional hazards regression. Results: A total of 875 patients with AML were included in the study, with a median age of 65 years old (range,18-95). According to the ELN risk category, 171 (20%) patients had favorable disease, 200 (23%) patients intermediate and 473 (54%) adverse. Patients received intensive treatment (IT; 40% of patients, 41% of whom with the addition of venetoclax) or low intensity treatments (LIT; 60% of patients, 72% with venetoclax). The overall response rate including complete remission (CR)/CR with incomplete hematologic recovery (CRi) was 73%. Among responding patients, 201 (32%) underwent alloSCT in first remission. After a median follow-up of 25 months, the median OS was 53 months for patients receiving IT and 11 months for patients receiving LIT (Figure 1). The median OS for favorable, intermediate and adverse risk patients was not achieved, 24 and 11 months, respectively. During this follow up time, 337 patients were alive and maintaining CR. 197 patients have relapsed after having achieved CR/CRi, 36 of them after undergoing alloSCT. Available data for analysis was available in 164 of these patients. The median age at relapse was 67 (21-95) and 57 (35%) received prior IT whereas 107 (65%) received LIT. At diagnosis, 15%, 16% and 69% were favorable, intermediate and adverse risk, respectively. The median time from best response to relapse was 7.5 (range,1-35) and 6.3 (range, 1-49) months for patients treated with IT and LIT, respectively. At the time of relapse, 36% of patients had a complex karyotype, 4% had MECOM gene rearrangement and 3% had KMT2A gene rearrangement. The most common mutations at time of relapse were TP53 (34%), DNMT3A (34%), TET2 (23%) and RUNX1 (19%). After relapse, 32 (20%) and 132 (80%) received salvage IT and LIT treatment, respectively. The CR/CRi rate for IT and LIT were 31% and 27%, respectively. The mOS from relapse was 3.4 and 5.5 months for patients with salvage IT and LIT, respectively (p=0.6). Age at relapse (mOS of 6.5 vs 5.1 months for patients age <60 and ≥60, respectively [p=0.1]), type of induction therapy (mOS of 6.6 vs 4.9 for patients receiving IT and LIT, respectively [p=0.07]), or risk classification at relapse (mOS of 4.9, 6.3 and 5.1 months for favorable, intermediate and adverse risk, respectively [p=0.7]) did not stratify patients. Duration of first remission longer than 12 months was associated with a better OS (mOS 8.1 vs 4.3 months, p=0.008). Univariate and multivariate analysis was performed, including clinical and biological variables at diagnosis and relapse (Table 1). Importantly, high white blood cell count at relapse (HR 2.1), short first remission (HR 1.6), complex karyotype at relapse (HR 1.7) and KMT2A rearrangement at relapse (HR 3.8) were independent predictors of outcome after relapse. Conclusion: Although outcomes of patients with AML have improved, disease relapse remains a major obstacle with poor outcomes despite the availability of new salvage strategies. Highly effective induction and maintenance regimens are needed to reduce the risk of relapse.

Pomalidomide and dexamethasone until progression after first salvage therapy in multiple myeloma.

Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.

Revised Prognostic Index for Patients with Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms in First Relapse

Introduction: Though many patients with acute myeloid leukemia (AML) will achieve a first complete remission (CR1), most patients will relapse. A previous analysis from HOVON on 667 consecutive AML patients in first relapse identified four key predictors for achieving a second CR (CR2), which improved overall survival (OS): age at relapse, CR1 duration, cytogenetic risk, and prior receipt of hematopoietic cell transplant (HCT), thereby developing a scoring system to aid in therapeutic decision making (Breems, JCO 2005). Since this original publication, other predictors of relapse have emerged, most notably measurable residual disease (MRD), and cytogenetic/molecular risk stratification has been refined in the form of ELN2017 (Dohner, Blood 2017). We hypothesize that incorporation of MRD and ELN2017 categorization into a risk stratification model will improve our ability to predict CR2 likelihood and OS after relapse. Methods: Eligible patients included those ≥18 years (yrs) old who received treatment (tx) at our center for AML or other high-grade myeloid neoplasms (≥10% marrow/peripheral blasts at diagnosis) between January 2008 and July 2019, who later relapsed. Using our IRB-approved institutional AML database, we obtained the following demographic and outcome parameters: age; gender; new diagnosis (ND) type (AML vs. other; de novo vs. secondary); ECOG performance status; TRM score; ELN2017 risk; CR1 date; CR1 details [CR vs. CR with incomplete hematologic recovery (CRi) and MRD status]; initial tx intensity [low being hypomethylating agents (HMA); intermediate being 7+3 or similar; high being FLAG-ida/CLAG-M or similar]; cycles to CR1; prior HMA before relapse; prior HCT before relapse; relapse date; relapse salvage tx type and intensity; response to salvage (CR vs. CRi + MRD status); CR2 date; subsequent HCT; and death date or date of last contact. We fit multivariable (MV) models for OS after first relapse (Cox) and CR2 after first relapse (logistic). A score for each respective outcome was developed by rounding the coefficients from the models. C-statistics (Cox) and area under the receiver operating characteristic curve (AUC; logistic) were also calculated. Results: We identified 315 eligible patients who achieved CR1 and relapsed. Among these, 266 received subsequent tx and were included in our analysis: the median age at relapse was 63 yrs (range 20-85); 40% (n=106) were female; 56% (n=148) received high-intensity tx for ND; 47% (n=125) had secondary AML at ND; 28% (n=75) had received prior HCT before relapse; 36% (n=95) had received prior HMA before relapse. For initial tx of first relapse, 52% (n=138) received high-intensity tx; 5% (n=13) received HCT; 12% (n=31) received intermediate-intensity tx; and 32% (n=84) received low-intensity tx. Overall, 60% (n=160) achieved a subsequent CR2. Significant covariates in the CR2 MV model were CRi following ND tx (odds ratio [OR] 0.85; 95% confidence interval [CI] 0.73-0.99), ≥2 cycles to CR1 (OR 0.86; CI 0.75-0.99), CR1 7-18 m (OR 1.22; CI 1.07-1.38), CR1>18 m (OR 1.31; CI 1.12-1.53), post-relapse HCT (OR 1.43; CI 1.1-1.86), and low-intensity tx post-relapse (OR 0.77; CI 0.68-0.87). Significant covariates leading to improved OS in the MV model were CR1 duration of 7-18 m (hazard ratio [HR] 0.5; 95% CI 0.36-0.69), CR1 duration >18 m (HR 0.36; CI 0.24-0.55); and post-relapse HCT (HR 0.49; CI 0.26-0.91). We derived scoring systems from these MV models (Table 1). A positive score indicates a favorable prognosis (median OS of 13.6 m); a score of 0 (median OS 6.5 m) or below (median OS 5.6 m) indicates a poor prognosis (Figure 1). When the Breems scoring system for OS was applied to our dataset, the C-statistic was 0.55; our score improved to a C-statistic of 0.61. The AUC for the CR2 score from our model was 0.69. Conclusions: The Breems system was not well-calibrated to our dataset, underscoring the need to develop an updated scoring model for OS and CR2 in relapsed AML patients. Surprisingly, factors such as CR1 MRD status and ELN2017 risk did not appear to be significant in MV analyses. Efforts are underway to update this dataset to include additional contemporary patients; we hope to enhance the prognostic scoring algorithm by capturing the effect of specific mutational profiling (e.g. TP53, FLT3, and others). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lenalidomide-based triplet regimens in first relapsed multiple myeloma patients: real-world evidence from a propensity score matched analysis.

Lenalidomide and dexamethasone (Rd)-based triplets, in particular carfilzomib-Rd (KRd) and daratumumab-Rd (DaraRd), represent a standard of care in lenalidomide-sensitive multiple myeloma (MM) patients in first relapse. Meta-analysis of randomized clinical trials (RCT), suggested better outcome with DaraRd. Trying to address this issue in clinical practice, we collected data of 430 consecutive MM patients addressed to Rd-based triplets in first relapse between January 2017 and March 2021. Overall, the most common used regimen was DaraRd, chosen in almost half of the cases (54.4%), followed by KRd (34.6%). Different triplets were used much less commonly. In an attempt to limit the imbalance of a retrospective analysis, we conducted a propensity score matching (PSM) comparison between DaraRd and KRd. After PSM, efficacy of DaraRd versus KRd was similar in terms of overall-response rate (ORR) (OR: 0.9, P=0.685) as well as of very good partial response (VGPR) or better (OR: 0.9, P=0.582). The median progression-free survival (PFS) was significantly longer for DaraRd (29.8 vs. 22.5 months; P=0.028). DaraRd was tolerated better, registering a lower rate of grade 3-4 non-hematological toxicity (OR: 0.4, P<0.001). With the limitations of any retrospective analysis, our real-life PSM comparison between DaraRd and KRd, in first-relapse MM patients, showed better tolerability and prolonged PFS of DaraRd, although with some gaps of performance, in particular of DaraRd, with respect to RCT. Carfilzomib-containing regimens, like KRd, still remain a valid second-line option in the emerging scenario of first-line daratumumab-based therapy.

Cost-effectiveness of CD19 chimeric antigen receptor T-cell (CAR-T) therapy versus autologous stem cell transplantation (ASCT) for high-risk diffuse large B-cell lymphoma (DLBCL) in first relapse.

7537 Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of &gt;$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.[Table: see text]

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML

AbstractEffective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline–based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

Therapeutic approach and outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors: An SFCE retrospective study.

Since the introduction of tyrosine kinase inhibitors (TKIs), the profile of pediatric relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has changed. However, the management of pediatric Ph+ ALL relapses is not currently standardized. We retrospectively analyzed the therapeutic strategies and outcomes of pediatric Ph+ ALL patients in first relapse who were initially treated with a TKI-containing regimen in one of the French pediatric hematology centers from 2004 to 2019. Twenty-seven children experienced a Ph+ ALL relapse: 24 (89%) had an overt relapse and three a molecular relapse. Eight involved the central nervous system. A second complete remission (CR2) was obtained for 26 patients (96%). Induction consisted of nonintensive chemotherapy for 13 patients (48%) and intensive chemotherapy for 14 (52%). Thirteen patients (48%) received consolidation. Allogenic hematopoietic stem cell transplantation (alloHSCT) was performed for 21 patients (78%). The TKI was changed for 23 patients (88%), mainly with dasatinib (n=15). T315I was the most common mutation at relapse (4/7). The 4-year event-free survival and survival rates were 60.9% and 76.1%, respectively. Survival was positively associated with alloHSCT in CR2. We show that pediatric first-relapse Ph+ ALL reinduces well with a second course of TKI exposure, despite the use of different therapeutic approaches. The main prognostic factor for survival was alloHSCT in CR2. Because of the small size of the cohort, we could not draw any conclusions about the respective impact of TKIs, but the predominance of the T315I mutation should encourage careful consideration of the TKI choice.

Efficacy of Daratumumab Containing Regimens Post Lenalidomide Maintenance in Transplant Eligible Patients: Real-World Experience from the Canadian Myeloma Research Group Database

Introduction Lenalidomide maintenance following autologous stem cell transplant (ASCT) remains a standard of care among transplant eligible patients with newly diagnosed multiple myeloma (NDMM). Many previous clinical trials done in patients following one prior line of therapy either excluded patients progressing on lenalidomide or included a very small proportion of these patients. Given the paucity of data in this setting, the optimal management of patients progressing on lenalidomide maintenance remains unknown. Daratumumab-containing triplet regimens have recently been introduced for these patients, typically in combination with pomalidomide (DPd), lenalidomide (DRd), or bortezomib (DVd). To our knowledge, there is no prospective data to allow comparison of the efficacy of these three regimens in patients progressing on lenalidomide maintenance, which is an increasingly common clinical scenario. Understanding the comparative efficacy, tolerability and toxicity of these regimens in patients progressing on lenalidomide maintenance in the 'real-world' is needed in order to help clinicians make appropriate decisions and guide future studies. Methods The Canadian Myeloma Research Group Database (formerly known as the Myeloma Canada Research Network Database, MCRN-DB) is a prospectively maintained disease specific database with over 7000 patients enrolled from 14 academic sites across Canada with legacy data collected from 2007. The Munster Myeloma database collects myeloma specific information in a German academic center and currently contains data from 800 patients collected from 2005. All consecutive patients treated with daratumumab based regimens in second line following relapse on lenalidomide maintenance were included in the analysis from the two databases analyzed up to 30/06/2020. Results A total of 1380 NDMM patients on lenalidomide maintenance post autologous stem cell transplant were identified in the two databases. From them, 73 patients were included in this analysis as they were treated with daratumumab containing regimen in second line. Specifically, 18 (24.7%) of these patients were treated with DPd, 32 (43.8%) patients with DRd, and 23 (31.5%) patients with DVd. The baseline characteristics, maintenance details, post-maintenance response rates and toxicity for each regimen are shown in Table 1. The median follow-up for the cohort from the time of daratumumab initiation was 8.3 months (range 0.4 - 40.0). Although, a higher proportion of patients in the DPd arm obtained a CR/VGPR compared to DRd or DVd, it did not reach statistical significance (p-value 0.06). The median PFS of the entire cohort was 16.96 months (95% CI 11.47-23.44). The median PFS of the individual regimens was as follows: DPd 17.65 months, DRd not reached and DVd 11.47 months as demonstrated in Figure 1 (p-value =0.46). Conclusion In summary, our results show that daratumumab-based regimens are effective among patients progressing on lenalidomide maintenance in the real world. Despite the small sample size, the results presented here are in line with recent sub-analyses of phase III studies examining the common daratumumab-based regimens used in this setting (CASTOR with median PFS of DVd between 7.8 months in all lenalidomide refractory patients and 27 months in all patients in first relapse; MM014 with median PFS of DPd after lenalidomide refractoriness of 21.8 months). The efficacy of DRd, in which daratumumab is added to an increased dose of lenalidomide, is notable and warrants further evaluation to identify which patients are most likely to benefit. Additional studies with longer follow-up are required to assess the optimal daratumumab-based regimen to be used in this growing population of patients relapsing after lenalidomide maintenance. Disclosures Mian: Janssen: Consultancy, Honoraria; Celgene: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. McCurdy:Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Leblanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. White:Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kotb:Karyopharm: Current equity holder in publicly-traded company; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding. Reece:Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria; Millenium: Research Funding; BMS: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding.

The Role of Whole Body STIR MRI in Assessing First Biochemical Relapse in Patients with Myeloma

Background: Myeloma remains an incurable disease and most patients will relapse. The optimal timing of salvage initiation remains uncertain although there is a trend to treating early biochemical relapse. In the current COVID-19 pandemic, delaying therapy of asymptomatic relapsed patients is also desirable, but avoidance of renal failure and symptomatic bony disease is important. Whole body STIR MRI with diffusion weighted imaging (DWI) has the potential to diagnose bone involvement at a very early, pre-symptomatic stage, before cortical destruction occurs. It may be a useful tool to assess the ability to defer therapy in myeloma patients with asymptomatic biochemical relapse.Methods: We performed a retrospective audit of newly diagnosed patients with symptomatic myeloma, diagnosed between April 2012 and Oct 2019. We studied only patients in first relapse who had achieved PR or better to first-line therapy. Patients were typically monitored with monthly serum protein electrophoresis and free light chain assessments. The preferred imaging modality during the study period was whole body STIR MRI with DWI analysis and additional dedicated spinal sequences. Response and relapse criteria were as defined by the IMWG with the exception that regular urine BJP monitoring was not performed. Rapid biochemical relapse was defined as per Sonneveld (ASH Education Book 2017). The decision to initiate therapy for relapse was at the discretion of the treating hematologist.Results: 125 patients with newly diagnosed symptomatic myeloma who achieved PR or better to first line therapy were identified. Median age at diagnosis was 64yrs (range, 32 to 89yrs) and 72% were male. Immunoglobulin type was IgG (54%), IgA (23%), light chain (22%) and IgD (1%). ISS stage was I (19%), II (60%) and III (21%) and 21% were high risk as defined by the presence of t(4;14), t(14;16) or del17p by bone marrow FISH. Half received autologous stem cell transplantation with bortezomib-based therapy being the commonest induction for both transplant- and non-transplant-eligible populations. Amongst this group with responsive disease, haematological response was CR (38%), VGPR (29%) and PR (33%).75 (60%) of patients have relapsed at a median of 32 months. For patients in CR and VGPR, it took a median of 92 days from the first presence or increase in monoclonal immunoglobulin until IMWG defined relapse criteria were met. At the time of IMWG defined relapse, in terms of assessing need for therapy, the patients clinical status was defined as: rapid biochemical relapse (15%), relapse in a patient with high risk FISH (26%), relapse in a patient with renal failure at diagnosis (15%) and meeting CRAB criteria exclusive of MRI findings (7%), leaving 37% (n=27) in slow biochemical relapse without a definite indication for urgent therapy. MRI was performed as the bone imaging modality in 20 of these 27 slow biochemical relapse patients at a median of 42 days (range, -12 days to 210 days) after IMWG defined relapse: 10 demonstrated new focal bone lesions, 3 no lesions, 4 stable lesions and 3 improved bone lesions. Of these 10 patients with no new MRI detected bone disease, two were treated immediately at physician discretion.Thus, only 8 of 75 relapses were asymptomatic with a normal MRI, had no other indication for urgent therapy and were observed. For this group, the median time to treatment was 96 days (range, 34 to 576 days). Of these 5 had therapy initiated at physician discretion in the absence of clinical deterioration at a median of 78 days post biochemical relapse, one had treatment started 38 days after relapse due to renal deterioration and two were observed for 6 months and 1.4 years prior to the development of progressive focal bone lesions on MRI. None of the 10 patients with slow biochemical relapse and no new focal MRI bone lesions developed symptomatic bone disease within 6 months of that normal MRI.Conclusion: Whole body STIR MRI identifies new focal bone lesions in half of patients with slow biochemical relapse and no other treatment indication, justifying early therapy initiation at biochemical progression. In the setting of the COVID-19 pandemic, whole body STIR MRI with DWI may also be a useful tool to identify patients with slow biochemical relapse who are suitable for careful observation rather than salvage chemotherapy. Only a minority (11% in our study) of relapses, however, are potentially suitable for this approach.DisclosuresMollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees.

PB2163 CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE “ON DEMAND” IN RELAPSED/REFRACTORY MULTIPLE MYELOMA: REAL LIFE EXPERIENCE AND NEW PERSPECTIVES ON DOSE‐DENSE CHEMOTHERAPY

Background:The natural history of Multiple Myeloma (MM) is characterized by improved survival rates but relapses are still common, thus new therapeutic approaches are still needed.Carfilzomib (K) is a selective and irreversible epoxyketone proteasome inhibitor approved in combination with dexamethasone (d) and lenalidomide (R) for the treatment of patients with relapsed‐refractory MM (1–3 previous lines of therapy) and as a single agent for the treatment of patients with relapsed or refractory MM (1 or more previous lines of therapy).Aims:The aim of this study is to describe the real life of our patients treated with KRd and to give new perspectives on dose‐dense chemotherapy.MethodsData from patients with relapsed/refractory MM treated with KRD in the Federico II University of Naples, were retrospectively analyzed.Response was evaluated according to International Myeloma Working Group Uniform Response Criteria. Disease assessments were performed on day 1 of each cycle. In patients that had obtained a PR, VGPR, CR in at least 3 consecutive measurements carried out at monthly intervals during treatment the therapy was discontinued and the patients were reassessed every 30 days. The same treatment was reintroduced when disease progressed according to clinical and/or biochemical parameters. Finally, a different line of therapy was employed when signs of disease resistance to KRd appeared.KRd treated patients were than divided into three cohorts as per chemotherapy dose‐density: in the first group patients received ≤50% of the expected cycles (low‐dose); in the second group patients received a dose comprised between 50% and 75% of the expected cycles (int‐dose); in the third group ≥75% of the expected cycles (high‐dose) was employed.The primary endpoint was the time to next treatment (TTNT) for the entire population and among the three dose dense cohorts.Secondary endpoint was the overall response rate (ORR).Results:From January 2016 to January 2019 forty‐two patients with a diagnosis of MM treated with KRD combination, relapsed after a previous therapy (1‐7) including bortezomib and Immunomodulatory Drugs (IMiDS), were enrolled. Median age was 63.2 years; Performance status was &gt;2 in the 40% patients. Patients with high cytogenetic risk were the ones treated with more than two previous chemotherapy lines. All patients with more than two previous lines had received IMIDs, while these drugs weren’t employed in the 40% of those previously treated with only one line. Bortezomib was employed in almost all patients. TTNT was 13 (range 1‐30) months for the entire cohort while the median TTNT for low‐dose cohort was not reached; the int‐dose and the high‐dose cohort had a median TTNT of 13 and 5 months respectively (figure). The ORR of the entire cohort was 95%.Summary/Conclusion:This retrospective analysis indicates that KRd improved the outcome of patients in first relapse, of patients with ≥ 2 previous lines of therapy and of those refractory to bortezomib and IMiDS.imageAlthough therapies for relapsed MM are licensed as continuous treatment until progression, our data suggest that less dose‐density appears to have the same efficacy of continuous treatments but with less toxicity and significant economic savings.

A Multicenter Open Label Phase II Study of Pomalidomide, Cyclophosphamide and Dexamethasone in Relapse Multiple Myeloma Patients Initially Treated with Lenalidomide, Bortezomib and Dexamethasone

A Multicenter Open Label Phase II Study of Pomalidomide, Cyclophosphamide and Dexamethasone in Relapse Multiple Myeloma Patients Initially Treated with Lenalidomide, Bortezomib and Dexamethasone

Impact on survival of early detection of recurrence in the follow‐up of high risk Hodgkin lymphoma in first complete remission

Despite the high complete response (CR) rate to first-line therapy, approximately one-third of patients with high risk Hodgkin lymphoma (HL) eventually relapses. In up to 30 to 50% of patients, relapses are initially evident only by imaging procedures, however a definitive consensus on the best surveillance procedure for high risk HL patients has not been reached yet. The purpose of this cohort study is to evaluate the long-term outcome after salvage treatment and ASCT, of high risk HL patients who relapse under imaging surveillance compared to the conventional clinical monitoring. We evaluated a total of 123 high risk HL patients in first relapse followed, after remission, either with a systematic imaging-based surveillance (Imaging cohort, n= 80) or with the standard clinical-based surveillance (Standard cohort, n = 43). Follow-up procedures within the imaging group involved either FDG/PET CT or ultrasound plus chest X-Ray. The 2-years EFS was significantly longer in the patients of the Imaging cohort with respect to the standard cohort (70% vs 37.2%, respectively - p=0.004) and the quality of responses was better in the former cohort (CR rate 68.8% vs 41.9% - p<0.004). Those differences were most likely due to the capability of imaging surveillance to identify early onset of clinically silent relapses whose EFS at 2 years is significantly better (78% vs 43%, respectively – p<0.0001). Our data indicate that the early detection of HL recurrence allows a timely administration of salvage therapy to patients with a more limited disease and, consequently, an EFS improvement.

Immunotherapy in lymphoma.

Immunotherapy in lymphoma.

Differential Outcome of Patients with Primary Refractory Vs. Relapsed Peripheral T-Cell Lymphoma: Analysis from a Prospective Multicenter US Cohort Study

Differential Outcome of Patients with Primary Refractory Vs. Relapsed Peripheral T-Cell Lymphoma: Analysis from a Prospective Multicenter US Cohort Study

Mitoxantrone and Etoposide for the Treatment of Acute Myeloid Leukemia Patients in First Relapse

Relapsed acute myeloid leukemia (AML) represents a major therapeutic challenge. Achieving complete remission (CR) with salvage chemotherapy is the first goal of therapy for relapsed AML. However, there is no standard salvage chemotherapy. The current study evaluated outcomes and prognostic factors for achievement of CR in 91 AML patients in first relapse who were treated with the mitoxantrone–etoposide combination regimen. The overall response rate (CR and CRi) was 25%. Factors that were associated with a lower rate of CR included older age, shorter duration of first CR, low hemoglobin, and low platelet count. The median overall survival for all patients was 7.4 months. The survival of patients who achieved CR and underwent allogeneic hematopoietic cell transplantation (allo-HCT) was higher than those who achieved CR and did not undergo allo-HCT (35.3 months vs. 16.8 months, p = 0.057). The median duration of relapse-free survival was 12.7 months in the patients achieving CR. Older age at the time of AML relapse was associated with worse overall survival. The all-cause 4-week mortality rate was 4%, and the all-cause 8-week mortality rate was 13%. The findings of this study underscore the need for newer therapies, especially those that will improve the ability for patients with relapsed AML to achieve CR and to allow them to receive additional therapies.

Randomized Phase II Trial of Timed Sequential Cytosine Arabinoside with and without the CHK1 Inhibitor MK-8876 in Adults with Relapsed and Refractory Acute Myelogenous Leukemia

Background: Cytosine arabinoside (ara-C) remains the backbone of most regimens for the treatment of AML. The incorporation of ara-C into DNA activates checkpoint kinase 1 (Chk1) causing replication fork slowing, the accumulation of cells in S phase, and diminished ara-C cytotoxicity. The selective Chk1 inhibitor MK-8776 abrogates ara-C-induced S-phase arrest, thereby enhancing ara-C-induced apoptosis in vitro.1 A phase I trial demonstrated the safety of MK-8876 in combination with infusional ara-C and correlative studies demonstrated increased ara-C-induced H2Ax phosphorylation in AML cells, consistent with unrepaired DNA damage.2 Herein, we report data from a phase II trial comparing ara-C plus MK8876 with ara-C alone.Methods: Patients with relapsed or refractory AML were randomized to receive either ara-C 2 gm/m2 via continuous infusion (CIV) over 72 hours on days 1 and 10 with MK-8776 100 mg flat dose infused over 30 minutes on days 2, 3, 11, and 12 (combo); or ara-C alone on the same schedule (control). The primary end point was response rate (CR+CRi). Adverse events (AEs) for all patients were reported according to the NCI-CTCAE version 4.0. Correlative studies were performed on blood and marrow samples collected prior to treatment on days 1, 2 and 3 and at one hour after MK-8776 infusion (PB only). Marrow and circulating blasts were analyzed using semi-quantitative flow cytometric determinations of blast cell gH2AX expression, a marker of DNA damage.Results: Thirty-two patients were treated at 4 sites with 14 assigned to the combo arm and 18 to the control arm. The study was stopped early due to lack of drug availability. The median age was 60 (range 29-72) and 17 (53%) were male. Nine (28%) had refractory AML, 16 (50%) were in first relapse, and 7 (22%) were in second relapse. Eleven (34%) had undergone a prior bone marrow transplant (BMT). Risk stratification classified 1 (3%) patient as favorable risk disease, 11 (34%) as intermediate-1, 8 (25%) as intermediate-2, and 11 (34%) as adverse risk.There were 5 (36%) responses (CR/CRi) and 1 (7%) partial response (PR) in the combo arm, and 8 (44%) responses and 1 (6%) PR in the control arm. Median survival did not differ significantly between the two groups (5.9 months in the combo arm vs. 4.2 months in the control arm). Sub-group analysis showed increased responses in the combo arm for the patients in first relapse (50% vs. 40%) and those with a prior BMT (50% vs. 29%). Most non-hematologic grade 3/4 treatment-related AEs were similar in the two groups including febrile neutropenia (64% vs. 61%), infectious complications (50% vs. 50%), and sepsis (21% vs. 17%). Patients in the combo arm experienced more QT prolongation (21% vs. 0%), hypertension (21% vs. 0%), and GI toxicities (21% vs. 0%); while those in the control arm had increased renal (0% vs. 11%) and liver toxicity (7% vs. 17%). Two deaths were attributed to treatment, and both were in the control arm.Eight combo patients had serial PB samples and 2 had serial marrow samples studied by flow cytometry. There was an increase in the percentage of gH2AX+ CD34+ cells on Day 2 directly after MK-8876 infusion (16.9% prior and 36.4% at one hour), which occurred to a lesser extent on Day 3 after MK-8876 infusion (12.7% prior and 15.6% at one hour). Three of eight patients demonstrated a sustained increase in gH2AX+ CD34+ from Day 2 to Day 3, and all three achieved either a PR or CR.Conclusion: This is the first phase II study building on prior work suggesting that inhibition of Chk1 would increase response to ara-C in patients with relapsed or refractory AML. The study confirmed that treatment with the combination is feasible with similar toxicities between the treatment and control groups. The response rates were similar between the two groups with improved responses in patients receiving the combo in first relapse and following BMT. Correlative studies support the finding that responding patients show a sustained increase in DNA damage and this may serve as a biomarker in future studies. Chk1 remains a potential target to improve treatment outcomes with ara-C.

Autologous Transplant, and Not ATO Alone, Remains the Preferred Therapy for Relapsed APL: A Report from the CIBMTR, EBMT and Two Specialized Centers

Introduction: Despite its favorable prognosis, 10-20% of APL patients relapse with contemporary therapeutic strategies. At relapse, reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). In the last two decades, arsenic trioxide (ATO) has become part of the standard reinduction regimens. Such an approach is often followed successfully by auto-HCT. However, long-term survivors have also been reported after ATO treatment alone without HCT. We retrospectively compared the outcome of auto-HCT, with or without ATO, and ATO-based therapy given alone following relapse in patients with APL.Patients and Methods: Data on APL patients in first relapse were collected from the two largest transplant registries (CIBMTR, EBMT) and two specialty referral centers (Hematology-Oncology & Stem Cell Transplantation Research Center, Shariati Hospital, Tehran and Christian Medical College & Hospital, Vellore, India). The outcome of patients who received ATO at relapse and did not undergo transplantation was compared to that of patients who received any reinduction therapy, including ATO and subsequent auto-HCT. Overall survival was calculated from two months post relapse with left truncation at date of CR2 for patients receiving ATO alone and date of transplant for those receiving auto-HCT. Cox proportional hazard regression was used to estimate the univariate and multivariate associations with overall survival. Potential prognostic factors included age, disease risk based on WBC >10,000/µl, the presence of extramedullary disease, and duration of CR1, in addition to the primary comparison of auto-HCT and ATO-based reinduction therapy.Results: 242 patients were identified, of whom 34 were excluded due to missing relapse date (n = 25), death or lost to follow-up before 2 months after relapse (n = 7), or receiving auto-HCT within two months of relapse (n = 2). The median age was 31, 63% of the patients were males and median WBC count at diagnosis was 4,750/µl. The final cohort of 208 patients included 68 receiving ATO alone and 140 receiving auto-HCT. The groups were comparable in terms of age, gender, duration of CR1 and risk group. Fifty-six percent of the auto-HCT patients received ATO-based treatment as salvage therapy and the others received various combinations of chemotherapy and ATRA.There is a statistically significant survival advantage for the HCT group (HR = 0.34 (0.27-0.42), p<0.001) compared to the ATO only group. At 5 years, OS was 42% (95% CI: 31% - 58%) and 78% (95% CI: 71% - 86%) for the ATO-only and HCT groups, respectively. In addition, there was a significant OS association with longer duration of CR1 (p=0.002) and presence of extramedullary disease (p = 0.041); which remained significant in a multivariate model (p < 0.001). Disease risk at diagnosis was not associated with OS.Conclusions: These data suggest that auto-HCT results in improved OS after APL relapse, better than ATO-based therapy alone. Further studies to identify improvements in auto-HCT and which patients treated with ATO alone may be cured are needed. DisclosuresDouer:Gilead: Consultancy. Rowe:Amgen: Consultancy; BioLineRx Ltd.: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Prongnostic Implication of Cytogenetic Abnomalities for Newly Diagnosed Muliple Myeloma in Young Patients: Tunisian Monocenter Experience

e126 relapse of 23,8 months [6-69]. One patient had CNS MM at diagnosis and 4 patients in first relapse. Three patients presented intraparenchymal focal lesions, 1 CNC myelomatosis and 1 intraparenchymal focal lesion associated with leptomenigeal infiltration. The patient, who presented CNS MM at diagnosis, received VCD followed by ASCT and he is in CR with a follow up of 19 months. Four patients presented CNS MM in relapse: 2 were treated with Lenalidomide and dexamethasone (Len+Dex) with an overall survival of 1 and 2 months since the diagnosis of CNS MM and 2 were treated with VCD (1 patient had an overall survival of 12 months and 1 is in VGPR with a follow up of 14 months since the diagnosis of CNS MM). Conclusion: There are no treatment guidelines for CNS MM and few new drugs cross the blood-brain barrier. The median overall survival from the time of diagnosis of SNC MM ranges from 2 to 6 months. Clinical results seem better when CNS involvement occurs at diagnosis compared to relapse setting. Clinical trials involving these patients are essential to improve outcomes.

Phase I/II Trial of Weekly Escalated Dose Bortezomib Combined with Lenalidomide and Dexamethasone in Patients in First Relapse or Primary Refractory Disease after First Line Therapy for Multiple Myeloma

Background Both Bortezomib and Lenalidomide monotherapy, as well as in combination with dexamethasone and chemotherapy, have shown high overall response rates (ORR) in relapsed and refractory multiple myeloma (RRMM). Recently, the combination of Bortezomib (1.0 mg/m2), Lenalidomide (15 mg) and Dexamethasone was reported to show efficacy in RRMM. (Richardson, Blood 2014) Here, we report the long-time follow-up results of a multicenter, dose-escalating phase I-II trial, HOVON86, which evaluated the effect of weekly escalated dose Bortezomib combined with Lenalidomide and Dexamethasone as reinduction treatment followed by Lenalidomide monotherapy for maintenance treatment in patients with RRMM after first line therapy. (Trial EudraCTnr 2007-002533-37)Methods In the dose escalation part of the study, the maximum tolerated dose (MTD) and recommended dose level (RDL) of weekly Bortezomib and Lenalidomide with Dexamethasone were determined according to a ‘3 + 3′ dose-escalation scheme. A maximum of 4 dose levels were planned. Bortezomib was administered once weekly by rapid intravenous administration on days 1, 8, and 15, at a starting dose of 1.3 mg/m2 and planned to be escalated to 1.6 mg/m2, Lenalidomide was administered days 1-21 followed by a one-week interval at a starting dose of 10 mg/day and planned to be increased to 15 mg at dose level 3 and 4. Low dose Dexamethasone was added at a fixed dose of 20 mg days 1,2,8,9,15, and 16. Cycles were repeated at 28 days for a maximum of 8 cycles. The MTD was defined as the level with 2 dose-limiting toxicities (DLT) minus 1 level. A phase II part of the study was performed at the MTD level. All patients received Lenalidomide maintenance at a dose of 10 mg/day, days 1-21 in 28 day cycles until relapse or progression. Patients received valaciclovir prophylaxis with Bortezomib and prophylactic salicylic acid throughout treatment.Results 81 patients with a first RRMM were enrolled, 4 patients were non-eligible based on not having measurable disease. The median age of all 77 evaluable patients at enrollment was 66 years (range, 46–84), 64% male, and 26%/5% of patients had ISS II/III disease. In the Phase 1 part, 15 patients received Bortezomib/Lenalidomide/Dexamethasone according to dose level 1: 1.3 mg/m2/10mg/20mg (n=3), dose level 2: 1.6 mg/m2/10mg/20mg (n=6) or dose level 3: 1.6 mg/m2/15mg/20mg (n=6). The DLT was reached at the 3rd dose level, due to two grade 3 non-hematological DLT’s. There were no DLT’s in dose level 1 or 2. Therefore, the RDL for the phase 2 part was established at Bortezomib 1.6 mg/m2, Lenalidomide 10 mg, Dexamethasone 20 mg.In the Phase 2 part of the study, the ORR after induction in 70 patients at the RDL of Phase I (n=6) and in Phase II (n=64), was 89%, with 64% CR +VGPR, table 1. The median number of cycles to achieve ≥PR was 1, while the median number of cycles to maximum response was 2. The median duration of response was 28 months. The median progression free survival (PFS) and overall survival (OS) were 19 and 42 months, respectively, Figure 1. The median time to progression was 27 months; the median time to next treatment was 19 months.Prognostic factors associated with PFS included complex karyotype, defined as showing 3 or more abnormalities; no prognostic factors were identified in association with OS.Hematologic toxicity NCI-CTC grade 1-4 occurred in 33/70 (47%) of patients, including 30% grade 3-4. Infectious complications concerned grade 2 in 29% and grade 3 in 16% of patients. Thrombo-embolic events (VTE) occurred in 2 patients (3%). 41/70 (59%) patients developed polyneuropathy (PN) grade ≥ 1; of these 41 patients, 18 patients experienced sensory PN, 2 patients had motor PN, and in 21 cases the type of PN was not further specified. 29 (41%) patients had grade 1-2, and the remaining 12 (17%) patients had grade 3-4 PN. 12/29 (41%) patients received a dose reduction upon development of PN grade 1-2, 11/12 (92%) patients upon development of grade 3-4 PN. 19/29 (66%) patients with grade 1-2 PN showed a complete recovery as compared to 6/12 (50%) patients with grade 3-4 PN.Conclusion Weekly Bortezomib 1.6 mg/m2 plus Lenalidomide 10 mg/day, combined with low-dose Dexamethason is a feasible, effective treatment for relapsed, refractory patients with manageable toxicity.Table 1Phase 1: n(%)Phase 2: n(%)Total: n(%)Total66470CR+VGPRNo3(50%)2(34%)25(36%)Yes3(50%)42(66%)45(64%)ORR: ≥PRNo1(17%)7(11%)8(11%)Yes5(83%)57(89%)62(89%) [Display omitted] [Display omitted] DisclosuresKersten:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees. Vellenga:Janssen: Research Funding. Bos:celgene: Research Funding. Lokhorst:Genmab: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding.