Consolidation Therapy In Patients Research Articles

High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

Anlotinib hydrochloride consolidation after concurrent chemoradiotherapy in stage III non-small-cell lung cancer: a truncated, randomized, multicenter, clinical study (ALTER-L029).

Anlotinib is an antiangiogenic drug that shows good efficacy and safety in patients with advanced non-small-cell lung cancer (NSCLC). This study aimed to explore the efficacy and safety of anlotinib for consolidation therapy in patients with stage III locally advanced, unresectable NSCLC after concurrent chemoradiotherapy (cCRT). This was a randomized, parallel-controlled, open-label, multicenter, phase II trial of patients with unresectable/nonoperated NSCLC treated with cCRT. The participants were randomized 2:1 to the anlotinib or control group. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the disease control rate (DCR) and overall survival. This study was terminated early due to poor recruitment. Nine and two participants were randomly assigned to the anlotinib and control groups, respectively. One participant in the control group was excluded due to taking prohibited medications before the first efficacy evaluation. In the anlotinib group, the median age was 63 (range, 37-74) years. Two participants achieved partial response, six stable disease, and one progressive disease as best response. The DCR was 88.9%. The median PFS was 11.5 months, and the 12-month PFS rate was 33.9%. All related adverse events were grade 1 or 2. Two participants had a dose adjustment during the study. The evaluable data suggest that anlotinib alone was effective and tolerable in consolidation therapy after cCRT in patients with stage III unresectable NSCLC. The results need to be confirmed by a large-sample trial. This clinical trial was registered on www.clinicaltrials.gov (NCT03743129). Registration date: 6 September 2018.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40months, whereas CD19+ FTCs vanished in 8 patients 3months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia in the Era of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO).

Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses, following the introduction of all-trans retinoic acid (ATRA) and subsequently of arsenic trioxide (ATO) treatment. As a result, a large proportion of patients with APL achieve long-term responses after first-line therapy, so performing a hematopoietic stem cell transplant as consolidation of first complete remission (CR) is no longer necessary. Even in the case of relapses, most patients obtain a new remission as a result of therapy with ATO and ATRA, but an effective consolidation treatment is necessary to maintain it. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the outcome of patients who achieve a new CR. Thus, the expert groups recommend transplantation as consolidation therapy in patients with a second CR, with the indication for autologous HSCT in cases with molecular CR and for allogeneic HSCT in patients with the persistence of minimal residual disease (MRD) or with early relapse. However, there is a variety of controversial aspects related to the role of HSCT in APL, ranging from the fact that outcome data are obtained almost exclusively from retrospective studies and historical analyses to questions related to the type of transplantation, the impact of minimal residual disease, conditioning regimens, or the role of other therapeutic options. All these questions justify the need for controlled prospective studies in the following years.

Identification of predictive factors for early relapse in patients with unresectable stage III non-small cell lung cancer receiving consolidation durvalumab after concurrent chemoradiation therapy.

Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation therapy (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance have not yet been identified. The present study included the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from January 2018 to December 2021. A total of 51 NSCLC patients treated with durvalumab consolidation therapy after definitive CCRT were included in the analysis. Early relapse was defined as patients experiencing relapse within 6 months of starting initial durvalumab therapy. Among the 51 patients, 15 (29.4%) relapsed during the study period. Median time from initial therapy of durvalumab to progression was 451.00 ± 220.87 days (95% confidence interval [CI]: 18.10-883.90) in overall patients. In multivariate analysis, younger age (adjusted odds ratio [aOR], 0.792; 95% CI: 0.642-0.977; p = 0.030), higher pack-years (aOR, 1.315; 95% CI: 1.058-1.635; p = 0.014), non-COPD (aOR, 0.004; 95% CI: 0.000-0.828; p = 0.004) and anemia (aOR, 234.30; 95% CI: 1.212-45280.24; p = 0.042), were independent predictive factors for early relapse during durvalumab consolidation therapy. Younger age, higher number of pack-years, non-COPD, and anemia were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals.

Rituximab-bortezomib-dexamethasone induce high response rates in iMCD in clinical practice.

Treatment options for idiopathic multicentric Castleman disease (iMCD) are currently limited, especially for patients who do not respond or are resistant to interleukin-6 inhibitors. For the first time, we innovatively designed a protocol using rituximab-bortezomib-dexamethasone (RVD) as first-line consolidation therapy in patients newly diagnosed with iMCD. Furthermore, we adopted a no-maintenance treatment strategy to simplify post-remission care. Five patients with iMCD were enrolled (including one with TAFRO syndrome) and underwent the RVD regimen, all of whom achieved partial response (PR) or better. After four cycles of RVD, three (60%) patients achieved PR, while one (20%) achieved a complete response. These five patients, who achieved PR or better, discontinued treatment but remained stable for a median follow-up of 11 months, with a duration of response of 7, 7, 10, 12 and 13 months, respectively. None of the patients experienced grade ≥3 adverse events during the observation period. Collectively, these findings demonstrated that the RVD regimen may be a promising treatment option for patients with iMCD. It was a safe and effective approach that resulted in lasting responses without the need for ongoing maintenance therapy.

High burden of clinically significant adverse events associated with contemporary therapy for pediatric T-cell acute lymphoblastic leukemia/lymphoma.

Despite improvements in survival for children with T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/LLy), morbidity remains high. However, data are lacking regarding comprehensive descriptions of clinically relevant adverse events (AEs) experienced during early intensive chemotherapy. This single-institution retrospective study evaluated children aged 1-21 years with T-ALL/T-LLy diagnosed from 2010 to 2020. Physician chart abstraction identified and graded 20 clinically relevant AEs. AE rates were analyzed by T-ALL or LLy, minimal residual disease status, induction steroid, and use of antimicrobial prophylaxis. Statistical comparisons used the Kruskal-Wallis test (continuous variables) and Chi-square or Fisher's exact test (categorical variables). The cohort included 120 patients (T-ALL: 88; T-LLy: 32). Most patients experienced AEs during induction (85 out of 120; 70.8%) and consolidation (89 out of 111; 80.2%). Nonsepsis infection was common in induction (26 out of 120; 21.7%) and consolidation (35 out of 111; 31.5%). Patients treated with dexamethasone during induction had significantly higher rates of nonsepsis infection and/or sepsis during consolidation than those who received prednisone (p<.01). Clinically significant AEs are extremely common during induction and consolidation therapy for patients with T-ALL/LLy. Infectious AEs are particularly prevalent. These results can inform conversations with patients and families and aid in the development of toxicity-related aims in the next generation of, prospective clinical trials in T-ALL/LLy.

EN-DALBACEN 2.0 Cohort: real-life study of dalbavancin as sequential/consolidation therapy in patients with infective endocarditis due to Gram-positive cocci

Infective endocarditis (IE) has high mortality and morbidity and requires long hospital stays to deliver the antibiotic treatment recommended in clinical practice guidelines. We aimed to analyse the health outcomes of the use of dalbavancin (DBV) in the consolidation treatment of IEs caused by Gram-positive cocci and to perform a pharmacoeconomic study. This observational, retrospective, Spanish multicentre study in patients with IE who received DBV as part of antibiotic treatment in consolidation phase were followed for at least 12 months. The study was approved by the Provincial Committee of the coordinating centre. The study included 124 subjects, 70.2% male, with a mean age of 67.4 years and median Charlson index of 4 (interquartile range: 2.5-6). Criteria for definite IE were met by 91.1%. Coagulase-negative staphylococci (38.8%), Staphylococcus aureus (22.6%), Enterococcus faecalis (19.4%), and Streptococcus Spp. (9.7%) were isolated more frequently, all susceptible to vancomycin. Before DVB administration, 91.2% had undergone surgery; 60.5% had received a second regimen for 24.5 d (16.6-56); and 20.2% had received a third regimen for 14.5 d (12-19.5). DBV was administered to facilitate discharge in 95.2% of cases. At 12 months, the effectiveness was of 95.9%, and there was 0.8% loss to follow-up, 0.8% IE-related death, and 3.2% relapse. Adverse events were recorded in 3.2%. The hospital stay was reduced by 14 d, and there was a mean savings of 5548.57 €/patient vs. conventional treatments. DBV is highly effective, safe, and cost-effective as consolidation therapy in patients with IE by Gram-positive cocci, with few adverse events.

Design and Rationale for a Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study of Sugemalimab as Consolidation Therapy in Patients With Limited-Stage Small-Cell Lung Cancer Who Have Not Progressed Following Concurrent or Sequential Chemoradiotherapy: The SURPASS Study

BackgroundThere is still a substantial need of more treatment options for patients with limited-stage small cell lung cancer (LS-SCLC). The standard therapy for LS-SCLC is platinum-based doublet chemotherapy administered concurrently with thoracic radiotherapy (cCRT). In China, sequential chemoradiotherapy (sCRT) is also a common practice. However, the disease inevitably progresses in most patients despite the curative intent and initial response. Materials and MethodsSugemalimab is an anti-programmed death ligand-1 (PD-L1) antibody that improved clinical outcomes for patients with stage III non-small cell lung cancer after cCRT or sCRT. The SUPPASS study is a phase II/III, randomized, double-blind, placebo-controlled, multicenter study (NCT05623267) that aims to investigate the efficacy and tolerability of sugemalimab as consolidation therapy in patients with LS-SCLC who have no progression following cCRT or sCRT. Approximately 346 patients will be randomized in a 1:1 ratio to receive sugemalimab 1200 mg or placebo every 3 weeks for up to 12 months. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall survival (OS), landmark PFS rate, landmark OS rate, objective response rate and safety. Longitudinal molecular residual disease (MRD) testing will be performed as preplanned exploratory analysis. ConclusionStudy results will help demonstrate the efficacy and tolerability of anti-PD-L1 antibody consolidation therapy in LS-SCLC patients who have not progressed following cCRT or sCRT, and help determine the clinical implications of MRD in LS-SCLC.

Phase 3 trial of durvalumab combined with domvanalimab following concurrent chemoradiotherapy (cCRT) in patients with unresectable stage III NSCLC (PACIFIC-8).

TPS8609 Background: The PACIFIC trial (NCT02125461) established up to 12 months of consolidation therapy with durvalumab as standard of care (SoC) for patients with unresectable stage III non-small-cell lung cancer (NSCLC) and no disease progression after platinum-based cCRT. To improve outcomes further in this population, novel immunotherapy combinations that build on the backbone of PD-L1 inhibition with durvalumab are being explored. Domvanalimab (AB154) is a Fc-silent humanized IgG1 monoclonal antibody that blocks interaction of the T cell immunoreceptor with Ig and ITIM domains (TIGIT; upregulated by immune cells) with CD112 and CD155 (expressed by tumor and antigen-presenting cells), reducing inhibition of T cells and natural killer cells and, thereby, promoting antitumor activity. The combination of TIGIT inhibition with PD-(L)1 inhibition has shown encouraging activity in phase 1 and 2 trials in metastatic NSCLC, with enriched benefit observed among patients with PD-L1 positive tumors (Rodriguez-Abreu, et al. 2020; Niu, et al. 2020). In ARC-7 (NCT04262856), a randomized, phase 2 trial, the combination of domvanalimab and PD-1 inhibition was associated with improvement in progression-free survival (PFS) versus PD-1 inhibition alone (HR, 0.55; 95% CI, 0.31–1.0) in treatment-naïve patients with metastatic NSCLC and high PD-L1 expression (tumor proportion score ≥50%) (Johnson, et al. 2022). PACIFIC-8 (NCT05211895) is assessing the efficacy and safety of durvalumab combined with domvanalimab as consolidation therapy in patients with PD-L1 positive, unresectable stage III NSCLC and no disease progression after platinum-based cCRT. Methods: PACIFIC-8 is a phase 3, double-blind, placebo-controlled, randomized, global trial. Eligible patients (aged ≥18 years) must have PD-L1 positive, unresectable stage III NSCLC (tumor cell [TC] expression ≥1% by central lab; VENTANA SP263 IHC assay), WHO performance status 0/1, documented EGFR/ALK wild-type tumor status, and not have progressed following definitive, platinum-based cCRT (≥2 cycles). Approximately 860 patients will be randomized (1:1) to receive SoC durvalumab (1500 mg IV) combined with either domvanalimab (20 mg/kg IV) or placebo, every 4 weeks for up to 12 months. The primary endpoint is PFS (RECIST v1.1) by blinded independent central review (BICR) in patients with PD-L1 TC ≥50%. Secondary endpoints include PFS (RECIST v1.1; BICR) in patients with PD-L1 TC ≥1%, overall survival, objective response rate and duration of response (RECIST v1.1; BICR), safety/tolerability, and patient-reported outcomes. Trial enrollment is ongoing. Previously presented at the European Society for Medical Oncology (ESMO) Congress 2022, FPN (Final Publication Number): 971TiP, Mustafa Özgüroğlu et al. – Reused with permission. Clinical trial information: NCT05211895 .

Durvalumab outcomes for patients with PD-L1 positive and negative stage III unresectable non-small cell lung cancer treated at veterans health administration facilities.

e18793 Background: Clinical trials and real-world studies have documented the benefit of durvalumab consolidation therapy in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC) following chemoradiotherapy (CRT). Methods: Patients with stage III UR-NSCLC on durvalumab following CRT, at any Veterans Health Administration (VHA) facility from 1/1/17 to 6/30/20, were included. Patients were followed from their durvalumab initiation date through the earliest of their last VHA visit, loss to follow up, death, or end of study. Electronic health record and chart review data were retrospectively collected to determine baseline characteristics, number of durvalumab doses, length of follow-up, and overall survival (OS). Chi-square and Wilcoxon rank sum tests were used to compare baseline characteristics for patients with PD-L1 negative (&lt;1%) and positive (1% or greater) tumors. Kaplan-Meier curves were constructed for OS. Cox proportional hazards regression, with controls for divergent baseline characteristics, were used to compare OS between the two groups. Results: Of 935 available patients, 340 had PD-L1 results: 221 had PD-L1 positive (65%) and 119 had PD-L1 negative (35%) tumors. The two groups of patients were largely similar with respect to baseline characteristics, including age, sex at birth, White race, smoking status, marital status, Charlson Comorbidity Index, ECOG status, histology, stage, EGFR, and RAS mutations (Table). Patients with PD-L1 positive and negative tumors had a similar median (interquartile range [IQR]) number of durvalumab doses (15 [6-24] vs 12 [5-23], p=0.38) and length of follow-up (31.5 [12.1-43.5] vs 28.7 [12.2-40.6] months, p=0.43). Kaplan-Meier survival curves were similar for patients with PD-L1 positive and negative tumors: estimated 12-month OS rates (95% CI) of 84% (78%-88%) vs 89% (81%-93%) and 24-month OS rates of 72% (65%-78%) vs 76% (67%-84%); median OS was not reached in patients with PD-L1 positive tumors and was 47.0 months for the PD-L1 negative group. Cox Proportional Hazards regression analysis also demonstrated similar OS for both groups (p=0.64). Conclusions: In this real-world study of a subpopulation of VHA patients with stage III UR-NSCLC and known PD-L1 levels, survival benefits with durvalumab were consistent with those reported in the PACIFIC trial, despite having worse baseline prognostic factors. Patients with PD-L1 positive and negative tumors experienced similar overall survival, including 12- and 24-month OS rates.[Table: see text]

Abstract 6757: Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation

Abstract Background: Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance were not identified. Patients and Methods: The present study used the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from 2018 to 2021. In all, 51 NSCLC patients that were treated with durvalumab consolidation therapy after definitive CCRT. Early relapse was considered if it occurred within 6 months of starting initial durvalumab therapy. Results: During study period, 15 (29.4%) relapsed among 51 included patients. Median time from initial therapy of durvalumab to progression was 107.73 ± 47.69 days in early relapse group. In mutivariate analysis, younger age (HR 0.713, 95% CI 0.572-0.888, P=0.003), higher pack years (HR 1.311, 95% CI 1.109-1.549, P=0.001), non-COPD (HR 0.030, 95% CI 0.001-0.677, P=0.027), anemia (HR 23.30, 95% CI 2.030-267.48, P=0.011) and stage IIIC (vs. stage IIIA) (HR 17.890, 95% CI 1.997-160.243, P=0.010) were independent predictive factors for early relapse during durvalumab consolidation therapy. Conclusion: Younger age, higher pack years, non-COPD, anemia and stage IIIC were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals. Citation Format: Chang Dong Yeo, Hye Seon Kang, In Kyoung Kim, Sang Haak Lee, Jin Woo Kim. Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6757.

Omission of staging PET/CT linked to reduced survival in stage III non-small cell lung cancer: insights from the LUCAS project real-world data.

Stage III non-small cell lung cancer (NSCLC) is a highly heterogeneous stage due to its subgroups (IIIA-IIIC) comprising both resectable and unresectable tumors. Accurate determination of the extent of the disease is essential for excluding stage IV and choosing the optimal treatment regimen. Whole body positron emission tomography and computed tomography scan (PET/CT) is recommended as an initial staging imaging in locally advanced NSCLC. Despite international guidelines for NSCLC diagnosis and treatment, they are not always adhered to due to various reasons. Even in such a groundbreaking study, the phase 3 trial PACIFIC investigating the efficacy of durvalumab as consolidation therapy in patients with stage III NSCLC PET/CT was not mandatory. With the premise that whole body PET/CT of the trunk is essential for diagnosing stage III NSCLC, we performed a retrospective study evaluating the relationship of the use of PET/CT versus conventional staging with CT of the chest and abdomen, in terms of survival. This retrospective study of stage III NSCLC patients used the Czech lung cancer registry LUCAS, which was established in June 2018. As of the data export (up to February 9, 2022), a total of 703 patients were eligible for the analysis. Overall survival (OS) was compared using Kaplan-Meier analysis and a Cox regression model. Continuous variables were tested using the Mann-Whitney test, and categorical variables using the Pearson's Chi-square or Fisher's exact test. A total of 703 patients were included in the cohort with an average age of 69 years. PET/CT was performed on 354 patients, and conventional staging using chest and abdominal CT on 349 patients. The median OS among patients with PET/CT was 20.9 months [95% confidence interval (CI): 18.1-23.7], and it was statistically significantly higher (P<0.001) than among patients without PET/CT, where the median OS was 9.0 months (95% CI: 7.3-10.6). The observed effect of PET/CT was also statistically significant when comparing individual stages (IIIA, IIIB, IIIC). The multivariate Cox model confirmed the use of PET/CT as an independent prognostic factor. The most common reason for omission of PET/CT was the local or time unavailability of the examination. Omission of PET/CT can mean a significant decrement in survival for the patients in stage III NSCLC, likely due to poor staging and suboptimal treatment. Routine use of PET/CT is strictly recommended for the optimal management of stage III NSCLC patients even outside the high-income countries.

Effects on Survival of Non-Myeloablative Chemoimmunotherapy Compared to High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDC-ASCT) As Consolidation Therapy in Patients with Primary CNS Lymphoma - Results of an International Randomized Phase III Trial (MATRix/IELSG43)

BACKGROUND: Patients with primary central nervous system lymphoma (PCNSL) eligible for intensive treatment approaches are currently treated with high-dose methotrexate (HD-MTX) based induction immuno-chemotherapy followed by consolidative high-dose chemotherapy and ASCT (HDC-ASCT). However, it is unclear whether overcoming chemo-resistance and subsequently eliminating minimal residual disease may also be achieved by conventional-dose non-myeloablative immuno-chemotherapy, comprising non-cross resistant cytotoxic agents able to cross the brain-blood-barrier. We thus conducted an international randomized phase III trial comparing HDC-ASCT with non-myeloablative consolidation in patients with newly diagnosed PCNSL (MATRix/IELSG43 trial, NCT02531841). This is the first report on its primary endpoint. METHODS: This open label, randomized phase III trial was conducted in 56 centers of 5 countries (Germany, Italy, Denmark, Norway, Switzerland). Main eligibility criteria included newly diagnosed PCNSL, HIV-negative, age 18-65 years irrespective of ECOG PS or 66-70 years with ECOG PS ≤ 2, and adequate organ function. Induction consisted of 4 cycles of MATRix regimen (rituximab 375 mg/m2/d days 0 & 5; methotrexate 3.5 g/m2 day 1; cytarabine 2 × 2 g/m2/d days 2 & 3; thiotepa 30 mg/m2 day 4, every 21 days). Stem cell harvest was conducted after the 2nd cycle. Pts achieving at least partial response (PR) after completion of induction were randomly allocated to either arm A with two courses of R-DeVIC regimen (375 mg/m2 day 0; dexamethasone 40 mg/d days 1 to 3; etoposide 100 mg/m2/d days 1 to 3; ifosfamide 1500 mg/m2/d days 1 to 3; carboplatin 300 mg/m2 day 1); or arm B, consisting of HDC with BCNU 400 mg/m2 (day -6) and thiotepa 2 x 5 mg/kg/d days -5 & -4) followed by ASCT. The primary endpoint progression-free survival (PFS) was analyzed with a Cox proportional hazards model, containing the randomized treatment as hypothesis variable and the stratification variable response status as a covariate. RESULTS: Between July 2014 and August 2019, 368 pts were registered; 346 started treatment, 260 (75%) completed the induction therapy, and 115 and 114 pts were randomly assigned to arm A and arm B, respectively. Main reasons for not reaching randomization were toxicities (n= 87; 25%) and disease progression (n= 36; 10%). Median age of the randomized pts was 59 years (range 21 - 70) with 22.3% of pts being 65 years or older. Distribution of patient characteristics were well balanced between arms. Median follow-up of all registered patients is 44 months (range 0,2-86). 239 of 346 (69%) pts responded to induction treatment, 27% achieved a complete remission (CR) and 52% a partial remission (PR). Both consolidation strategies were well tolerated: R-DeVIC and HDC-ASCT were completed in 100 (87%) and 111 (97%) pts, respectively. 13 (3.8%) pts died of treatment-related complications during induction treatment, 11 of them due to neutropenic infectious complications. Consolidation treatment with R-DEVIC or HDC-ASCT resulted in a substantial increase of pts with CR (65% in arm A and 68% in arm B, respectively; p= 0.71). To date, there were 79 PFS events: 67 pts experienced progressive disease after randomization (47 for arm A and 20 for arm B). 6 pts died of toxicity during consolidation treatment (2 arm A and 4 arm B), and 6 pts died of unrelated causes while relapse-free (5 arm A and 1 arm B). The 3-year PFS (primary endpoint) differed significantly between the two arms: 79% (95% CI 71-86) after HDC-ASCT and 53% (95% CI 43-62%) after R-DeVIC (HR 0.42; p=0.0003). The 3-year OS was 86% (95% CI 78-91) for HDC-ASCT arm and 71% (95% CI 61-78) for R-DeVIC arm (HR 0.47; p=0.01). The evaluation of neurocognitive functions showed no difference between arms. CONCLUSION: This international randomized phase III trial demonstrates that consolidation with HDC-ASCT results in significantly better outcome than non-myeloablative chemoimmunotherapy. This comes along without any measurable negative effect on neurocognitive functions and with an excellent risk-to-benefit ratio. HDC-ASCT is the standard consolidation therapy for fit PCNSL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: Tagraxofusp-Based Therapy to Eradicate Measurable Residual Disease of Acute Myelogenous Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation

Background Numerous studies convincingly demonstrate that measurable residual disease (MRD) in AML at time of allogeneic cell transplantation (alloHCT) is a powerful, independent predictor of subsequent relapse. Attempts to eradicate AML MRD pre-transplant with consolidation chemotherapy have been unsuccessful, with reported MRD conversion rates as low as 20% (Appelbaum et al., Blood 2019). Tagraxofusp is an IL-3 truncated diphtheria toxin recombinant protein that binds CD123 with high affinity. Preliminary data using tagraxofusp as consolidation therapy in AML patients has demonstrated good tolerability (Lane et al., Blood 2017). Pathways of resistance to tagraxofusp have been identified preclinically as loss of the intracellular target for diphtheria toxin, diphthamide, through methylation of an enzyme involved in diphthamide synthesis. Treatment with a hypomethylating agent has the potential to restore expression of diphthamide and increase tagraxofusp sensitivity in AML cells (Togami et al., J Clin Invest 2019). Design This is a single-arm, open-label, multi-center phase Ib/II clinical trial to evaluate the safety and effectiveness of tagraxofusp +/- azacitidine in AML patients who are in first or second remission with detectable MRD and are planned to undergo alloHCT. MRD will be measured by multi-dimensional flow cytometry with sensitivity of 0.02% (Hematologics). Patients will be enrolled in a modified 3+3 dose escalation design with two cohorts: cohort A) tagraxofusp 12 mcg/kg IV qday on days 1-5; and cohort B) azacitidine 75 mg/m2 subq qday on days 1-5 plus tagraxofusp 12 mcg/kg qday on days 8-12. Patients achieving MRD-negativity after cycle 1 will proceed to alloHCT. If a patient remains MRD-positive, an additional cycle of investigational therapy will be administered. All patients will proceed to alloHCT after no more than 2 cycles of investigational therapy. Both cohorts contain a dose escalation and a dose expansion phase. Cohort B will open if cohort A is not efficacious. Up to 44 participants will be enrolled in this trial at University of California Los Angeles and University of California San Francisco (two constituent sites of the University of California Hematologic Malignancies Consortium). Objectives The primary objective is to estimate the rate of conversion from MRD-positive pre-investigational therapy to MRD-negative after 1 or 2 cycles of investigational therapy. Key secondary objectives include to determine the safety of tagraxofusp +/- azacitidine in this patient population and to evaluate if adverse effects of this investigational therapy lead to delays in alloHCT. Exploratory objectives will involve use of single cell RNA sequencing to investigate if response to investigational therapy is predicted by leukemia-specific biomarkers and to evaluate if putative cell surface markers (inferred from RNA detection) are associated with MRD persistence. Main Outcomes The primary endpoint is MRD status after 1 or 2 cycles of investigational therapy. Key secondary endpoints include dose-limiting toxicities (any grade 4 or 5 non-hematologic toxicity or any grade 3 or greater hematologic toxicity at day 42) and number of days between investigational therapy and alloHCT. Conclusions There is an unmet need to improve outcomes in AML with detectable MRD pre-transplant. The strategy in this study is to employ tagraxofusp as an alternative mechanism of action to eradicate chemo-resistant AML cells responsible for subsequent relapse. In order to mitigate any potential resistance the residual leukemia population may have against tagraxofusp, azacitidine will be added to optimize the likelihood for MRD negativity and the possibility for improved outcomes after alloHCT. This study was sponsored by the ASH CRTI. References Appelbaum J, Loeb A, Gardner K, et al. Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):260-260. Lane AA, Sweet KL, Wang ES, et al. Results from Ongoing Phase 1/2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with Minimal Residual Disease (MRD). Blood. 2017;130(Supplement 1):2583-2583. Togami K, Pastika T, Stephansky J, et al. DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. J Clin Invest. 2019;129(11):5005-5019. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Transition from Initial Therapy to Hematopoietic Cell Transplantation for Non-Favorable Risk Acute Leukemia and MDS Patients in the Era of Haploidentical Donor Availability: Assessment of Efficacy, Barriers and Racial Disparities in 269 Consecutive Patients Treated in an Integrated Leukemia/HCT Program

Hematopoietic cell transplantation (HCT) remains the most effective consolidation therapy in patients with non-favorable risk acute leukemia (AL) and MDS. However, prior studies have demonstrated that only a relatively small proportion of patients who may benefit, actually proceed to HCT. Lack of timely access to conventional matched donors, and delays in referral to transplant physicians have historically been important obstacles. At our center, AL care and HCT services are provided by the same physicians eliminating referral delays, and donor search/ transplant evaluation for all patients is commenced at program entry. Furthermore, HLA-haploidentical (haplo) donors have routinely been utilized since 2006. We hypothesized that these factors would increase the proportion of AL patients proceeding to HCT and decrease time to transplantation. We also analyzed other barriers to transplantation at our center, which includes a relatively high proportion of treated black patients. Methods: All patients aged <75 receiving initial therapy at our center for non-favorable risk AML, ALL or MDS between 2016 and 2021 were included. Non-favorable was defined as intermediate and poor-risk AML by NCCN criteria, NCCN poor-risk ALL patients (age <40) and all ALL patients aged >40), MDS EB-1 and EB-2 and CMML). Data were extracted from our institutional leukemia and transplant database where they had been prospectively entered. Results: Of 269 consecutive patients who received initial therapy at our center for non-favorable risk AL and MDS between Jan 2016 and Dec 2021, 160 (59.5%) proceeded to HCT at a median of 119d (range 58-910d) from initial therapy. For patients who did not proceed to HCT, most common cited reasons were: comorbidities (36.7%), poor KPS, lack of adequate caregiver support, refractory malignancy (19% each) and patient refusal (17.4%) (Table 1a). Lack of a donor and insurance issues were rarely a cause (3% each). For patients aged <60, 71% proceeded to HCT versus only 47.3% of patients aged 60-75 (p<0.001). Comorbidities (15% vs 49.3%, p<0.001) and KPS (10% vs 24.6%, p=0.06) were less common as reasons for not proceeding to transplant in patients aged <60 vs 60-75, whereas lack of caregiver support was more common in patients aged <60 (30% vs 13%, p=0.031). Of 73 black patients treated, 52.1% received HCT vs 60.2% of 181 treated white patients (p=0.23)(Table 1b). However, lack of caregiver support (37.1% vs 11.1%, p=0.002) and induction death (17.1% vs 5.6% p=0.05), were more common reasons in black patients for no HCT. AML and ALL patients had a similar likelihood of proceeding to HCT (57.6% vs 61.6%) but refractory disease was more common in AML (25.6% vs 3.6%, p=0.012) as a reason for no HCT. For AML patients, a higher proportion of patients with intermediate risk disease vs poor-risk disease proceeded to HCT (71.7% vs 50.8%, p=0.007). On logistic regression analysis, age (OR 1.46 per 10 yr increment, p<0.001) and NCCN poor-risk (OR 1.83, p=0.032) were significant factors for failure to proceed to HCT. Characteristics of patients who proceeded to HCT were: median age 55 (18-75); 49% male; race- white 68%, black 24%, Asian 7%; donor -haplo 41%, MRD 29%, MUD 22%, auto 8%; cell source- PBSC 93%, BM 4%, CBU 3%; disease status - CR1 83%, other 17%. Median time from initial treatment to HCT were shorter for AML vs ALL (114 vs 136 d, p=0.002), MRD and haplo vs MUD - 113d each vs 148 d, p=0.011) but were similar for black vs white patients (112d vs 120d, p=0.91). In a landmark analysis, patients receiving HCT within 6 months since starting treatment had significantly better OS than those without HCT within 6 months (Fig 1). On multivariable Cox analysis assessing transplant as a time-dependent covariate, adjusting for patient age and year of treatment, HCT was of significant benefit compared to no-HCT for overall survival (HR 0.59, p=0.012) and disease-free survival (HR 0.64, p=0.025). Conclusions: Our data suggest that in a modern cohort treated within an integrated AL/HCT program incorporating routine use of haplo donors, up to 60% of all treated patients (71% for age <60) with non-favorable risk AL and MDS can proceed to HCT in a median of 118 d from initial treatment. This approach results in no significant difference in proportion transplanted or time to HCT between black and white patients but caregiver support maybe a greater barrier in black patients. HCT is associated with a significant survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased LFS Following Hematopoietic Cell Transplantation As Compared to Conventional Consolidation Therapy in Patients >60 Years with AML in First Complete Remission and a Matched Donor: Results of a Randomized Phase III Study

Increased LFS Following Hematopoietic Cell Transplantation As Compared to Conventional Consolidation Therapy in Patients >60 Years with AML in First Complete Remission and a Matched Donor: Results of a Randomized Phase III Study

Sintilimab after Concurrent Chemoradiotherapy in Locoregional Recurrent ESCC after Definitive Treatment: A Single-Arm, Phase II Study

<h3>Purpose/Objective(s)</h3> After definitive treatment of esophageal cancer, patients are at high risk of recurrence with a subsequent 8-10 months survival time. Chemoradiotherapy (CRT) effectively treats locoregional relapse; however, efficient consolidation therapy is lacking. Sintilimab is a highly selective, humanized, monoclonal antibody against PD-1, which showed a prolonged survival benefit and a favorable safety in advanced esophageal squamous cell carcinoma (ESCC) patients. The study evaluated the efficacy of sintilimab as consolidation therapy in patients with locoregional recurrent ESCC after definitive treatment. <h3>Materials/Methods</h3> This is a single-arm, phase II study. Patients with locoregional recurrent ESCC, who completed CRT without progression, were enrolled and received sintilimab (200mg, iv, Q3W) up to 12 months. Sintilimab was administered 17 to 60 days after the patients had received CRT. The primary endpoint was progression free survival (PFS), and the second endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). <h3>Results</h3> Between November,2019 to September, 2021, total of 27 patients were enrolled: 22 males (81.5%), median age 63 years (range, 36-76), 25 squamous cell carcinomas (92.6%), 20 stage-IV (74.1%), 27 ECOG PS 1(100%), and 15(55.6%) with smoking history. The median follow-up time was 12.7 months. The median PFS and OS were 8.25 months (95% CI, 3.71-NA) and 15.67 months (95% CI, 7.29-NA). The 6-months and 12-months PFS were 61.7% (95% CI,45.6-83.6) and 35% (95% CI,19.3-63.4). The 6-months and 12-month OS were 77.8% (95% CI,63.6-95.2) and 54.4% (95% CI,38.3-77.3). ORR was 33.3% (95% CI,17.2-54.6), including 1 CR, 6 PR. DCR was 95.2% (95% CI,74.1-99.8). 10 cases of grade 3 or 4 adverse events occurred, including lymphopenia, leukopenia, thrombocytopenia, anemia, and myocarditis, mainly caused by chemoradiotherapy. Two cases of immune related adverse events occurred, including pneumonitis and hypothyroidism. <h3>Conclusion</h3> Sintilimab has been shown encouraging clinical benefits and acceptable safety as the consolidation therapy after CRT for locoregional recurrent esophageal cancer. The long-term efficacy is still under follow-up.

EP05.01-003 First Real-World Data on Unresectable Stage III NSCLC Patients Treated with Durvalumab after Chemoradiotherapy in Asia Area

The PACIFIC trial demonstrated the survival benefit of durvalumab as consolidation therapy in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT). However, it is necessary to assess the effectiveness of durvalumab consolidation using real-world data.