Subsequent Stem Cell Transplantation Research Articles

Single-Center Experience of Patients with Plasma Cell Leukemia in the Era of New Therapeutics

Introduction: Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥5% plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM; however, outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents. Methods: We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen. Results: Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 (2.0; 22.9) months. All patients were treated with a proteasome-inhibitor (PI)-based induction therapy, and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only 1 patient achieved a remission with daratumumab and subsequent allogenic SCT. Conclusion: With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous SCT for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devastating and needs new therapeutic approaches.

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Tafasitamab and Lenalidomide in People with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 molecule designed to enhance phagocytosis and antitumor activity by preventing CD47-mediated inhibitory signaling. Maplirpacept currently is being evaluated in an ongoing, multi-center, two-part, Phase 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05626322), to evaluate the effects of maplirpacept, in combination with tafasitamab and lenalidomide in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients, and the study will be split into two parts (Figure 1). Phase 1b will determine the maximum tolerated dose or recommended Phase 2 dose (2 dose levels) of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide. In Phase 2, participants will be randomized to high or low doses of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide, as per the Oncology Center of Excellence ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be administered in 28-day cycles. Maplirpacept will be given weekly, by intravenous (IV) infusion, for the first three cycles and subsequently every two weeks. Tafasitamab will be administered, by IV infusion, on Days 1, 4, 8, 15 and 22 in cycle 1, weekly in cycles 2 and 3, then every 2 weeks in cycle 4 and beyond. Lenalidomide will be taken orally, daily for Days 1 to 21 of each 28-day cycle, for the first 12 cycles. In Phase 1b, approximately 20 participants will be allocated to sequential doses of maplirpacept, co-administered with approved doses of tafasitamab and lenalidomide, to select doses for further assessment in Phase 2. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 28 days following the first dose. In Phase 2, approximately 50 participants will be randomized to 1 of 2 different doses of maplirpacept, co-administered with tafasitamab and lenalidomide. The primary endpoint for Phase 2 is objective response as per the Lugano Response Classification Criteria 2014. Secondary endpoints are frequency of adverse events, frequency of clinical laboratory abnormalities, objective response (Phase 1b only), complete response, duration of response, duration of complete response, progression free survival, maplirpacept, tafasitamab and lenalidomide PKs, and immunogenicity of maplirpacept and tafasitamab. Inclusion criteria (Table 1) are adults with histologically confirmed, measurable relapsed and/or refractory DLBCL not otherwise specified, T cell/histiocyte rich large B-cell lymphoma, or Epstein-Barr virus positive DLBCL according to the 5th edition of the WHO classification of lymphoid neoplasms. Additionally, participants with follicular lymphoma grade 3b, or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse are also eligible. Participants with evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible if relapsed or refractory to at least one line of therapy for DLBCL. Further inclusion criteria are participants who are not a candidates for, or are unwilling to receive, high-dose chemotherapy and subsequent stem cell transplant and/or are unable to undergo chimeric antigen receptor T-cell (CAR-T) therapy (e.g. due to logistical limitations), treatment with at ≥1 prior line of systemic therapy (for Phase 2, at least 1, and no more than 2, prior lines of systemic therapy) and prior therapy must include an anti-CD20 antibody. Participants must have adequate bone marrow, renal and hepatic function and an Eastern Cooperative Oncology Group performance status ≤2. Participants must provide a baseline tumor tissue sample (fresh or archival), for biomarker analysis. Exclusion criteria include previous treatment with anti-CD47, anti-CD19 (other than CAR-T) or immunomodulatory agents, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, and participants with active, uncontrolled viral, bacterial or fungal infections.

Real-World Study in Acute Leukemia: Epidemiology, Treatment Patterns and Outcomes for Newly Diagnosed AML in Adult Patients from Latin America - Loyal Study

Introduction. Acute myeloid leukemia (AML) is the most frequent leukemia among adults and representing 90% of all cases of acute leukemia in adults. Differences in incidence and burden of AML among regions of the world have been reported. When compared with registries from the US, UK and Sweden, Latin-America (LA) AML has a younger age at diagnosis (median age of 40-47 versus 64 -67 years old). Furthermore, single center studies have suggested poor treatment outcomes in LA. For example, Silveira et al reported a median age at diagnosis of 46 y, frequency of favorable cytogenetics of 26% and median overall survival (mOS) of 12 months in the Brazilian cohort of patients with newly diagnosed AML (nAML) whereas the respective values at Oxford University were 51.5y, 11% and 48 months in British patients. However, wider studies across the region are scarce and there is a need to further explore AML patient characteristics and treatment outcomes in LA. Methods. This is a non-interventional, retrospective multicenter study that aims to describe the epidemiology, clinical and demographic characteristics, treatment patterns, survival outcomes and healthcare resource use of adult patients with nAML in Argentina, Brazil, Chile, and Colombia. Data from medical records of eligible patients that met the inclusion criteria (≥ 18 years old at diagnosis, confirmed diagnosis of nAML between 01 January 2015 and 31 December 2019, and receiving at least one line of treatment) in these LA countries were considered for the analysis, which was descriptive in nature as no hypothesis has been tested. Results: A total of 518 nAML patients were included in the study, 166 from Argentina, 205 from Brazil, 63 from Chile, and 84 from Colombia. Table 1 shows the demographics and clinical characteristics. At treatment initiation, an evaluation of fitness (eligibility) for intensive chemotherapy was available for 94% of the patients (n=489). The majority were considered fit (75.5%; n=391) and received standard 7+3 therapy. About 11% of patients (n=9) were refractory to induction therapy. Median OS for fit patients was 11.9 months, whereas for unfit patients was 5.8 months. Mutational status of genes listed by the European LeukemiaNet (ELN) Classification of 2017 was not available for the majority of cases; risk categories were assigned based on cytogenetics. Patients in the favorable-risk category had a mOS of 30.5 months, whereas those in the intermediate- and unfavorable-risk had 11.1 and 9.1 months, respectively (Figure 1). The probability of 5year OS rates for favorable, intermediate- and unfavorable-risk groups were of 38.8%, 16.6% and 20.9%, respectively. Eighty-six patients (17%) discontinued treatment with reasons being adverse event/toxicity (33%; n=28), death (32%; n=27), and disease progression (17%; n=14). Only 24% of patients (n=125) underwent a subsequent stem cell transplantation (SCT), mainly allogenic (98%; n=121). For SCTs, identical (matched) related (50%; n= 59) and haploidentical donor (35%; n=41) were the most common. Patients not eligible to intensive chemotherapy were treated with HMA (9%; n=47) and LDAC (5%; n=25), with 10% of the patients receiving palliative/supportive care. The most common treatment protocols used in relapsed or refractory (R/R) patients were high-dose cytarabine (HDAC) (31%; n=85), followed by FLAG-IDA (24%; n=66). Conclusions: This study of newly diagnosed acute leukemia characterizes real-world treatment patterns and outcomes in LA clinical practices. Prior to this study, there has been limited published data on the epidemiology and treatment patterns across LA. This study highlights that for nAML patients, the most common treatment in LA is 7+3 and most patients are classified as fit. The vast majority of patients had their risk accessed by cytogenetics analysis only, reflecting the limited access to molecular tests. Fewer patients underwent stem cell transplantation as part of the treatment compared to that reported in US and Europe, probably due to restricted availability of hospital beds dedicated to bone marrow transplantation. When evaluating the overall survival, the study shows higher mOS for favorable risk. In addition, mOS for intermediate and poor cytogenetic risk were similar. A broader access in the region to molecular tests, transplant and new therapies are needed in order to reduce the gap in outcome, especially for patients with intermediate-risk.

Bendamustine Plus Brentuximab Has Superior Efficacy to Brentuximab Monotherapy As Third-Line Treatment for Classical Hodgkin Lymphoma: A Real-World, Multicentre UK Analysis

Purpose: The introduction of targeted agents has been a major advance in the treatment of classical Hodgkin lymphoma (HL) but the optimal application and sequencing of these agents is unclear. The CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) is licensed for treatment of relapsed and refractory (R/R) HL as monotherapy and is available in the United Kingdom as third-line (3L) therapy for HL. BV has been evaluated in combination with chemotherapy in single-arm trials with very promising results, but randomised data are lacking. The aim of this analysis was to compare the efficacy of BV monotherapy with BV plus bendamustine (BVB) as 3L treatment of HL in a real-world UK cohort. Methods: Data were retrospectively collectively for consecutive patients receiving treatment for R/R HL with intent to consolidate with stem cell transplant (SCT) between 01/2015 and 12/2019 at 11 UK centres. Use of BVB was principally determined by availability, due to regional differences in BV funding in the UK, rather than patient disposition. Response was assessed by PET according to the Lugano Classification. Most analyses use descriptive statistics. Time-to-event analyses are measured from the start of 3L treatment until the first event (death for overall survival and death or further therapy for treatment failure) with groups compared using Kaplan Meier survival analysis and Cox regression. Results: 96 patients received BV and 30 received BVB. Baseline demographics are provided in the Table. Patients receiving BVB were slightly younger in age at diagnosis (p=0.031), but a slightly higher proportion had primary refractory disease (p=0.16) and failed to respond to second-line therapy (p=0.034). Numerically fewer patients in the BVB arm had received prior SCT (p=0.16). Patients received a median of 4 cycles of BV monotherapy (range 3 - 5). Patients treated with BVB received a median of 3 cycles of bendamustine (IQR 2 - 4) and 4 cycles of BV (IQR 3 - 5); 2 patients discontinued bendamustine after 1 cycle due to adverse reactions. Complete metabolic response was achieved in 34 patients (37.4%) with BV and 22 patients (73.3%) with BVB, with overall response rates of 57.3% and 93.3%, respectively (OR 9.2; 95% CI: 2.06 - 40.86; p=0.004). SCT consolidation was performed after 3L treatment in 33 patients (34.4%) following BV (26 autologous, 7 allogeneic) and 22 patients (73.3%) after BVB (17 autologous, 5 allogeneic). Median follow-up was 30.1 months after BV (IQR: 15.3 - 46.8) and 18.1 months after BVB (15.4 - 29.8). Freedom-from-treatment-failure (FFTF) rates at 18 months were 41.5% (95% CI: 30.8 - 51.8) after BV and 62.9% (39.3 - 79.4) after BVB (HR 0.45, 95% CI 0.23 - 0.88; p=0.019; see Figure). Overall survival rates at 18 months were 76.9% (66.0 - 84.7) after BV and 88.4% (68.1 - 96.1) after BVB (HR 0.37, 95% CI 11 - 1.23; p=0.11. There were 29 deaths following BV, including 17 (17.7%) due to HL, 6 (6.3%) due to toxicity of SCT or subsequent treatment and 6 (6.3%) due to other causes/unknown. There were 3 deaths following BVB, all due to toxicity of SCT or subsequent treatment (10%). Eight patients received single-agent bendamustine after failure of BV monotherapy, at a median of 2.4 months after commencing BV. The median number of bendamustine cycles delivered was 2 (range 1 - 6). The overall response rates was 62.5%. Two patients (25%) achieved complete metabolic response; both underwent subsequent SCT. Conclusion: In this retrospective analysis, use of BVB as 3L treatment for R/R HL was associated with higher response rates, transplant rates and FFTF compared with BV monotherapy. Although toxicity data were not available, our results are otherwise consistent with phase 2 trial data with BVB as second-line therapy (LaCasce, Blood 2018;132:40, Broccoli, Blood Cancer Journal 2019;9:100). These data demonstrate that BVB is a highly effective regimen in R/R HL, and support its use in transplant-fit patients.

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Glofitamab in People with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 fusion protein constructed to enhance phagocytosis and antitumor activity via inhibition of CD47-mediated signaling. Maplirpacept is currently being investigated in an ongoing Phase 1, multi-center, 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05896163), to evaluate the effects of maplirpacept in combination with fixed doses of glofitamab, after a single dose of obinutuzumab, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients; the study will be split into 2 parts (Figure 1). Phase 1b will determine the maximum tolerated dose of maplirpacept, with fixed doses of glofitamab and obinutuzumab. In Phase 2, participants will be randomized to low or high doses of maplirpacept, with fixed doses of glofitamab and obinutuzumab, consistent with the FDA ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be given intravenously in 21-day cycles. At Cycle 0, participants will receive a single pre-treatment dose of obinutuzumab followed by 2 step-up doses of glofitamab. The combination of maplirpacept with full dose glofitamab will be given at Cycle 1 Day 1. Maplirpacept will be given weekly for the first 3 cycles, then every 3 weeks. Glofitamab will be given every 3 weeks for up to 11 cycles. Subsequently, participants will continue to receive maplirpacept alone. In Phase 1b, participants will be allocated to sequential doses of maplirpacept, given with fixed doses of glofitamab, after 1 dose of obinutuzumab, to select doses of maplirpacept for further evaluation. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 21 days following the first dose. In Phase 2, participants will be randomized to 2 different doses of maplirpacept, administered with fixed doses of glofitamab, after 1 dose of obinutuzumab. The primary endpoint for Phase 2 is objective response as per the Lugano 2014 response criteria. Secondary endpoints include frequency of adverse events and clinical laboratory abnormalities, objective response (Phase 1b only), duration of response, complete response, duration of complete response, progression free survival, serum concentration vs time for maplirpacept and glofitamab, and immunogenicity of maplirpacept and glofitamab. Adult patients with histologically confirmed relapsed or refractory DLBCL (including DLBCL NOS, primary mediastinal large B cell lymphoma and transformed follicular lymphoma, T cell/histiocyte-rich large B-cell lymphoma, Grade 3b follicular lymphoma or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse), will be eligible (Table 1). Participants with histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible, except for participants with history of Waldenström macroglobulinemia. Treatment with at least 1 prior line of anti-CD20 antibody-based therapy will be included. For Phase 2, no more than 2 prior lines of systemic therapy will be permitted. Patients who are not candidates for, or who are unwilling to undergo high dose chemotherapy and subsequent stem cell transplant and/or are unable or unwilling to receive chimeric antigen receptor T-cell therapy (e.g. for logistical reasons) will be eligible. All patients should have adequate bone marrow, hepatic, and renal function (eGFR ≥45 mL/min) and ECOG performance status ≤2. Exclusion criteria include prior treatment with an anti-CD47 agent, prior anti-CD20xCD3 containing regimen, refractoriness to an obinutuzumab monotherapy containing regimen, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, high grade B-cell lymphoma with BCL2 and Myc rearrangement, active bacterial, viral, fungal, mycobacterial, parasitic, or other infection.

Real-World Outcomes of Brexucabtagene Autoleucel (brexu-cel) for Relapsed or Refractory (R/R) Adult B-Cell Acute Lymphoblastic Leukemia (B-cell ALL): Evidence from the CIBMTR Registry

Background Brexu-cel is a CD19 CAR T therapy first approved by the FDA in 2021 for adult patients (pts) with R/R B-cell ALL. In the pivotal phase II ZUMA-3 single arm trial, brexu-cel achieved a high rate (71%) of complete remission or complete remission with incomplete hematological recovery (CR/CRi) with a manageable safety profile. Here, we report outcomes of brexu-cel in a broad real-world patient population. Methods A total of 197 pts with B-cell ALL were infused with brexu-cel and prospectively enrolled between July 2021 and May 2023 in the CIBMTR registry across 67 centers in the US. In this analysis, we included 138 pts with at least one scheduled follow-up at Day 100 and evaluable safety and effectiveness outcomes. Descriptive statistics, Kaplan-Meier estimator and cumulative incidence functions were used to summarize outcomes. Results Median age was 43 years (range, 19.4-79.4; 19% were age ≥60 years) and 52% were males. Pts had a diverse ethnic background: 50% non-Hispanic White, 28% Hispanic, 11% non-Hispanic Black and 7% non-Hispanic Asian. More than half (55%) of pts had poor cytogenic risk score at diagnosis. Prior to lymphodepletion (LD), the majority of pts had: ECOG performance status of 0 or 1 (80%); at least one clinically significant comorbidity (79%); and Ph-negative disease (64%). Furthermore, 44% had evidence of ≤5% bone marrow blasts; of these (n=49), 65% were MRD negative. Extramedullary disease and CNS involvement was observed in 22% and 10% of pts prior to LD, respectively. As such, based on adapted criteria available in the registry data, 91% of pts in this cohort would have been ineligible for ZUMA-3. Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab. One third (35%) had prior allogeneic (allo) stem cell transplant (SCT). Moreover, 41% of pts received bridging therapy prior to LD. Median time from leukapheresis to brexu-cel infusion was 32 days (inter-quartile range [IQR] 27-42)) and median follow-up time was 5.9 months (95% CI: 5.1-6.1) (Table 1). Overall CR/CRi rate by Day 100 post infusion was 76%; 70% were still in remission at 6 months post initial response (95% CI: 55-80). For those who were not in response before LD, 63% of them converted into a CR/CRi. Relapse free survival at 6 months was 53% (95% CI: 42-62). The overall survival rate at 6 months was 78% (95% CI: 69-84); primary causes of death were primary disease (n=13/32, 41%) and infection (n=7/32, 22%). About one third (31%) of responders received a subsequent allo SCT. High response rates were observed in all pts regardless of age, prior exposure to blinatumomab, allo SCT, or presence of extramedullary disease prior to LD. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT consensus) occurred in 9% and 24% of pts, respectively (Table 2). Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%). Most of these adverse events were resolved within 3 weeks of infusion (CRS, 94%; ICANS, 80%). Prolonged cytopenia and neutropenia 30 days post infusion was experienced by 42% and 33% of pts, respectively. Conclusion In this largest-to-date real-world evidence study of brexu-cel in adult pts with B-cell ALL, response and safety outcomes were consistent with findings from ZUMA-3, even with 91% of patients not meeting ZUMA-3 eligibility criteria. Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors

Spermatogonial stem-cell-derived neural-like cell transplantation enhances the functional recovery of a rat spinal cord injury model: characterization of evoked potentials.

Severe spinal cord injuries (SCIs) usually result in the temporary or permanent impairment of strength, sensation or autonomic functions below the sites of injuries. To date, a large number of therapeutic approaches have been used to ameliorate SCIs, and subsequent stem cell transplantation appears to be a promising strategy. The aim of this study was to evaluate the therapeutic effect of stem cells by changes in the evoked potentials at different time points after a transplantation of spermatogonial stem cells (SSCs) to differentiate the source neurons in a rat model with SCIs, as well as through histopathology. A modified Plemel spinal cord lateral compression model was used. The experiment was divided into a blank, a control and a SSC transplantation group. Motor activity scores, sensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were assessed through motor resuscitation as well as histologic evaluation on each experimental group to determine the improvement. Consistent with our results, motor scores and evoked potentials were significantly improved in the SSC transplantation group. In addition, a histologic assessment showed that the transplanted stem cells had a significant restorative effect on the reconstruction of tissue cells. 1 week after the stem cell transplantation, the SSC transplantation group showed improvement in spinal cord functions and spinal cord pathologic injuries. After 2 weeks and beyond, the SSC transplantation group showed significant improvement in spinal cord functions and spinal cord pathology compared to the control group, meanwhile the evoked potentials and motor function of the hind limbs of rats in the SSC transplantation group were significantly improved. Therefore, the therapeutic strategies for spermatogonial stem cells will be an effective program in the study on SCIs, and we suggest the somatosensory evoked potentials as a tool to assess the degree of recovery from SCIs after the transplantation of stem cells.

A phase 2 study of the combination of decitabine (DAC), venetoclax (VEN), and ponatinib in patients (Pts) with chronic myeloid leukemia (CML) in accelerated phase (AP)/myeloid blast phase (MBP) or Philadelphia-chromosome positive (Ph+) acute myeloid leukemia (AML).

e19044 Background: CML-AP/MBP and Ph+ AML are therapeutic challenges. Based on published pre-clinical data of synergism (Leonard et.al., Sci Transl Med 2016), we hypothesized that combining ponatinib with DAC and VEN might lead to high rates of response and facilitate allogeneic stem cell transplantation (SCT). Methods: The study (NCT04188405) enrolled pts ≥ 18 years of age with CML-AP, CML-MBP or Ph+ AML with ECOG PS ≤ 3 and adequate liver/renal function. Pts with significant uncontrolled cardiovascular comorbidities were excluded. Therapy was with DAC (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycles 2-24. Each cycle was for 28 days. Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate (ORR) with the regimen. Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, including 4 pts with prior ponatinib. 5 of 13 tested pts (38%) had an ABL1 kinase domain mutation (T315I, Q252H, L384M in 1 pt each and E255K in 2 pts). The median number of cycles received was 3 (range, 1-7). 11 pts (73%) responded; 6 pts (40%) with CR/CRi and 5 (33%) with MLFS. Best response was achieved after cycle 1 in 9 of 11 (82%) responders. All 4 pts with CML-AP responded, and 9 of 11 pts (82%) with prior TKI exposure responded. Four pts underwent subsequent SCT. At a median follow-up of 9.8 months, the median overall survival (OS) was 11.0 months, and the estimated 10-month OS was 63%. The median relapse-free survival was 5.7 months. Among the 11 responders, 5 relapsed (one after SCT), and 6 are in ongoing response (3 after SCT). One pt had a related grade 3 mucositis. No grade 4-5 related non-hematological adverse events were observed. Of the 10 pts who received > 1 cycle of therapy, 5 pts had delay (>1 week) in initiation of subsequent cycles due to cytopenias. The 60-day mortality rate was 0%. Two pts died on study, one from leukemia and one from infection while in MLFS. Conclusions: A triplet combination of DAC, VEN and ponatinib was well-tolerated and resulted in an ORR of 73% in this poor-risk population of pts with advanced Ph+ leukemias. Clinical trial information: NCT04188405 . [Table: see text]

Baseline Liver Elastography Does Not Predict Risks of Hepato-Toxicity to Reduced Dose Inotuzumab Therapy Combined with Minihcvd in B-Cell Acute Lymphoblastic Leukemia

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody drug conjugate that is FDA approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-cell ALL). Liver toxicity, particularly veno-occlusive disease (VOD) was the most important grade 3 toxicity in the Phase III INO-VATE study of InO, driven by the active cytotoxic agent calicheamicin conjugated to InO, especially in pts who underwent subsequent stem cell transplantation (SCT) (Kantarjian et. al, NEJM 2016). However proper assessment of liver function and fibrosis through elastographic measurements might predict the risks of subsequent liver toxicity with InO. Aim: We aimed to study the extent of liver toxicity, including VOD, in pts treated with InO and its correlation to baseline liver elastography. Methods: Pts with B-cell ALL treated with InO containing low intensity combination regimen [miniCVD-InO- blinatumomab-rituximab (previously published; Jabbour et. al. Cancer 2018)] as part of a clinical trial (NCT01371630) underwent baseline liver elastography and were prospectively monitored for any evidence of liver toxicity, including VOD. Elastography was done within 4 weeks prior to the first infusion of InO and liver stiffness was stratified based on the median shear wave velocity (SWV) using the acoustic radiation force impulse (ARFI) technique. Elastographic median SWV >1.7 m/s was considered as evidence of definite liver fibrosis. We captured the patient characteristics, history of known liver disorders, baseline liver function tests, total dose of InO administered and any subsequent liver toxicities including VOD. Any antecedent or subsequent history of SCT was noted; liver toxicity was graded according to the NCI CTCAE, v5. The dose of InO was capped at a cumulative maximum of 2.7mg/m2 of body surface area (administered in fractionated doses) and all pts received concurrent ursodiol prophylaxis with InO. Results: From Jan 2018- April 2022, 50 consecutive pts treated with the above regimen and with baseline elastography reports available as part of the research protocol were analyzed. The median age of the pts was 54.9 years (yrs) (range, 21.7-87.7 yrs) and only 1 pt had a known prior liver ailment of non-alcoholic fatty liver disease (NAFLD). Baseline characteristics are mentioned in Table 1. The median InO dose received by the pts were 1.5 mg/m2 (range, 0.9-2.7 mg/m2) and only 11 pts (22%) received the maximum cumulative InO dose of 2.7 mg/m2. A total of 11 pts (22%) had a baseline maximum SWV >1.7 m/s which radiologically corresponds to possible compensated advanced chronic liver disease (cACLD) and no pts had a SWV >2.1 m/s (corresponds to clinically significant portal hypertension; CSPH). All pts achieved CR/CRi as best response and 14 pts (28%) underwent consolidative SCT. Only one pt developed a VOD of the liver, diagnosed based on clinical and radiological findings, at D+60 post haploidentical-SCT with Flu/Mel140 conditioning and post-transplant cyclophosphamide. This pt had normal baseline liver elastography and had received a cumulative InO dose of 1.5 mg/m2. Another 5-pts (10%) had ≥ grade 3 liver toxicity (1 pt with hyperbilirubinemia and 4 pts with ALT elevation), all of whom had baseline SWV <1.7 m/s on elastography. On regression analysis using age, cumulative InO dose, baseline values of total bilirubin, ALT and INR, and SWV cutoffs as covariates, no factor significantly affected the risks of ≥ grade 3 liver toxicity. After adopting the use of reduced dose fractionated InO administration regimen, routine ursodiol prophylaxis and avoiding peri-transplant azole antifungal prophylaxis in InO exposed B-cell ALL pts at our center, the frequency of liver toxicites including VOD has significantly reduced compared to the 11% rate of VOD described in the INO-VATE study. With these improvisations reducing the overall frequency of InO induced liver toxicity, the positive predictive value of a pre-InO elastography to envisage the risks of subsequent VOD and other liver toxicity in these pts is highly limited. Conclusion: In a prospectively monitored group of pts of B-cell ALL treated with fractionated InO containing combination regimen, baseline liver elastography did not predict the risk of subsequent liver toxicity. Sequential liver elastographies to monitor dynamic changes in SWV needs to be analyzed in future studies to further assess its predictive role for InO induced liver toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Older Patients with Aplastic Anemia Treated with Frontline Anti-Thymocyte Globulin (ATG)-Based Immunosuppressive Therapy

Background: Advances in the treatment of aplastic anemia (AA), such as the addition of eltrombopag (EPaG) to immunosuppressive therapy (IST) and the expanded use of unrelated and haploidentical stem cell transplant (SCT) have steadily improved outcomes. However, little is known about the characteristics and outcomes of patients (pts) ≥ 60 years (yrs) of age with newly diagnosed AA who have been treated with an ATG-based regimen. Presumed low bone marrow (BM) reserves, higher frequency of underlying clonal hematopoiesis, intolerance to therapy, comorbidities, and challenges in proceeding to salvage SCT have led to the speculation that response and survival of these pts to IST may be inferior than their younger counterparts. Methods: We retrospectively analyzed the characteristics and outcomes of pts ≥ 60 yrs of age (OLDER) at the time of diagnosis of AA treated with frontline (F/L) ATG based therapy at our center and compared them to pts < 60 yrs of age (YOUNG) treated with F/L ATG over the same time period. We captured their clinical characteristics, cytogenetic abnormalities, mutations in DNMT3A (D), ASXL1 (A) and TET2 (T), exposure to EPaG, response, time to response (TTR) and survival. Overall response included complete and partial response per the standard definitions. Relapse free survival (RFS) was tabulated from the time of best response to loss of response, 2nd ATG infusion, salvage SCT or death (whichever was earlier) and overall survival was tabulated from the time of response to death from any cause. Results: From Jan 2011-May 2012, 43 OLDER pts were treated as F/L for AA of whom 41 (95%) received ATG based therapy; 68 YOUNG pts were treated as F/L for AA over the same time period of whom 62 (91%) received ATG based regimen. Four YOUNG pts vs. no pts in the OLDER group received upfront SCT, and 2 pts in each group were treated with non ATG based therapy: single agent CSA, EPaG, or alemtuzumab. Comparative baseline characteristics are depicted in Table 1. There were no differences in the baseline WBC, peripheral blood lymphocyte percentage and platelet counts between the ATG treated OLDER and YOUNG groups. Both groups had similar frequencies of cytogenetic abnormalities and PNH clones, though OLDER pts had mutations in D-A-T genes compared to the YOUNG group (62% vs. 38%, p=0.05). Both groups had equal concurrent exposure to EPaG with ATG. Cumulatively 23/41 (56%) pts in the OLDER group had an overall response (OR) compared to 43/62 (70%) pts in the YOUNG group (p=0.1); 11/23 (48%) and 23/43 (53%) responders in each group attained CR respectively. There were no differences in OR rates in both groups based on concurrent EPaG exposure: 61% vs. 46% with and without EPaG, respectively, in the OLDER group (p=0.5) and 74% vs 60%, respectively, (p=0.38) in the YOUNG group. On logistic regression analysis using baseline platelet counts, PB lymphocyte (%), D-A-T mutations, karyotype, and EPaG use as covariates, none affected the odds of OR in the 2 groups. The median TTR was 111 days (range, 10-323 days) and 177 days (51-410) in YOUNG AND OLDER groups, respectively; and this was not affected by EPaG use in either group. At a median follow of 38 months (mos) from ATG initiation (53 mos for the OLDER group and 32 mos for the YOUNG group), the median RFS was 49 mos and 39 mos (p=0.6) and median OS 55 vs. not reached (NR) (p <0.0001) in OLDER and YOUNG groups respectively (Fig.1). Significantly more pts in the YOUNG group underwent a subsequent SCT (19% vs. 5%) due to loss of response/ no response, possibly accounting for the higher OS rates. Rates of transformation to MDS or AML was 5% in both groups. Conclusion: Frontline ATG based IST in older pts with AA is a feasible and safe treatment option with promising response rates of 56% and median RFS more than 4 years; figures which are comparable to younger pts with AA treated with IST. The overall risks of transformation to MDS/AML on long term follow-up remain low (≈5%). Further studies assessing the response of the ATG+EPaG combination in these pts and the possibilities of clonal evolution with time needs to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SEVERE COMBINED IMMUNODEFICIENCY SCREENING AND STEM CELL TRANSPLANT-AN ECONOMIC EVALUATION SCHEME

Background: Severe Combined Immunodeficiency (SCID) is a rare genetic disease that affects newborn immune system and costs healthcare system a substantial amount of money. Screening and stem cell transplant may offer a cost-effective alternative to the current medical practice. Objective: To determine the cost-effectiveness of screening newborn for SCID with subsequent stem cell transplant versus standard of care. Materials and Methods: An economic evaluation was proposed, using Treeage software on a set of evidence-based propabilities and variables. Outcomes: as shown on the tree, we count the death from SCID. Its given the payoff 1, while the survival is payoff 0. The outcome of interest is death averted by screening live birth and implementing subsequent stem cell transplant for those who tested +ve.

Development of Novel CAR Therapies for Diffuse Large B-Cell Lymphoma Using Genome-Wide Overexpression Screens

Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure.While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells.The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former.Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. [Display omitted] DisclosuresMimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.

Cost Effectiveness Analysis of Venetoclax Plus Azacitidine Versus Azacitidine in Newly Diagnosed Adult Patients with Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy from a United States Payer Perspective

Background: The phase 3 VIALE-A trial (NCT02993523) demonstrated that venetoclax plus azacitidine (VEN+AZA) improved overall survival (OS) and led to higher remission rates compared with AZA monotherapy, in patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Based on the results from VIALE-A, VEN+AZA received full United States (US) Food and Drug Administration approval in October 2020 for patients with ND AML aged ≥75 years, or who were ineligible for intensive induction chemotherapy due to comorbidities. This study aims to assess the long-term cost-effectiveness value of the VEN+AZA regimen from the VIALE-A trial from a US third-party payer perspective.Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of treatment with VEN+AZA vs. AZA among patients with ND AML, who are ineligible for intensive chemotherapy, over a lifetime time horizon. The model included three health states: event-free survival (EFS), progressive/relapsed disease, and death. Within the EFS state, patients were further partitioned into time spent in complete remission (CR) or CR with incomplete marrow recovery (CRi), and time spent in non-CR/CRi. Efficacy inputs (OS, EFS, and CR/CRi rate) for both treatment arms were estimated using VIALE-A data. Best-fit parametric models per Akaike information criterion (AIC) were used to extrapolate OS until it reached EFS, and extrapolate EFS for each treatment until Year 5. Patients who remained in EFS after Year 5 were considered cured, and were assumed to have the same mortality as the US general population. Mean time on treatment (ToT) for both regimens was based on the time observed in VIALE-A. The costs for drug acquisition, drug administration for initial and subsequent treatments, subsequent stem cell transplant procedures, adverse events (AEs), and healthcare resource utilization (HRU) associated with each health state were obtained from the literature or publicly available data. All costs were inflated to 2021 US dollars. Utilities for each health state were estimated using EuroQol-5 dimension-5 level (EQ-5D-5L) data from VIALE-A, based on the US crosswalk value set. Information on disutilities due to Grade 3/4 AEs were obtained from the literature. Incremental cost-effectiveness ratios (ICERs) per life year (LY) and quality-adjusted life year (QALY) gained were estimated. Deterministic sensitivity analyses (DSA), scenario analyses and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the results.Results: Over a lifetime time horizon, compared with AZA, VEN+AZA was associated with an increase of 1.89 LYs (1.10 vs. 2.99, respectively) and 1.45 QALYs (0.84 vs. 2.30, respectively). Patients in the VEN+AZA arm incurred higher total costs ($250,486 vs. $110,034 for patients in the AZA arm). The ICER for VEN+AZA vs. AZA was estimated to be $74,141 per LY gained, and $96,579 per QALY gained. Results from the DSA and scenario analyses supported the base-case findings, with ICERs ranging from $60,922 to $138,554 per QALY gained. The results were most sensitive to alternative approaches for ToT estimation, subsequent treatment HRU costs, cure time point, and the extrapolation approach for EFS. Results from PSA showed that compared with AZA, VEN+AZA was cost-effective in 99.9% of cases at a willingness-to-pay (WTP) threshold of $150,000.Conclusions: Compared with AZA monotherapy, VEN+AZA results in a favorable ICER of $96,579 per QALY gained over a lifetime time horizon. The base-case results suggest that, compared with AZA, VEN+AZA is a cost-effective strategy based on a WTP threshold of $150,000 per QALY gained. Sensitivity analyses support the base-case results. Thus, VEN+AZA offers a cost-effective strategy in the treatment of patients with ND AML who are ineligible for intensive chemotherapy from a US third-party payer perspective. DisclosuresPratz: Agios: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Chai: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Yin: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Nie: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Iantuono: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Downs: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ma: Genentech, Inc.: Current Employment, Other: May hold equity.

Cost-Effectiveness Analysis of CTL019 for the Treatment of Pediatric and Young Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia in the United States

Introduction: CTL019 (tisagenlecleucel) is a chimeric antigen receptor T-cell therapy (CAR-T)for the treatment of relapsed or refractory (r/r) pediatric/young adult patients (pts) with B-cellacute lymphoblastic leukemia(ALL). Current treatments for r/r pediatric ALL (pALL) include clofarabine monotherapy (Clo-M), clofarabine combination therapy (Clo-C), blinatumomab (Blin), other salvage chemotherapies (SC), and allogeneic stem cell transplant (SCT). The prognosis for r/r pALL is poor and SCT is considered as the only potentially curative option. However, less than 50% of pts with multiple relapses achieve CR from existing treatments, and even fewer are eligible for and ultimately receive SCT. CTL019 is a potentially promising treatment option for pALL pts with multiple relapses, with complete remission (CR) rates between 69-95% based on data from phase I/II trials (ELIANA, ENSIGN, and CHP959). The current study aimed to compare the life year (LY) and quality-adjusted life year (QALY) gained using CTL019 vs. comparator treatments, and estimate the value-based prices for CTL019 at different incremental (incr) cost effectiveness ratios (willingness-to-pay [WTP] thresholds) for the treatment of r/r pALL from a US third-party payer perspective.Methods: A partitioned survival model with monthly cycle and 3% discount rate was developed to assess the incr cost effectiveness of CTL019 compared to Clo-M, Clo-C, Blin, SC, and 2nd SCT, for the treatment of r/r pALL over a 20-year time horizon. The model included three health states: event-free survival (EFS), progressive disease, and death. Efficacy inputs (overall survival [OS] and EFS) for CTL019 were based on pooled data of three phase I/II single-arm trials. Efficacy inputs for the comparators were based on publications of clinical trial and SCT registry that enrolled similar pts (although with notable differences); Kaplan-Meier curves of OS and EFS, where available, were used to reconstruct proxy patient-level data. Parametric models were fitted to extrapolate EFS and OS for each treatment until year 5. Afterwards, the model assumed no additional progression, and that all pts alive at 5 years would experience the same mortality risk consistent with long-term survivors of pALL. Pre-treatment (lymphodepleting for CTL019 and induction therapy for SCT) and treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent SCT costs, and medical costs for each health state were obtained from public databases and literature. All costs were inflated to 2016 USD. Utilities for each health state and disutilities for AEs were based on literature. Incr LY, incr QALY, and incr cost per QALY gained were estimated comparing CTL019 to each comparator. Value-based prices, defined as the price that would achieve the incr cost effectiveness ratios (WTP thresholds) of $100,000, $150,000, $200,000, and, $300,000 per QALY gained, were calculated for CTL019 vs. each comparator. Deterministic sensitivity analyses (DSA) were performed to test the robustness of the results.Results: Over a 20-year time horizon, treatment with CTL019 led to an increase of 4.62, 3.79, 3.68, 2.08 and 2.05 in discounted LYs and an increase of 4.29, 3.64, 3.64, 2.32 and 2.31 in discounted QALYs relative to Clo-M, Clo-C, Blin, SC, and SCT respectively. CTL019 value prices to reach a specified incr cost effectiveness ratio (WTP threshold) of $150,000/QALY ranged from $604,289 to $779,487 across comparators. The value prices ranged between $951,745 and $1,364,525 when the incr cost effectiveness ratio (WTP threshold) was set at $300,000/QALY (Table 1). Results from the DSA generally supported the base case findings, with the largest variation observed when time horizon and the parametric survival functions were varied. Compared to Clo-M, Clo-C, Blin and SC, CTL019 trials enrolled more severe pts who had failed more lines of prior therapies, which suggested that the estimated CTL019 LY and QALY benefits were conservative.Conclusions: Compared to existing treatments, CTL019 showed promising efficacy results for the treatment of pediatric/young adult ALL pts, with incr QALY gains of 2.31-4.29. Using specified incr cost effectiveness ratios (WTP thresholds) from $100,000/QALY to $300,000/QALY, the value-based prices for CTL019 ranged from $488,470 to $1,364,525. [Display omitted] DisclosuresHao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Eldjerou:Novartis Pharmaceutical Corporation: Employment. Yang:Novartis Pharmaceutical Corporation: Other: Author is an employee of Analysis Group, which received consulting fees from Novartis for this study; Analysis Group Inc.: Employment. Qi:Novartis Pharmaceutical Corporation: Other: Author is an employee of Analysis Group, which received consulting fees from Novartis for this study; Analysis Group Inc.: Employment. Globe:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Immune checkpoint inhibitors in combination with radiotherapy as salvage treatment for relapsed/refractory classical Hodgkin lymphoma: A retrospective analysis in 12 patients.

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20-30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

Characterization of BCL-2 alternative proteins and outcome in patients with peripheral T-cell lymphoma (PTCL).

e19531 Background: The outcome of patients with PTCL, NOS is generally very poor, and the identification of biologically rational targets, which may translate into effective and non-toxic treatment strategies, is a high priority. The pro-survival BCL-2 family members BCL-2, BCL-XL (BCL2L1), BCL-W (BCL2L2), BCL2A1 and MCL-1 contribute to tumor maintenance, progression, and chemo-resistance across a range of cancers, but their contributions in PTCL, NOS are poorly understood. Methods: Patients with PTCL, NOS treated between 09/2000 and 09/2019 and with available tissue biopsy were included in the study. Diagnosis was retrospectively confirmed by two expert hematopathologists. BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 expression was assessed by immunohistochemistry (IHC), and the percentage of positive tumor cells assessed by standard microscopy. The 2014 Lugano Classification was used to define response to therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and were compared using log-rank test between patient groups. Results: Twenty-seven patients were included in the study: 67% were male, 52% ≥ 65 year old, and 48% had stage IV disease; 59% were previously treated and 41% received &gt; 2 lines of therapy, including stem cell transplant (SCT) in 19%. The median expression of BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 by IHC was: 30% (range: 0-100%), 10% (range: 0-90%), 100% (range: 40-100%), 20% (range: 0-90%), and 70% (range: 1-100%), respectively. BCL-2A1 was significantly higher in previously treated patients (35% vs 5%, p = 0.02), and in those who had previously received &gt; 2 lines of therapy (40% vs 5%, p = 0.02). Twenty-four (89%) patients were treated after tissue biopsy, 17 (63%) with chemotherapy, 7 (26%) with biological therapy, and 6 (22%) received subsequent SCT. Five (24%) patients achieved complete remission (CR); only BCL-W associated with response, a higher expression (quartiles 3 and 4) being observed among patients not achieving CR (median 100% vs 90%, p = 0.07). After a median follow-up of 28 months (95% CI, 14-42 months), 22 (81%) patients progressed or died, and median PFS was 4 months (95% CI, 2-6 months); only BCL-W associated with PFS, a shorter median PFS being observed for patients with higher expression (3 months vs 7 months, p = 0.001). At most recent follow-up, 17 (63%) patients died, and median OS was 6 months (95% CI, 1-12 months). only BCL-W associated with OS, a shorter median OS being observed for patients with higher expression (4 months vs not reached, p = 0.004). Conclusions: High expression of BCL-W associates with significantly worse outcome in patients with PTCL, NOS. While clinical trials investigating the safety and efficacy of BCL-2 inhibition in PTCL, NOS are ongoing, these results suggest that concomitant BCL-W inhibition may be beneficial, and functional studies aimed at confirming these findings are highly needed.

Estimation of radiation absorbed dose in man from 166Ho-EDTMP based on biodistribution data in Wistar rats

Bone marrow malignancies including multiple myeloma are treated by the myeloablative radiotherapy and subsequent stem cell transplantation. Radiopharmaceuticals are used for the selective delivery of radiation absorbed dose to bone marrow. In this work, the radiation absorbed dose of various organs of the adult man from 166Ho-EDTMP radiopharmaceutical was estimated based on biodistribution data in Wistar rats. The MIRD dose calculation method and the Sparks and Aydogan methodology for extrapolation of %IA of organs from animal to human were applied. The results shows that, more than 61% of injected activity is cumulated on the surface of the trabecular and cortical bones. Red marrow and osteogenic cells radiation absorbed doses were estimated to about 1.4 and 3.1 mGy/MBq, respectively. Compared to other aminophosphonate radiopharmaceuticals, 166Ho-EDTMP requires a minimum activity to deliver a therapeutic dose of 25 Gy to the red bone marrow. The result were compared with available data from literature.

OP206 Expert Elicitation Of Probabilistic Distributions to Inform Survival Modelling of CD19 Chimeric Antigen Receptor T-Cell Therapies

IntroductionIn 2018, the National Centre for Pharmacoeconomics (NCPE) was commissioned to conduct a health technology assessment (HTA) of one of the first commercially available chimeric antigen receptor (CAR) T-cell therapies, tisagenlecleucel. CAR T-cells are a major advance in personalized cancer treatment, demonstrating promising outcomes in relapsed/refractory pediatric acute lymphoblastic leukemia (pALL). However, the results are based on short-term follow up, limiting their value in predicting long-term survival and leading to uncertainty about the most appropriate survival modeling method to employ. This study aimed to address these limitations by means of expert elicitation.MethodsAn expert elicitation method, the histogram technique, was employed. A predefined discrete numerical scale was presented in Microsoft Excel® and the expert was asked to place twenty crosses on a frequency chart. These crosses represented the expert's beliefs about the distribution of particular quantities. Each cross represented five percent of the probabilistic distribution. Individual distributions were then aggregated across experts using linear pooling.ResultsA total of seventeen experts were invited to take part; eight agreed to participate and five completed the exercise. Three experts did not consider tisagenlecleucel to be a “curative” therapy because patients had a higher risk of death, compared with the age- and sex-matched general population. The aggregated distributions indicated the five-year overall survival rate to be thirty-three percent (95% CI 8.65–56.88) in patients who do not receive a subsequent stem cell transplant and twenty percent (95% CI 2.38 -52.04) in those who do.ConclusionsThe results of this study will be used to calibrate CD19 CAR T-cell therapy survival estimates presented in HTA submissions to the NCPE to ensure more robust assessments. They will also be used to inform the construction of a de novo cost-utility model for examining the cost effectiveness of CD19 CAR T-cell therapies for relapsed/refractory pALL in the Irish healthcare setting.

Congenital acute myeloid leukemia: challenges and lessons. A 15-year experience from the UK

Congenital Acute Myeloid leukemia (CAML) is a rare leukemia diagnosed within the first 28 days of life. Dismal survival rates of approximately 25% at two years from diagnosis have not improved despite multiple treatment protocols, and there lacks international consensus for optimal management of these vulnerable patients. We report a retrospective analysis of our fifteen-year experience from a large UK tertiary pediatric center, focusing on treatment modalities and outcomes, including late therapeutic toxicities. To our knowledge, this is the first UK series of congenital leukemia patients reported. Twelve patients with a median age of 16.4 days (1–60) were diagnosed with CAML in fifteen years. All patients presented unwell; 92% demonstrating skin involvement. 10 (83%) received chemotherapy; with 1 death at presentation and 1 spontaneous remission. 5 (42%) received subsequent stem cell transplant. Only 4 (33%) remain alive, with 5 (42%) dying in disease remission with treatment-related mortality. Documented cardiotoxicity was observed in 3 (25%) patients, with a further 2 (17%) suspected but not receiving postmortem. Treatment of congenital AML raises challenging diagnostic, therapeutic and ethical questions and requires multi-center, international collaboration to see improvements.

Interim Results of a Multicenter, Single-Arm Study to Assess Blinatumomab in Adult Patients (pts) with Minimal Residual Disease (MRD) of B-Precursor (BCP) Acute Lymphoblastic Leukemia (GMALL-MOLACT1-BLINA)

Interim Results of a Multicenter, Single-Arm Study to Assess Blinatumomab in Adult Patients (pts) with Minimal Residual Disease (MRD) of B-Precursor (BCP) Acute Lymphoblastic Leukemia (GMALL-MOLACT1-BLINA)