Refractory Acute Lymphoblastic Leukemia Research Articles

A Novel Universal CD7-Targeted CAR-T Cell Therapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia and T-Cell Lymphoblastic Lymphoma

Background Universal CAR-T (UCAR-T) using gene-editing techniques has attracted significant attention due to its prompt availability for patients. To date, there are only a few clinical case reports of universal CAR-T therapy for T-cell malignancies. Here, we explored the efficacy and safety of CD7-targeted UCAR-T (RD13-01) cells for relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in a phase I clinical trial (NCT04620655). Methods RD13-01 is an allogeneic, healthy donor-derived, and CRISPR/Cas9-edited anti-CD7 CAR-T cell product. RD13-01 consists of a CAR with a CD7-binding single-chain variable fragment (scFv), a 4-1BB costimulatory domain, CD3ζ signaling domain, a γc intracellular domain, in addition to an NK inhibitory (NKi) ligand containing an EC1-EC2 extracellular domain of E-cadherin fused to a CD28 co-stimulatory domain. The CAR and the NKi ligand are linked by an F2A self-cleaving peptide. Intravenous fludarabine (25-30 mg/m2/d), cyclophosphamide (300mg/m2/d) and etoposide (100 mg/m2/d) were given to all patients on Day -6 to Day -3 prior to CD7 UCAR-T cell infusion. Results Between December 2020 and May 2022, 10 patients (7 males, 3 females), 7 with T-ALL and 3 with T-LBL were enrolled. Median patient age was 16.5 years (range: 2-27 years). Patients had a median of 4.5 (2-6) prior lines of therapies. Two patients relapsed from a previous allogeneic hematopoietic stem cell transplant (allo-HSCT) within 6 months. In addition, 3 patients who showed no response (NR) to prior autologous CD7 CAR-T therapy were also included. Patient characteristics are shown in Table 1. Four patients harbored high-risk genotypes including STIL-TAL1, TP53, BCR-ABL, and others. By morphology, the median bone marrow (BM) blasts at enrollment were 60% (4%-96.5%). Of the eight patients with peripheral blood (PB) blasts, the median blasts were 27% (9%-85%). At enrollment, 8 patients had extramedullary disease (EMD) including 3 with central nervous system (CNS) involvement (1 CNS-1, 2 CNS-3), 3 with diffuse involvement, and 3 had localized EMD. The median transfection efficiency of the RD13-01 product was 64.6% (range: 59.0%-91.2%). A single dose of CD7 UCAR-T cells were infused to the first 3 enrolled patients at 0.5-1×107 cells/kg. Subsequently, 6 patients received a medium dose of 2×107cells/kg, and 1 received a high dose of 4×107cells/kg. By the cut-off date of July 11, 2021, the median observation time was 153 days (range: 28-315 days). On day 28 post infusion, 8/10 (80%) patients achieved complete remission (CR) in BM/PB, and 7 of the 8 patients were minimal residual disease (MRD) negative. Notably, the 3 patients who had failed prior autologous CD7 CAR-T therapy achieved CR. The first enrolled 2 patients who received the low dose showed NR and withdrew on day 28. Among the 7 patients with EMD, 4 achieved EMD CR at the median day 30, 1 had progression disease (PD) and 2, with NR in BM, withdrew prior to EMD evaluation. With a median time of 47 days (40-67 days) following infusion, 6 patients in CR (including 1 MRD +CR) underwent consolidation allo-HSCT, and 4/6 remained progression-free longest up to 315 days. However, 2/6 relapsed without CD7 lost on day 186 and day 200, respectively, and subsequently died. In addition, 1 CR patient died from bacterial infection on day 35. One PD patient received salvage transplantation and died from relapse on day 150. Post infusion, 9/10 patients experienced grade I cytokine release syndrome (CRS) and 1/10 had grade 3 CRS. Only 1 patient with CNS-3 experienced grade 3 neurotoxicity. By qPCR, CD7 UCAR-T cells reached a median peak level of 1.43×106 copies /μg genomic DNA (1.11×105~4.33×106)copies /μg genomic DNA, which occurred on day 12 (7-24 days). The median peak of circulating CD7 UCAR-T was 47.6% (0.01%~83.9%) occurring on day 7 (6-19 days), as measured by flow cytometry (Figure.1). Conclusions Our phase I trial showed that the allogeneic "off-the-shelf” RD13-01 product was safe and dose-dependently effective in treating patients with heavily pretreated T-ALL/LBL, including those with EMD and prior allo-HSCT, those who already failed autologous CD7 CAR-T therapy, and who could not manufacture autologous CAR-T from the patient's own PB due to high blasts in PB and those with rapid disease progression. Long-term observation and more patients are needed to further evaluate the safety and efficacy of CD7 UCAR-T cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Analysis of 53 Patients with Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LBL) Treated with CD7-Targeted CAR-T Cell Therapy

Analysis of 53 Patients with Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LBL) Treated with CD7-Targeted CAR-T Cell Therapy

Impact of Inotuzumb Ozogamicin on Outcome in Relapsed or Refractory Acute B-Lymphoblastic Leukemia Patients Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Background: The outcome of patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) is poor. At present, allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative option for patients with r/r B-ALL with best outcomes achieved after effective salvage re-induction therapy and transplantation in complete remission (CR). Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allo-HCT. Inotuzumab ozogamicin (INO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, developed as a targeted therapy for B-cell malignancies. Rate of VOD/SOS is increased after therapy with INO. Aims: To characterize a series of relapsed/refractory (r/r) ALL patients (pts) and evaluate outcome after treatment with INO prior to allo-HCT, particularly with respect to risk of VOD/SOS. Methods: We studied 25 r/r pts (median age, 34 years; range, 16-64 years), who were treated with INO between 2016 and 2022 within a compassionate use program (n=7) or in-label after EMA approval (n=18) One of the 25 pts were previously treated with tyrosine kinase inhibitors for chronic myeloid leukemia and progressed to blast crisis of B-lymphoid lineage. All 25 pts were CD22 positive at relapse/progressive disease. Up to 4 INO cycles (≤2 cycles, n=22; 3-4 cycles, n=3) were administered according to the previously approved regimen. Results: At the time of r/r B-ALL median white blood cell and platelet counts were 47.1/nl (range, 1.3-300/nl) and 33.5/nl (range, 5-313/nl), respectively. Five pts (20%) were female; ECOG was ≤ 2 in all pts. Cytogenetic analysis at the time of r/r EM-ALL was available in 14 pts. Six pts displayed a t(9;22), 6 had a normal karyotype, 1 was complex and 1 had a deletion 6q as well as trisomy 13. Seventeen (68%) patients achieved CR after the first INO cycle. Prior to allo-HCT, 17 (68%) pts achieved CR, 3 (12%) a partial remission, 4 (16%) were refractory and one (4%) relapsed after CR achievement. Median follow-up was 41.6 months (95%-CI, 31.1-NR) and median overall survival (OS) was 9.0 months (95%-CI, 5.78-RD months; Figure 1). One- and two-years OS rates were 45.2% (95%-CI, 28.8-70.8%) and 40.7% (95%-CI, 24.8-66.7%), respectively. VOD/SOS after allo-HCT occurred in 7 (28%) pts. Of those, 5 pts died due to VOD and multi-organ failure, all had received ≤2 INO cycles. Risk factor for VOD/SOS was allo-HCT during first-line therapy (p=0.05), whereas age, gender, donor, dose intensity of conditioning or remission status before allo-HCT had no impact. Relapse/progressive disease occurred in eight (32%) pts and all pts succumbed of their disease. Cumulative incidences of relapse/progression or death after 12 months were 20.7% (standard error,E 8.5%) and 32.7% (standard error, 9.8%). Eight (32%) pts died in remission and nine (36%) pts are in ongoing CR. Conclusions: This outcome analysis demonstrates that treatment with INO is an effective approach with successful bridge-to-transplant. However, risk of VOD/SOS is high, necessitating continuous monitoring and recognition of VOD/SOS risk factors.

Efficacy and Safety of Donor-Derived CD7 CAR T Cells for r/r T-Cell Acute Lymphoblastic Leukemia/Lymphoma: Interim Analysis from a Phase 2 Trial

Background: Results of a phase I trial of donor-derived CD7 chimeric antigen receptor (CAR) T cells for relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) (Pan et al. J ClinOncol 2021;39:3340-3351) have been reported previously. Herein, we report interim findings of the phase 2 trial on the efficacy and safety of donor-derived CD7 CAR T cells for relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma. Methods: The subjects in phase 2 were screened from the similar I/E criteria of phase 1 trial. Patients with prior stem cell transplantation (SCT) received CAR T cells from prior SCT donors, while patients without SCT history received CAR T cells from new donors who also provided stem cells for transplantation post CAR T therapy. The phase 2 trial was using Bayesian optimal phase 2 (BOP2) design to evaluate the efficacy and safety of the target dose of 1 × 106 (±20%) CD7 CAR T cells per kg of body weight in refractory/relapsed T-cell acute lymphoblastic leukemia/lymphoma (NCT04689659). The primary endpoint was efficacy with safety secondary. An interim analysis of phase 2 trial could be performed when the first 20 patients who receive CD7 CAR T cells have completed 3 months from infusion or discontinued earlier. Survival status were continuously followed up while severe adverse events (SAEs) were recorded until receiving other anti-leukemia therapy. Results: Eighteen (90%) of twenty enrolled patients responded in phase 2 trial and were followed up with a median time of 11.0 months (range 7.6-14.6) until May, 14th, 2022. Patients in phase 1 and 2 trial had similar baseline characteristics, whereas phase 2 trial included more patients with mediastinal malignancies.(Fig. A) The best overall response (BOR) rate was 90% at 3 months. The objective response rate (ORR) were 90% and 90% at 1 and 3 months post-infusion, which were similar to 95% and 95% at 1 and 3 months in phase 1 trial. The 3-months complete remission (CR) rate in patients with mediastinal tumors was lower than that in patients without mediastinal tumors, although there was no significant statistical difference (p=0.07, Fig. B) Of total 18 responders that were followed up, 12 (67%) patients who received no further therapy, all had continuously detectable CAR T cells until the last visit, three remained in remission, seven had a relapse (three CD7+, and three CD7-, one unknown), and two died of infection; 8 (44%) patients proceeded to SCT and no CAR T cells were detectable after SCT, and among them five remained in remission, two had a relapse (CD7-), and one died of infection. Patients relapsed at a median time of 4 (range 1.6-10.5) months. The one-year progressive-free survival (PFS) and overall survival (OS) rates were 62.3% (95% CI, 38.3-86.3) and 60.0% (95% CI, 38.5-81.5). Patients without mediastinal mass had longer OS than patients with mediastinal mass. (p<0.05, Fig. C) Updated phase 1 data at a median 1.5-year follow-up, shows PFS and OS rates of 60.0% (95%CI, 38.4-81.6) and 70.0% (95%CI, 50.0-90.0) Short-term adverse events included grade 3 or higher cytokine release syndrome (10%) and grade 1-2 graft-versus-host disease (GVHD, 40%), which were all reversible. Three late-onset (> 30 days post-infusion) SAEs occurred in 3 responders, including 1 grade 5 sepsis at month 2, 1 grade 5 fulminant hepatitis at month 2, and 1 grade 5 pneumonia at month 5. Severe infections occurred in 2/3 patients with no further therapy, and the total T cells in them reached a median count of 654.34/μL (range 41.87-1210.46), which were substantially lower than normal levels despite steadily increasing. The safety analysis was similar to the phase 1 trial of donor-derived CD7 CAR T cells. (Fig. D) Conclusions: Interim results from a phase 2 trial of donor-derived CD7 CAR T cell therapy showed similar encouraging activity in treating r/r T-ALL with phase 1 trial. Relapse emerges as major issues impeding long-term outcomes. CD7-negative relapse was commonly observed under CAR T cell surveillance. Late onset GVHD and infections may occur and should be carefully managed. Patients with mediastinal mass had poor overall survival and needed been further investigated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CNCT19 CAR T-Cell Therapy in Relapsed or Refractory B-Cell Lymphoma: Long-Term Results of a Pilot Prospective Clinical Study

Background: Chimeric antigen receptor (CAR) T-cell targeting tumor cells depends on the single chain variable fragment (scFv) against the specific tumor antigen. Most anti-CD19 CAR-T products have the scFv deriving from hybridoma clone FMC63. We developed a new hybridoma clone HI19α which binds to distinct CD19 episodes. CNCT19 was a second-generation CAR T-cell with scFv derived from clone HI19α and 4-1BB/CD3-ζ costimulatory domain. The results of CNCT19 in pediatric and adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia had previously been reported [Runxia Gu et al. J Hematol Oncol. 2020 Sep 7;13(1):122]. Herein, we reported the outcome and long-term follow-up of a pilot study administrating CNCT19 in relapsed or refractory B-cell lymphoma. This trial was registered at www.clinicaltrials.gov as NCT03029338. Methods: Patients with R/R CD19-positive B-cell lymphoma were eligible for this study. Subjects with active central nervous system involvement were excluded. Lymphodepleting chemotherapy comprising fludarabine (25~30mg/m2, day -4,-3,-2) and cyclophosphamide (350mg/m2 day -4, -2) was administrated once the CNCT19 product was available. We infused CNCT19 cells in three regimens: three-day split dose (10%-30%-60%, patient (P)1-P10), two-day split dose (40%-60%, P11-P17), and single dose (P18-20). Results: From May 2017 through March 2019, 20 patients were enrolled. Diagnosis of histological subtypes included diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS) in 14 (70%) patients, DLBCL transformed from chronic lymphocytic leukemia in 1 (5%) patient, follicular lymphoma (FL) grade 3b in 1 (5%) patient, and mantle cell lymphoma (MCL) in 4 (20%) patients. Considering the differences in efficacy and survival between the population with MCL and those with LBCL, we here reported the results of 16 patients who had diseases of DLBCL or FL 3b. The median age was 51 (range 16 to 69), and 62.5% were male. The majority (87.5%) of patients had advanced stage disease, and 11 (68.8%) had non-GCB immunophenotype. Double expressor lymphoma (DEL, cut-off for MYC, >=40%, BCL2, >=50%) was identified in 11 (68.8%) patients, with one of them having MYC and BCL2 rearrangement. TP53 mutation and/or deletion were detected in 5 of 6 (83.3%) patients. The patients had received a median of 3 (range 2 to 7) lines of prior therapy. Thirteen (81.3%) patients had diseases refractory to last-line therapy. The median dose of infused CNCT19 cells was 2.48×106 (range 1.87 to 5.06×106) per kilogram of body weight. Cytokine release syndrome (CRS) occurred in 11 (68.8%) patients, all of whom were grade 1. Only one patient experienced CAR-T-cell-related encephalopathy syndrome (CRES), manifesting as distal muscle weakness of the bilateral upper limb, and he recovered completely after corticosteroids treatment. Twelve (75.0%) patients achieved a response after CNCT19 infusion, with a complete response (CR) rate of 37.5%. The ORR and CR rate at 3 months was 62.5% and 31.3%, respectively. Two patients with ongoing partial remission underwent allogeneic hematopoietic stem-cell transplantation, and both of them died of progressive disease at 6 months and 11 months post CNCT19 infusion, respectively. As of July 5, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 44.5 months. The median progression-free survival and overall survival were 6.5 (95% CI 1.0 to NA) months and 12.7 (95% CI 2.9 to NA) months, respectively. Six (37.5%) patients remained alive by data cut-off. Conclusions: CNCT19 cells exhibited comparable efficacy and favorable safety in patients with R/R DLBCL and FL3b. A phase 2 clinical trial (NCT04586478) of administrating CNCT19 in R/R large B-cell lymphoma and high-grade B-cell lymphoma is underway.

The Efficacy of Chidamide Maintenance Therapy after CAR-T Therapy for Refractory or Relapsed B-Cell Acute Lymphoblastic Leukemia

Introduction Anti-CD19 chimeric antigen receptor (CAR) T-cells therapy has achieved unprecedented efficacy in refractory or relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) patients, with up to a 90% complete remission (CR) rate. However, a large body of clinical data has shown that the relapse rate post CD19 CAR-T therapy remains high. Our published study of 254 patients with R/R B-ALL treated with CD19 CAR-T showed the median time to relapse following CAR-T cells infusion was 100 days. Patients who received consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) post CAR-T therapy demonstrated much higher overall survival (OS) and leukemia-free survival (LFS) compared to those who received CAR-T therapy alone (1-year OS of 77.8% vs. 35.4%, p<0.0001; 1-year LFS of 70.9% vs. 33.3%, p<0.0001, respectively). However, there are still many patients who cannot undergo allo-HSCT, including those who have relapsed following allo-HSCT and elderly patients. Prolonging disease-free survival (DFS) after CAR-T therapy in these patients remains a challenge for physicians. Studies have shown that the histone deacetylase (HDAC) inhibitor chidamide can up-regulate T-cell activity and down-regulate derived suppressor cell (MDSC) expression. Chidamide also promotes the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhances CAR-T function. Here we explore the efficacy of chidamide as maintenance therapy post CAR-T in B-ALL. Patients and methods We analyzed 19 patients with R/R B-ALL who received CD19 CAR-T at our center (NCT04546893) between October 2019 and July 2022. All patients achieved CR on day 30 following CD19 CAR-T cells infusion and were unable to bridge to allo-HSCT within 3 months. We administered chidamide as maintenance therapy to all 19 patients between 30 to 90 days after CAR-T infusion. Chidamide was continuously administered until the patient relapsed, transferred to transplant, or had intolerable side effects. Results On Day 30 post CD19 CAR-T, 19/19 (100%) patients achieved CR or CR with incomplete count recovery (CRi)(Figure 1). Sixteen of 18 (88.89%) who had bone marrow involvement achieved minimal residual disease (MRD)-negative CR. The median time from CAR-T cell infusion to start chidamide therapy was 30 days (range: 30-90 days) and the median duration of chidamide administration was 90 days (range: 12-420 days). No patient experienced cytokine release syndrome (CRS) or encephalopathy while taking chidamide. All side effects that occurred were mild. Two patients experienced nausea and vomiting and one patient had mild bone marrow suppression. No other side effects occurred. The median follow-up time was 12 months (range: 1-33 months), the 12-month OS rate was 83.1% and the 12-month DFS rate was 62.4% (Figure 2). Five patients received allo-HSCT following chidamide maintenance and 13 patients who did not undergo transplantation had 12-month OS of 83.3%, 12-month DFS of 62.9%. Six patients were monitored for the proportion of CAR-T cells in T lymphocytes following chidamide therapy. In all six patients, the proportion of CAR-T cells increased but to different degrees. Conclusions For those patients with R/R B-ALL for whom allo-HSCT is not available following CD19 CAR-T therapy, HDAC inhibitor chidamide as maintenance therapy is a viable option to reduce the risk of relapse rate following CD19 CAR-T therapy. This study demonstrated that chidamide could prolong OS and DFS in some patients who achieved CR after CD19 CAR-T therapy. Chidamide was safe, inexpensive and convenient to take orally. The inclusion of more patients and extended observation time is needed for further evaluation of chidamide maintenance therapy following CAR-T cell therapy in patients with R/R B-ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Peripheral Blast Count at Apheresis Acts Independent of Disease Burden As a Risk Factor for Survival Following Tisagenlecleucel in Children and Young Adults

Introduction: Chimeric antigen receptor (CAR) T-cells have provided a therapeutic option for patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) who have failed standard chemotherapy approaches. Despite initial responses, relapse rates after tisagenlecleucel approach 40% for pediatric patients necessitating a need to improve outcomes with this therapy. High pre-infusion disease burden (defined as ≥5% blasts on marrow or extramedullary disease) has been associated with inferior overall survival (OS) and event free survival (EFS) (Schultz 2021). However, it remains unclear if debulking disease will improve outcomes. Additionally, bridging chemotherapy used to debulk may introduce toxicity, without established benefit. Peripheral blast count represents high burden disease in the bone marrow. No current clinical standard exists guiding peripheral blast thresholds prior to apheresis. It remains unclear if having peripheral blasts at the time of apheresis is a surrogate marker for disease burden, or if peripheral blasts at time of apheresis collection has inherent independent predictive value. Methods: We performed a retrospective analysis from the Pediatric Real-World CAR Consortium (PRWCC) consisting of 15 US institutions. All patients with data available regarding their peripheral blast count at time of apheresis were included. Primary outcomes were day 28 response, EFS (events; second malignancy, relapse, or death) and OS. Baseline factors of interest included age at diagnosis, sex, pre-infusion disease burden, prior lines of therapy, prior CD19 therapy, time from diagnosis to CAR infusion, CAR dose, prior stem cell transplantation (SCT), and timing of 1st relapse post SCT (Schultz 2021). The impact of peripheral blast count at apheresis was assessed using Cox models adjusting for all baseline factors of interest. Kaplan Meier (KM) curves were reported for time-to-death and time-to-first event. Results: Of 185 patients who were infused with tisagenlecleucel in the PRWCC database, 162 patients had peripheral blast data at time of apheresis available for analysis: 120 (74%) had no peripheral blasts on CBC and 42 (26%) had >0 blasts at apheresis. A greater proportion of patients with >0 blasts had high disease burden (79%) compared to those with no peripheral blasts (44%) (table 1). The median (interquartile range, IQR) from apheresis to CAR T infusion is 7 weeks (wks) (5.2-10 wks) and there was no difference in time to infusion for patients with no blasts (n=120): 7 wks (6-10) compared to those with >0 blasts (n=42): 6 wks (5-8.8). Day 28 response did not differ between those with no blasts (87% CR) and those with >0 blasts (83% CR) (p=0.83). With a median follow-up of 334 (143-536) days (>0 peripheral blasts; 248 (92, 520), no blasts; 353 (186, 549)), death occurred more often in patients with >0 blasts (43%) when compared to those with no blasts (22%). Patients who had >0 blasts had significantly inferior event-free survival (p=0.008) and overall survival (p=0.004) compared to those with no peripheral blasts at apheresis. Univariate analysis showed that for every 10% increase in blast percentage, the hazard of death increased 1.19-fold (95% confidence interval (CI) 1.05-1.35;p=0.006) and the hazard of events increased 1.10-fold (95% CI 0.99-1.23; p=0.077). High pre-infusion disease burden had a significantly higher hazard of death (p=0.002) and of event (p=0.002), compared to no detectable disease. After adjustment for baseline factors including high vs no vs low disease burden, multivariable analysis demonstrated higher blasts remained significantly associated with higher hazard of death (p=0.004) and event (p=0.04). KM curves were stratified by pre-infusion disease burden (high versus low/no) and peripheral blast count at apheresis (no blasts versus >0 blasts) (figure 1). Patients with low/no disease burden and no blasts at apheresis had the best EFS when compared to those with high disease burden (p<0.001). Although not statistically significantly, amongst patients with high pre-infusion disease burden, those with >0 blasts had slightly worse OS (p=0.13) and EFS (p=0.47) compared to those with 0 blasts. Conclusion: Higher peripheral blasts at apheresis associates with inferior outcomes after tisagenlecleucel, even after multivariable analysis. Further study is needed to determine the mechanism of this association and if it is modifiable. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient Characteristics, Treatment Patterns, and Cost Variations By Race/Ethnicity Among Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia Initiating First Salvage Therapy

Patient Characteristics, Treatment Patterns, and Cost Variations By Race/Ethnicity Among Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia Initiating First Salvage Therapy

Blinatumomab Prior to CAR-T Cell Therapy-A Treatment Option Worth Consideration for High Disease Burden.

The optimal bridging therapy before CAR-T cell infusion in pediatric relapsed or refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) still remains an open question. The administration of blinatumomab prior to CAR-T therapy is controversial since a potential loss of CD19+ target cells may negatively impact the activation, persistence, and, as a consequence, the efficacy of subsequently used CAR-T cells. Here, we report a single-center experience in seven children with chemorefractory BCP-ALL treated with blinatumomab before CAR-T cell therapy either to reduce disease burden before apheresis (six patients) or as a bridging therapy (two patients). All patients responded to blinatumomab except one. At the time of CAR-T cell infusion, all patients were in cytological complete remission (CR). Four patients had low positive PCR-MRD, and the remaining three were MRD-negative. All patients remained in CR at day +28 after CAR-T infusion, and six out of seven patients were MRD-negative. With a median follow-up of 497 days, four patients remain in CR and MRD-negative. Three children relapsed with CD19 negative disease: two of them died, and one, who previously did not respond to blinatumomab, was successfully rescued by stem cell transplant. To conclude, blinatumomab can effectively lower disease burden with fewer side effects than standard chemotherapeutics. Therefore, it may be a valid option for patients with high-disease burden prior to CAR-T cell therapy without clear evidence of compromising efficacy; however, further investigations are necessary.

Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia.

Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n = 12) and/or after (n = 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4-23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI): 38.7-73.4) and overall survival (OS) was 77.8% (95% CI: 64.5-93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28-655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OS/EFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OS/EFS for patients treated with InO prior to CART-19 are similar.

A multicenter study of ICU resource utilization in pediatric, adolescent and young adult patients post CAR-T therapy.

Tisagenlecleucel is associated with remarkable outcomes in treating patients up to the age of 25 years with refractory B-cell acute lymphoblastic leukemia (ALL). Yet, due to unique and potentially life-threatening complications, access remains limited to higher-resource and certified centers. Reports of inequity and related disparities in care are emerging. In this multicenter study of ALL patients admitted for anti-leukemia therapy, who required pediatric intensive care (ICU) support (n = 205), patients receiving tisagenlecleucel (n = 39) were compared to those receiving conventional chemotherapy (n = 166). The median time to ICU transfer was 6 (0-43) versus 1 (0-116) days, respectively (p < 0.0001). There was no difference in the use of vasopressor, ionotropic, sedating, and/or paralytic agents between groups, but use of dexamethasone was higher among tisagenlecleucel patients. Patients receiving tisagenlecleucel were more likely to have cardiorespiratory toxicity (p = 0.0002), but there were no differences in diagnostic interventions between both groups and/or differences in ICU length of stay and/or overall hospital survival. Toxicities associated with tisagenlecleucel are generally reversible, and our findings suggest that resource utilization once admitted to the ICU may be similar among patients with ALL receiving tisagenlecleucel versus conventional chemotherapy. As centers consider improved access to care and the feasibility of tisagenlecleucel certification, our study may inform strategic planning.

Blinatumomab plus hyper-CVAD: the prelude to a new era in acute lymphocytic leukaemia

Blinatumomab, a CD19/CD3 bispecific T-cell engager active as monotherapy in relapsed or refractory B-cell acute lymphocytic leukaemia, was approved for adults with positive minimal residual disease (MRD) in Europe and the USA in 2018. Approval was granted on the basis of a single-arm, phase 2 study, in which 78% of included patients had an MRD-negative complete response and promising outcomes and acceptable toxicity were seen.1,2 Early experiences have also been encouraging with blinatumomab as first-line treatment of Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphocytic leukaemia in older adults (aged >65 years)—a population that has previously had poor outcomes owing to adverse biology and poor tolerance to chemotherapy.

Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial

Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes. We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients. Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related. Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia. Amgen.

Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently.

CD19 chimeric antigen receptor (CAR) T cells have shown robust efficacy in relapsed and refractory acute lymphoblastic leukemia (R/R ALL), but compromising result in chronic lymphoblastic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). CD19 relapse and the lack of CAR-T cell persistence which result in treatment failure are considerable obstacles to overcome. CAR-T targeting CD20 is an option for salvaging CD19 CAR-T failure. Previous studies have established variant structures of bispecific CAR-T which could avoid antigen-loss and immune escape. Here, we constructed tandem and loop CAR structures targeting both CD19 and CD20 antigen. Bispecific CAR-T cells could eliminate either CD19 or CD20 negative lymphoma cells, suggesting they exhibited dual antigen targeting of CD19 and CD20. By comparing the efficiency of four bispecific CAR modified T cells, it was found that loop2019 CAR was the best structure among them to eradicate lymphoma cell lines and patients' primary lymphoma or CLL cells in a very low dose in vitro and prolong the survival time dramatically in lymphoma xenograft mice model. These data highlighted the potential of loop2019 CAR-T in clinical treatment.

UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial

The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10-3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 106, 6-8 × 107, or 1·8-2·4 × 108 total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete. Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0). UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. Servier.

ALL-220 Azacitidine in Combination With Venetoclax Maintenance Post Allogeneic Hematopoietic Cell Transplantation in T-Cell Acute Lymphoblastic Leukemia

Relapsed and/or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with few available salvage options and usually carries a dismal outcome with only 10% of patients surviving at 5 years. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy in R/R T-ALL remains problematic, as up to half of patients will relapse post allo-HSCT. Post-transplant maintenance in acute myeloid leukemia (AML) has long been debated, with recent implementation by transplant centers, especially the use of hypomethylating agents (HMAs) and targeted agents such as FLT3 inhibitors. In T-ALL, this concept has not been explored yet with very little data. The aim of this case series is to present a novel approach for post-transplant maintenance in patients diagnosed with R/R T-ALL. This is a case series including 4 patients with R/R T-ALL who underwent allo-HSCT at the American University of Beirut Medical Center and received post-transplant maintenance with low-dose 5-azacitidine and venetoclax. We identified four adult patients diagnosed with high-risk T-ALL (three patients with mature T-ALL and one with early T-precursor [ETP] ALL) with a median age of 35 years (range, 31-45 years). All received post-allo-HSCT maintenance with 5 days of low dose 5-azacitidine at 32 mg/m2 daily with venetoclax 100 mg orally daily for 5 days with voriconazole every 28 days. The median duration of maintenance treatment was 12.75 months (range, 9.5-23.5 months). All patients remain in continuous complete remission with undetectable measurable residual disease after a median follow-up of 15 months from the date of allo-HSCT (range, 12-25 months). Both HMAs and venetoclax possess significant antitumor activity effects against AML/myelodysplastic syndrome, and their efficacy in R/R T-ALL has been demonstrated in multiple case series. These encouraging results along with our case series of successful maintenance treatment with azacitidine with venetoclax in T-ALL are worth exploring in larger prospective trials.

The risk factors and early predictive model of hematotoxicity after CD19 chimeric antigen receptor T cell therapy.

Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.

Genome-wide CRISPR screens identify ferroptosis as a novel therapeutic vulnerability in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer diagnosed in children. Despite the great progress achieved over the last 40 years, with cure rates now exceeding 85%, refractory or relapsed ALL still exhibit a dismal prognosis. This poor outcome reflects the lack of treatment options specifically targeting relapsed or refractory ALL. In order to address this gap, we performed whole-genome CRISPR/Cas drop-out screens on a panel of seven B-ALL cell lines. Our results demonstrate that while there was a significant overlap in gene essentiality between ALL cell lines and other cancer types survival of ALL cell lines was dependent on several unique metabolic pathways, including an exquisite sensitivity to GPX4 depletion and ferroptosis induction. Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX4-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of BALL to ferroptosis induction using patient-derived B-ALL samples.

Engaging Patients and Caregivers in an Early Health Economic Evaluation: Discerning Treatment Value Based on Lived Experience.

Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment. We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data. Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration. Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models.

Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study

Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia. We did an international, multicentre, retrospective cohort study at 15 hospitals across ten countries in Europe. Eligible patients were children aged younger than 3 years at screening between Sept 1, 2018, and Sept 1, 2021, who were screened for tisagenlecleucel therapy for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia according to licensed indications. Patients received a single intravenous infusion of tisagenlecleucel. We tracked chimeric antigen receptor T-cell therapy outcomes using a standardised data reporting form. Overall survival, event-free survival, stringent event-free survival, B-cell aplasia, and toxicity were assessed in all patients who received a tisagenlecleucel infusion. 38 eligible patients were screened, of whom 35 (92%) received a tisagenlecleucel infusion. 29 (76%) of 38 patients had KMT2A-rearranged acute lymphoblastic leukaemia, and 25 (66%) had relapsed after previous allogeneic haematopoietic stem-cell transplantation (HSCT). Patients had previously received a median of 2 lines (IQR 2-3) of (non-HSCT) therapy. Seven (18%) of 38 patients had received inotuzumab and 14 (37%) had received blinatumomab. After a median of 14 months (IQR 9-21) of follow-up, overall survival at 12 months after tisagenlecleucel infusion was 84% (64-93; five patients had died), event-free survival was 69% (47-83; nine events), and stringent event-free survival was 41% (23-58; 18 events). The probability of ongoing B-cell aplasia was 70% (95% CI 46-84; seven events) at 12 months. Adverse events included cytokine release syndrome, which occurred at any grade in 21 (60%) of 35 patients and at grade 3 or worse in five (14%), and neurotoxicity at any grade in nine (26%), none of which were severe. Measurable residual disease-negative complete response with or without haematological recovery occurred in 24 (86%) of 28 patients who had measurable disease. These data suggest that tisagenlecleucel has antitumour activity and has an acceptable safety profile for young children and infants with B-cell precursor acute lymphoblastic leukaemia. None.