Refractory Acute Lymphoblastic Leukemia Research Articles

Real-world experience of disease-burden-adapted immunotherapy protocol for relapsed and refractory acute lymphoblastic leukemia from BJ Wadia hospital

Real-world experience of disease-burden-adapted immunotherapy protocol for relapsed and refractory acute lymphoblastic leukemia from BJ Wadia hospital

Outpatient Administration of Blinatumomab Infusion and Hematopoietic Stem Cell Transplantation as Treatment for Patients with Refractory Acute Lymphoblastic Leukemia in a Pediatric Oncologic Center in Mexico

Outpatient Administration of Blinatumomab Infusion and Hematopoietic Stem Cell Transplantation as Treatment for Patients with Refractory Acute Lymphoblastic Leukemia in a Pediatric Oncologic Center in Mexico

FLAG Regimen and Bortezomib: A Study of Eight Cases with Relapsed Leukaemia

Historically, relapsed and refractory Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML) have been associated with a dismal prognosis. Relapse-refractory ALL is associated with cure rates of <10% in adults and 30% in the paediatric population. Similarly, the five-year survival rates for relapsed and refractory AML are only 10%. This case series describes eight patients with relapsed/refractory leukaemia (6 with ALL and 2 with AML) who received the FLAG-Bortezomib protocol from January 2021 to August 2022. In this case series, the authors investigated the remission rate and toxicity of the regimen, including Intensive Care Unit (ICU) admissions and the incidence of neutropenic sepsis. In the present study, the rates of culture-positive sepsis and High Dependency Unit (HDU) admission were 50% (4/8) and 37.5% (3/8), respectively, with no post-chemotherapy mortality in this cohort. Morphologic remission was documented in 87.5% (7/8) of cases, and negative minimal residual disease was achieved in 62.5% (5/8), with 100% (2/2) remission in those with AML. One patient with ALL experienced disease progression during treatment. The FLAG with Bortezomib protocol induces remission in relapsed and refractory ALL and AML patients with an acceptable toxicity profile. This protocol requires rigorous blood product support in the form of packed red blood cells, platelet-rich plasma, and single-donor platelet apheresis. It serves as a bridge to stem cell transplant.

Chimeric Antigen Receptor T Cell Therapy for Acute Leukemia.

The worldwide use of CD19 chimeric antigen receptor (CAR)-T cells has increased the response rate in patients with refractory or relapsed B-cell acute lymphoblastic leukemia. Clinical practice has become much safer with the help of immunotherapy-related toxicity management guidelines, such as the ASTCT consensus grading system. Tocilizumab and steroids are the major interventions for controlling cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New drugs and interventions for uncontrolled CRS and ICANS, including JAK1/2 inhibitors, have also been investigated. The combination of ruxolitinib and steroids effectively controlled severe CRS without impeding CAR-T cell expansion. Patients with refractory CNS3 status and CNS masses were excluded from the clinical trials because of the high risk of severe ICANS. Intracranial injections of steroids and Ommaya capsule implantation were effective. For some heavily treated patients, the difficulties in CAR-T cell manufacturing and expansion may be resolved by combination with blinatumumab. Relapse is a major concern after CAR-T therapy, and combination interventions, such as allogeneic stem cell transplantation, dual-target CAR-T cell therapies, and sequential CD19/22 CAR-T infusion, have been investigated in many centers. For T-lineage-targeted CAR-T therapies, the CAR T-cell fratricide can be overcome using many techniques. The efficacy and safety of CD7+ CAR-T cell therapy have been widely reported in recent years. A high response rate can be achieved when the immune reconstitution is prolonged. Infections, particularly viral reactivations, should be carefully monitored, as relapses are another potential issue. Switching targets and eliminating residual CD7+ CAR-T cells in the blood are key points for patients who relapse after CD7+ CAR-T cell therapy. CAR-T cell therapies for AML have not been investigated in a large-scale cohort, except for CD19-positive AML with the AML1-ETO fusion gene.

Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia.

UCART19 is an "off-the-shelf" genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells. UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Responder patients (12/25) had higher UCART19 expansion (C max) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28. UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

A phase 1 study to evaluate the safety, pharmacology, and feasibility of continuous infusion nelarabine in patients with relapsed and/or refractory lymphoid malignancies.

Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) and lymphoblastic lymphoma (T-LBL). Although effective in R/R T-ALL, significant neurotoxicity is dose-limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule. The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5days (120hours), rather than the standard, short-infusion approach. Twenty-nine patients with R/R T-ALL/LBL or T-cell prolymphocytic leukemia (T-PLL) were treated, with escalating doses of nelarabine from 100 to 800mg/m2 /day × 5days. The median age of the patients was 39years (range, 14-77years). The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy was observed in 34% of patients, including four ≥grade 3 events related to nelarabine. Notably, there was no nelarabine-related central neurotoxicity on study. The maximum tolerated dose was not reached. Pharmacokinetic data suggested no relationship between dose of nelarabine and accumulation of active intracellular ara-GTP metabolite. Higher intracellular ara-GTP concentrations were statistically associated with a favorable clinical response. Preliminary evaluation of continuous infusion schedule of nelarabine suggests that the safety profile is acceptable for this patient population, with clinical activity observed even at low doses and could broaden the use of nelarabine both as single agent and in combinations by potentially mitigating the risk of central nervous system toxicities.

“A.B.C.” of Immunotherapy in Hematological Malignancies…Promise and Perils

AbstractThe treatment landscape of hematological malignancies has been evolving at an extremely fast pace. Hematological malignancies are diverse and distinct from solid tumors. These constitute challenges, which are also unique opportunities for immunotherapy. The five categories of immunotherapies that have found success in the management of hematological malignancies are allogeneic hematopoietic stem cell transplant, monoclonal antibodies and innovative designs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and B cell targeting small immunomodulatory molecules. Allogeneic stem cell transplant rightly called our bluntest weapon is the oldest form of successful immunotherapy. Alternate donor transplants and improvement in supportive care have improved the scope of this immunotherapy option. Among monoclonal antibodies, rituximab forms the prototype on which over a dozen other antibodies have been developed. The bispecific T-cell engager (BiTE) blinatumomab engages cytotoxic CD3 T cells with CD19 acute lymphoblastic leukemia (ALL) cells, which is an effective treatment method for relapsed refractory ALL. Immune checkpoint inhibitors have established their role in hematological malignancies with high PD-L1 expression, including relapsed refractory Hodgkin's lymphoma and primary mediastinal B cell lymphoma (BCL). Small immunomodulatory drugs targeting the B cell receptor downstream signaling through BTK inhibitors, SYK inhibitors, PI3K inhibitors (idelalisib), and BCL-2 inhibitors (venetoclax), and immunomodulatory imide drugs (lenalidomide) have also emerged as exciting therapeutic avenues in immunotherapy. CAR T cells are one of the most exciting and promising forms of adoptive immunotherapy. CAR T cells are rightly called living drugs or serial killers to keep patients alive. CAR T cells are genetically engineered, autologous T cells that combine the cytotoxicity of T cells with the antigen-binding specificity of CARs. CARs are antigen-specific but major histocompatibility complex/human leukocyte antigen-independent. There are five approved CAR T cell products for the management of relapsed refractory leukemias, lymphoma, and multiple myeloma. The past and present of immunotherapy have been really exciting and the future looks incredibly promising. The challenges include widening the availability and affordability beyond specialized centers, identification of potentially predictive biomarkers of response, and experience in the management of complications of these novel agents. The combinational approach of multiple immunotherapies might be the way forward to complement the treatment strategies to harness the immune system and to improve survival with good quality of life.

Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial

Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy. We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing. Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed. The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response. Takeda Oncology and Amgen.

Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: A Phase 1 Trial

Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. Inotuzumab ozogamicin is an approved CD22 targeting antibody for pts with R/R B-ALL; however, the toxin calicheamicin can lead to veno-occlusive disease (VOD) of the liver, especially after allogeneic SCT (allo-SCT). ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here results from an ongoing phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of phase 2 is to evaluate efficacy (CR/CRi rate). Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). A 3+3 dose-escalation design was used for phase 1. ADCT-602 was initially given IV once every 3 weeks; based on the PK data, the administration schedule was later amended to weekly infusions. Results: From November 2018 to July 2022, 21 pts (11 women, 10 men) with R/R B-ALL were enrolled and received treatment with ADCT-602. The median age was 39 years (range, 21-82) and pts had received a median of 5 (range, 2-9) prior therapies [inotuzumab ozogamicin 12/21 (57%); blinatumomab 18/21 (86%); venetoclax 12/21 (57%)]. A total of 8/21 (38%) had a prior CD19 CAR-T, including 1 pt who had both CD19 and CD22 CAR-T. Ten (10/21, 48%) pts had a prior allo-SCT, including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70% (range, 16-96). The median CD22 expression on blasts was 97% (range, 33.6-100). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing. A total of 10 pts were treated at the weekly dose level [30µg/kg, n=3; 40µg/kg, n=4; 50µg/kg, n=3]. One pt (30µg/kg weekly dose level) had grade 4 thrombocytopenia possibly related to ADCT-602. One pt (50µg/kg weekly dose level) had a DLT of prolonged myelosuppression (marrow blast clearance without blood count recovery). No pt had VOD. Notably, all 3 pts treated at the 50µg/kg weekly dose level (a dose level expected to be close to RP2D) had evidence of anti-tumor activity (2 pts achieved MRD negative CR; one pt had bone marrow blast clearance). First pt at this dose level was a 26-yr-old with R/R B-ALL with PAX5-JAK2 fusion with 5 prior therapies including 2 CD19 CAR-T and an allo-SCT who achieved MRD negative CR and is receiving ongoing therapy in Cycle 5. Second pt at this dose level was a 66-yr-old with TP53- and KRAS-mutated B-ALL with 2 prior therapies including modified BFM regimen and blinatumomab who achieved MRD negative CR and is receiving ongoing therapy in Cycle 4. Third pt at this dose level was a 21-yr-old with TP53- and KRAS-mutated B-ALL with 4 prior therapies including inotuzumab and a CD19 CAR-T who had morphologic blast clearance without blood count recovery. Two additional pts treated at lower doses levels (1 each at 30µg/kg Q3week and 30µg/kg weekly schedule) achieved MRD negative CR. All responding pts had CD22 expression noted in >97% of the blasts by flow cytometry. Conclusions: In this phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with one pt with DLT noted at the 50µg/kg weekly dose level. Notably, all 3 pts treated at this dose level had evidence of clinical activity with 2/3 pts achieving MRD negative CR. Due to 1 pt with DLT at this dose level, this cohort is being expanded to treat 3 additional pts. This trial continues to accrue pts and updated data will be presented at the ASH meeting.

Real-World Data on the Incidence and Management of Blinatumomab Toxicities in Adult Patients with Minimal Residual Disease and Relapsed or Refractory Acute Lymphoblastic Leukemia

Background: Blinatumomab is a CD19/CD3 bispecific monoclonal antibody administered as a continuous infusion and requires dose escalation in relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL); whereas patients with minimal residual disease-positive (MRD) ALL are initiated at the target dose. The purpose of this study was to evaluate the real-world incidence of cytokine release syndrome (CRS) and/or neurotoxicity requiring treatment interruption between MRD and R/R ALL. Methods: This single-center, retrospective study included patients > 18 years of age who received at least one dose of blinatumomab for MRD or R/R ALL between October 30th, 2018 to December 1st, 2021. The primary outcome was incidence of documented CRS and/or neurotoxicity requiring treatment interruption. Management of toxicities was also evaluated in patients requiring blinatumomab interruption. All results were evaluated using descriptive statistics and/or the Fisher's exact test. Results: Overall, 34 patient encounters met inclusion criteria. Fifteen patients were diagnosed with MRD ALL and 19 patients had R/R disease. Patient characteristics are summarized in Table 1. The median age was 39 in the MRD ALL cohort and 45 in the R/R ALL cohort with a Karnofsky performance score of at least 70 percent in both cohorts. Most patients received only one line of therapy prior to blinatumomab which was consistent between both groups as majority of patients were either refractory or in CR-1.Therapies prior to blinatumomab included hematopoietic stem cell transplant (HSTCT) and/or chimeric antigen receptor (CAR) T-cell therapy in both the ALL MRD and ALL R/R cohorts (13% and 7% vs 26% and 5% respectively). There was no difference in the incidence of CRS and/or neurotoxicity requiring blinatumomab interruption between MRD and relapsed or refractory patients (40% vs 21%, p=0.28) (Table 2). Majority of patients requiring treatment interruption was due to Grade >3 toxicity in both groups (33% vs 11% in MRD ALL and R/R ALL respectively). Only one patient in each group required treatment interruption due to grade >3 CRS. No baseline characteristics were identified as significant risk factors for toxicities between groups; however, a history of HSCT and administration of concurrent antiepileptics did trend toward having a lower associated risk of developing severe toxicities. MRD patients were more likely to develop toxicity after a smaller cumulative dose and sooner following blinatumomab initiation (30.3 vs 183.4 hours). Time to resolution of toxicity was similar for MRD and R/R at 43 and 55 hours (p=NS). Toxicity management strategies varied among all patients with steroid treatment being the most common therapeutic management of blinatumomab-related toxicity. Exploratory outcomes suggest MRD patients were more likely to achieve remission with blinatumomab as compared to relapsed or refractory patients (87% vs 53%, p=0.035). Conclusion: Dosing strategies for MRD and relapsed or refractory ALL did not impact the incidence of blinatumomab-related toxicities requiring treatment interruption. Neurotoxicity was the most common reason for treatment interruption. To minimize neurotoxicity risk, we are starting a clinical study to assess the efficacy of intrathecal chemotherapy as a preventative measure to help reduce toxicity and minimize treatment interruptions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Consolidation with Allogeneic Hematopoietic Cell Transplant Improved Survival Outcomes of Adults with Relapsed / Refractory Acute Lymphoblastic Leukemia Following Response to Memory-Enriched CD19CAR T Cells

Background: CD19-directed chimeric antigen receptor (CD19CAR) T cell therapy produces excellent remission rates in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). While a small number of adult patients (pts) who respond to CD19CAR T cells have durable remission without additional therapy, most do not, and it remains debatable whether consolidation with allogeneic hematopoietic cell transplantation (alloHCT) after CD19CAR T cells should be offered to every adult responder with r/r ALL, especially in context of a second consolidative alloHCT in pts who relapsed following prior alloHCT. Here we report a subanalysis from our recently completed phase 1/2 prospective study (NCT02146924) using memory-enriched CD19CAR T cells in adults with r/r ALL to assess the role of alloHCT consolidation on outcome. Methods: This study assessed the safety and efficacy of naïve, stem and central memory (Tn/mem)-derived CAR T cells delivered at the recommended phase 2 dose (RP2D; 200x106 CAR T cells) in adults with r/r ALL. If pts achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi) post CAR T cells, they could receive optional consolidation with alloHCT per the treating physician discretion anytime 4 weeks after infusion. We evaluated the adjusted association between relapse free survival (RFS) and time varying status for alloHCT consolidation, Philadelphia (Ph)-like status, bone marrow blasts at time of lymphodepletion (LD; <5% vs. ≥5%) and presence of extramedullary disease (EMD) at LD among the responders by performing a pre-specified Cox proportional hazards regression model. Results: We enrolled 58 pts at the RP2D who underwent leukapheresis; 46 pts received CD19CAR T cells. The median age for pts who received CD19CAR T cells was 38 years (range, 22-72), with 15 (33%) pts ≥ 50 years. The median number of prior lines of therapy was 3 (range, 1-9); 29 (63%) pts had prior alloHCT, and 29 (63%) and 15 (33%) pts failed blinatumomab and inotuzumab before enrollment, respectively. Eighteen (39%) had Ph-like genotype and 16 (35%) had EMD at LD. Forty (87%) patients achieved CR/CRi, 1 (2%) progressed and 5 (11%) were unevaluable for response. Twenty-one (53%) responders proceeded directly to alloHCT consolidation while in CR/CRi post CAR T cell therapy, including 10 pts who received their second alloHCT. Notably, 6/13 pts with EMD at LD who achieved CR/CRi after infusion underwent alloHCT consolidation. The median time to transplant was 79 days (range, 50-192) post CAR T cell infusion. For the 40 responders, with a median follow up of 11.4 months (range, 3.3-65.8) post CAR T cell infusion, median overall survival (OS) was not reached, and median RFS was 17.1 months (95%CI: 6.9 to NA). The 12-month OS and RFS were 63.2% and 52.6%, respectively. Among responders, 12-month RFS were 81% and 16% for those who did and those who did not undergo consolidation with alloHCT in CR/CRi, respectively. In the prespecified multivariable analysis, only consolidation with alloHCT post CAR T cells was independently associated with superior RFS [adjusted hazard ratio (HR)=0.16; 95% CI: 0.05-0.48; P= 0.001]. Of the 19 pts who responded to CAR T cells and did not have alloHCT consolidation, 11 relapsed with a median time of 3.4 months (range, 2.1-10.3) post CAR T cell infusion, 3 pts died in remission, and 5 pts remained alive and in remission at last contact or date of censoring, with a median follow up of 9.7 months (range, 3.3-51.8) including 1 pt who was censored at day 99 post infusion upon initiating ponatinib maintenance. Of the 21 pts who responded to CAR T cells and underwent alloHCT consolidation, 2 pts relapsed (6.9- and 12.4-months post-transplant) of whom 1 died after relapse and 1 received a second CAR T cell infusion and was censored for OS at the date of second infusion, 3 pts died in remission, and 16 pts remained alive and in remission. (Figure A) The 100-day non-relapse mortality rate post-transplant was 5% (n= 1). OS was comparable for responders who had their first or second alloHCT post CAR T cells (12-months OS= 82% vs 79%, p= 0.9; Figure B). Conclusion: Outcomes of alloHCT consolidation in adults with high-risk r/r ALL after achieving remission with Tn/mem CD19CAR T cells were promising, including for pts receiving their second alloHCT, and transplant led to improved survival outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single Cycle of Blinatumomab Followed By High-Dose Chemotherapy in the Induction Therapy for Ph-Negative Acute Lymphoblastic Leukemia in Adults. Primary Endpoint Analysis of the Blina-Cell Trial

Background: Blinatumomab induces a high proportion of complete molecular responses in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and ALL with persistent or recurrent measurable residual disease (MRD) after initial therapy. However, responses are generally short if they are not followed by allogeneic stem cell transplantation (HSCT). We infer that blinatumomab needs to be incorporated sequentially into the early phase of treatment to enhance rates of MRD negativity, lower the need of HSCT and improve survival. Methods: Induction therapy in the Blina-CELL Phase 2 trial (NCT04554485) consisted of run-in phase (dexamethasone 10 mg/m2 days 1-7, cyclophosphamide 200 mg/m2 days 3-5, vincristine 2 mg day 6, and daunorubicin 45 mg/m2 days 6-7), first induction phase (blinatumomab 9 µg/day days 12-19 and 28 µg/day days 20-40), and second induction phase (dexamethasone 10 mg/m2 days 50-54, vindesine 3 mg/m2 day 50, methotrexate 1.5 g/m2 day 50, etoposide 250 mg/m2 days 53-54, and cytarabine 2x 2 g/m2 day 54). Consolidation chemotherapy was identical to the GMALL 07/2003 protocol. Intensive intrathecal prophylaxis was given in both induction and consolidation phases. The primary endpoint was MRD evaluated by quantification of IG/TR rearrangements at week 11 (at the end of induction II). The minimum sensitivity and quantitative range of all assays was 10e-4. Results: Twenty-nine patients started this treatment between May 2019 and March 2022. One patient terminated the study after 3 days of blinatumomab infusion due to elevated liver function tests, one was considered a screening failure due to the missing MRD target. Twenty-seven patients were evaluable. Median age was 41 years (range, 19-65). Median white blood cell count (WBC) at diagnosis was 6.2 x 109/L (range, 0.6-67.7). Twenty-five patients (93%) achieved complete remission (CR) at the end of induction I, 2 (7%) were refractory (both had BCR::ABL1-like phenotype). No patient died during the induction phase. Of the 25 patients in CR, 13 (52%) had complete molecular response (CMR) at day 40 (upon termination of blinatumomab infusion), 11 (44%) had positive non-quantifiable MRD and one (4%) patient had quantifiable MRD >10e-4. Primary endpoint assessment at week 11 showed 20 (80%) patients in CMR, 3 (12%) with positive non-quantifiable MRD and 2 (8%) with MRD ≥10e-4. Four (16%) patients underwent HSCT due to MRD failure or reappearance, all were pre-treated with a further 1-2 cycles of blinatumomab. Three of them (75%) entered HSCT in CMR. One patient was transplanted in CMR for high-risk features (proB, KMT2A rearrangement). The follow-up period is still ongoing. With 18 months of median follow, the overall and relapse-free survival in the study is 18.2 and 15.9 months, respectively. The most frequent grade 3-4 adverse events of blinatumomab therapy were: febrile neutropenia (15%), elevated ALT/AST (11%), soft tissue infection (7%) and low fibrinogen (7%). Only one case of grade 3 cytokine release syndrome was documented. No neurotoxicity events were observed during the induction phase of treatment. Conclusion: Remission induction strategy combining one cycle of blinatumomab with one cycle of high-dose chemotherapy provides a high molecular response rate (CMR or non-quantifiable MRD) of 92%. This approach translates into a low transplant rate due to a high MRD response and has a favourable safety profile. Longer follow-up is needed to evaluate survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Ongoing Pilot Study of Targeted Radioimmunotherapy (131-I Apamistamab) Conditioning Prior to CD19-Targeted CAR T-Cell Therapy for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

An Ongoing Pilot Study of Targeted Radioimmunotherapy (131-I Apamistamab) Conditioning Prior to CD19-Targeted CAR T-Cell Therapy for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

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

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

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

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.