Refractory B-cell Acute Lymphoblastic Leukemia Research Articles

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

Outcome after Inotuzumab Ozogamicin for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia and Extramedullary Disease

Outcome after Inotuzumab Ozogamicin for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia and Extramedullary Disease

CNCT19 for Treatment of Patients with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-cell ALL) in Children and Adults

▪Background: The incidence of B-cell ALL follows a bimodal distribution, with the first peak occurring in childhood and a second peak occurring around the age of 50. While the prognosis for pediatric patientshas improved over the past decades, prognosis for the elderly remains very poor. Despite a high rate of response to induction chemotherapy, only 30-40% of adult patients with ALL will achieve long-term remission. Patients with primary refractory and chemo-refractory B-cell ALL have an extremely poor prognosis.A chimeric antigen receptor (CAR) specific for the CD19 B lymphocyte molecule has provide an option of treating B-cell malignancies. Although these CAR-modified T cell products target the same antigen, the designs of CD19-targeted CAR T-cells vary significantly. CNCT19 is autologous CD19-directed genetically modified T cell immunotherapy. The structure of chimeric antigen receptor (CAR) includes CD19scFv-hCD8α hinge-CD8α TM-4-1BB-CD3ζ in tandem. The patent protected CD19scFv sequence is derived from CD19 monoclonal antibody HI19a featured with high specificity and affinity to CD19. This strong binding capability to CD19 leads to killing of the CD19 positive malignant B-cells. Use of 4-1BB co-stimulatory domain is expected to reduce the severity of treatment-associated cytokine release syndrome (CRS) and neurologic toxicities (NT) while maintaining a stronger and longer-term anti-tumor effect.Methods: CNCT19 has been investigated in an open-label, phase 1/2 clinical trial for adult and pediatric patients with r/r ALL who have failed ≥ 2 lines prior therapies. Leukapheresis to obtain T cells was performed following the SOP of the local hospitals. CNCT19 was infused 2 to 14 days after lymphodepletion. All the patients were hospitalized up to 2 weeks. All the PIs have been trained for the management of CNCT19-treatment related CRS and neurotoxicities. A PI committee was involved in the management of CRS and neurologic toxicity. The primary objectives of the study were to determine the safety and the clinical outcomes, including ORR within 3 months, PFS, and overall survival (OS).Results: As of October 2020, 63 patients (adults: n=32 >18 years, children: n=31 < 18 years) have received CNCD19 treatment and all subjects have been followed at least for one year.All grade adverse events occurred in 54 patients (54/63 = 85.7%). Grade ≥3 CRS and NEs occurred in 12 (12/63 = 19%) and 13 (13/63 = 20%), respectively. Out of 63 patients, 59 (59/63= 93.6%) have had overall responder rate (ORR) defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi). Among the 59 responded patients, the minimal residual disease (MRD) was negative in 56 patients (56/69 = 94.9%) and 23 patients (38.9%) received allogeneic-HSCT treatment. The relapse-free survival (RFS) and overall survival (OS) were summarized in adult and pediatric groups separately in the following table.Conclusions:CNCT19 treatment of patients with r/r ALL demonstrates improved ORR, PFS, and OS both in children and adults. A pivotal clinical trial is going on in China to evaluate the ORR, PFS, and OS with a clinical plan to decrease the severity of treatment-related adverse events (CRS/NE). [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Recent Updates on Blinatumomab: A Bispecific T-Cell Engaging Antibody in Relapsed and Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Blinatumomab is a bispecific T-cell engaging antibody that binds and allows CD3 cytotoxic T cells to recognize and eradicate CD-19 positive malignant B cells. Blinatumomab is currently under study for relapsed and refractory B-cell acute lymphoblastic leukemia (RR B-ALL).Methods: A comprehensive literature search was conducted across various data sets, including PubMed, Cochrane, and Embase, and presented data in ASH and ASCO. A review of the most recent data is summarized in this abstract.Results: Eight clinical trials are currently under various phases of the study evaluating blinatumomab in RR B-ALL. In the phase 1/2 trial by Locatelli et al., 110 patients treated with blinatumomab showed complete remission (CR) with <5% blast cells of 62.7% at a dose of 5-15 µg/m 2. In phase 1b trial by Horibe et al., nine Japanese children received blinatumomab at a dose of 5 µg/m 2/day for week 1, followed by (f/b) 15 µg/m 2/day for week 2-4 and showed an CR in 56% patients.In a phase II study, Martinelli et al., treated 45 patients at a dose of 9 µg/day in week 1, f/b 28 µg/day; 36% of the patients achieved CR. In another phase II trial by Gokbuget et al., a 15 µg/day dose in 20 patients resulted CR in 50% pts. Topp et al. reported CR of 43% in 39 patients, and Stein et al. reported 45% CR in 64 patients treated with a similar regimen.In phase III trials, Rambaldi et al., reported 36% CR in 119 patients and, Kantarjian et al. reported CR of 43.9% in 271 patients treated with blinatumomab at a dose of 9 µg/day during week 1 and 28 µg/d onwards for up to 3 and 6 cycles, respectively.In all the trials, blinatumomab was given via 4-week continuous IV infusion followed by 2-week treatment-free interval per cycle. The most common grade 3 and 4 adverse effects are listed in the table 1.Conclusion: Blinatumomab is showing promising results in RR B-ALL with a good side effect profile. However, the final results of these trials are awaited. [Display omitted] DisclosuresAnwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.

Ikaros Mediates Antigen Escape Following CD19 CAR T Cell Therapy in r/r B-ALL

Despite impressive response to front-line treatment, relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) remains one of the most common causes of death in children with cancer. In pediatric and adult r/r B-ALL, CD19 CAR T cell (CART19) therapy has shown impressive results with over 80% of patients achieving complete remission. However, as an unintended consequence of long-term persistence of CAR T cells and the resulting sustained pressure against CD19 expressing cells, 30 - 70% of initial responders will eventually relapse with CD19 loss. Early identification of patients that will respond successfully to CART19 therapy vs. those at risk for CD19 Neg relapse would support clinical decision making and improve patient care.To address this problem, we profiled by mass cytometry (CyTOF) 25 pre-CART19 samples including patients that achieved a durable complete remission (CR, n = 6), patients that underwent CD19 Neg (n = 11) or CD19 Pos relapse (n = 4) and patients that were refractory to CART19 (n = 4). For 14 of those patients, we also analyzed paired post-CART19 samples: 8 from CD19 Neg relapse, 2 from CD19 Pos relapse, and 4 from refractory tumors. We observed a significant increase in the proportion of leukemic early progenitor non-B cells (called early-non-BI) after CD19 Neg relapse, suggesting that CD19 loss is associated with the loss of other B cell features. In addition, in the pre-CART19 samples we identified a subpopulation of CD19 Pos pro-B cells that resemble early-non-BI cells. We hypothesized that these pro-B “discordant” cells are able to lose CD19 expression and escape the immune pressure exerted by the CART19, leading to CD19 Neg relapse. Closer analysis revealed lower levels of IKAROS in pro-B discordant cells from patients that underwent CD19 Neg relapse, than in those that achieved a durable CR.To further explore the difference between pro-B discordant cells from patients that achieved a durable CR or underwent CD19 Neg relapse, we performed single cell REAP-seq (RNA expression and protein sequencing) from 3 pre-CART19 CR and 3 pre-CART19 CD19 Neg relapse r/r B-ALL samples. From this analysis, we confirmed a subpopulation of leukemic pro-B like cells with decreased expression of IKZF1 in those patients that underwent CD19 Neg relapse.IKAROS is a transcription factor that plays a crucial role in B cell lineage specification and commitment and is a known B-ALL tumor suppressor. Genetic alterations affecting the IKAROS gene, IKZF1, have been associated with poor response to front-line treatment and they are a factor in relapse risk stratification. However, a role for IKAROS in CART19 failure has not been described. To assess if there is a correlation between the levels of IKAROS and CD19 surface expression, we manipulated IKAROS levels in B-ALL cell lines through RNA silencing and targeted protein degradation approaches. Consistently, we observed that CD19 surface expression diminishes upon IKAROS downregulation. To determine how IKAROS regulates CD19 expression, we performed CyTOF, RNA-seq and ATAC-seq analysis of isogenic B-ALL cell lines with wild-type or reduced (IKAROS KD) IKAROS levels. While the chromatin accessibility to CD19 regulatory regions did not change, CD19 mRNA levels were lower in IKAROS KD cells. Interestingly, we found that IKAROS regulates several genes associated with mRNA splicing. In particular, CD19 mRNA preferentially retains intron 10 in IKAROS KD cells. The inclusion of intron 10 introduces several premature stop codons. Moreover, IKAROS KD B-ALL cells more closely resemble myeloid cells based on their gene expression profiles, suggesting a loss in their B cell identity.In summary, this is the first description of a leukemia-specific subpopulation of CD19 Pos pro-B discordant cells in patients prior CART19 administration. Furthermore, lower levels of IKAROS in this subpopulation correlates with poor response to CART19 therapy. Preliminary molecular analysis suggests that low IKAROS result in retention of CD19 intron 10 and loss of B-cell identity (Figure 1). Future research will focus on in-depth characterization of the myeloid-like phenotype induced by low levels of IKAROS expression, and the impact that intron 10 retention has on CD19 mRNA stability and surface expression. [Display omitted] DisclosuresMullighan: Pfizer: Research Funding; Amgen: Current equity holder in publicly-traded company; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Barrett: Tmunity Therapeutics: Current Employment. Davis: Novartis Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Research Funding.

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation

Background: Genetic lesions in the RAS-ERK pathway (NRAS, KRAS, RAF1, MAP2K1, PTPN11, NF1) are oncogenic drivers in ~40% of B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with chemoresistance and relapse. During normal B-cell development, persistent activation of RAS-ERK-signaling induces negative B-cell selection and cell death (Yasuda et al., 2011). The deleterious effect of persistent RAS-ERK signaling is mainly caused by PRDM1-mediated repression of BCL6 (Setz et al., 2018). Hence, the tumor suppressor PRDM1 and the proto-oncogene BCL6 are reciprocal antagonists during B-cell development (Shaffer et al., 2002). Genetic lesions that cause permanent activation of the RAS-ERK pathway in B-ALL would be expected to cell death as in normal B-cell development. Here we examined the mechanistic basis of how oncogenic activation of RAS-ERK signaling in B-ALL not only avoids cell death but also promotes malignant transformation.Results: Strikingly, doxycycline-inducible expression of NRAS G12D in murine B-cell precursors, resulted on dramatic increases of BCL6 mRNA (~390-fold) and protein (~50-fold) levels, which came at the expense of PRDM1. For these reasons, we explored mechanisms underpinning transactivation of BCL6 and tested whether RAS-dependent induction of BCL6 represents a mechanism to oppose PRDM1-mediated cell death.Consistent with transactivation of BCL6 downstream of ERK-activation, ChIP-seq analysis revealed binding of ERK-dependent transcription factors (CREB1, ELK1, EGR1, JUND and C-JUN) to the BCL6 promoter in human B cells. Highlighting an essential role of Erk-signaling in RAS-mediated upregulation of Bcl6 expression, pharmacological ERK-inhibition abrogated NRAS G12D-mediated Bcl6 induction. Likewise, Erk2-deletion abolished the ability of B-ALL cells to induce expression of Bcl6. Furthermore, pharmacological activation of ERK (BCI-215) markedly induced BCL6 expression. Together, these findings reveal a new pathway of BCL6-activation in B-ALL cells that depends on oncogenic RAS-ERK-signaling.To address the mechanistic role of BCL6 in RAS-driven B-ALL, we established a genetic model for Cre-mediated deletion of Bcl6 in NRAS G12D B-ALL cells. Genetic ablation of Bcl6 resulted in rapid depletion of B-ALL cells and compromised colony formation. Notably, Bcl6-deletion prevented leukemia-initiation in transplant recipient mice (P=0.007). Furthermore, patient-derived RAS-driven B-ALL cells were highly sensitive to pharmacological inhibition of BCL6 using peptide (RI-BPI) and small molecule (FX1) inhibitors. Importantly, treatment with RI-BPI delayed onset of fatal disease and prolonged survival of transplant recipient mice (P=0.009). We then tested whether targeting BCL6 can be leveraged in combination with existing treatment regimen and found that RI-BPI potentiated the effects of vincristine on killing patient-derived RAS-driven B-ALL cells. Hence, BCL6 represents a previously unrecognized therapeutic target in RAS-driven B-ALL that can be leveraged to sensitize to conventional chemotherapy.Mechanistically, genetic ablation or pharmacological inhibition of BCL6 increased expression of PRDM1 in RAS-driven B-ALL cells. shRNA-mediated knockdown of Prdm1 rescued Bcl6-deficiency in RAS-driven B-ALL cells. While Bcl6-deletion resulted in cell death of B-ALL cells, this was largely reversed by loss of Prdm1. Altogether, our findings suggest that compromised leukemogenesis was a result of aberrant PRDM1 expression in BCL6-deficient RAS-driven B-ALL cells.Conclusions: While permanent activation of the RAS-ERK pathway induces negative selection and cell death in normal B-cell precursors owing to excessive activation of the PRDM1 tumor suppressor, B-ALL cells carrying RAS-activating lesions have evolved a mechanism to evade PRDM1-mediated cell death by massive (>300-fold) upregulation of BCL6. In RAS-driven B-ALL, oncogenic expression of BCL6 suppresses PRDM1 and enables malignant transformation. Importantly, BCL6 expression in RAS-driven B-ALL represents a previously unrecognized synthetic lethality. Hence, peptide and small molecule inhibition of BCL6 de-represses PRDM1, reconstitutes PRDM1-dependent tumor suppression and represents a selective vulnerability in RAS-driven B-ALL cells that can be leveraged to overcome conventional mechanisms of drug-resistance in refractory B-ALL. DisclosuresNo relevant conflicts of interest to declare.

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

TT52CAR19: Phase 1 Trial of CRISPR/Cas9 Edited Allogeneic CAR19 T Cells for Paediatric Relapsed/Refractory B-ALL

Background‘Off-the-shelf’ CAR T cell therapies are being investigated as alternatives to autologous CAR therapy, and can be generated using genome editing from allogeneic donors. Strategies to address HLA barriers include disruption of T cell receptor expression to prevent GVHD and removal of cell surface HLA expression to obviate host mediated rejection, as well as removal of CD52 to create a survival advantage in the presence of Alemtuzumab. In this study, lentiviral mediated CAR19 expression is linked to CRISPR editing through the incorporation of CRISPR guide RNA sequences within the vector 3'Long terminal repeat (LTR). The trial is in progress using pre-manufactured batches of TT52CAR19 T cells.Investigational medicinal product (IMP)Three allogeneic non-HLA matched donor derived CAR19 T cell banks were manufactured from steady state apheresis harvests from registry volunteer donors, using a semi-automated process under compliant conditions. Cells were activated with anti-CD3/CD28 (Transact) reagent and transduced with a lentiviral vector, TT52CAR19, and dual guide sgRNA cassettes targeting the T cell receptor alpha chain (TRAC) and CD52 loci. Next electroporation of Cas9 mRNA elicited transient genome editing, and automated magnetic bead depletion removed remaining TCRαβ+ T cells (mean 0.7%) and enriched CAR19+ T cells (mean 92.8%). Cells were cryopreserved in aliquots suitable for dose-banding and subjected to release testing, including flow cytometry, quantification of copy number (mean 3.83) and exclusion of replication competent lentivirus. Potency of each bank was confirmed in human:murine chimera experiments.Trial sponsorship & approvalsThe study is open at a single site and is sponsored by Great Ormond Street Hospital NHS trust and is supported by the Medical Research Council and National Institute for Health Research. Clinical trial authorisation was awarded by the MHRA after expert review, and ethical approval including gene therapy advisory committee (GTAC) review, and health research authority (HRA) approval. The study is open label, single arm and non-randomised.Study aims and ObjectivesThe study aims to establish the safety and feasibility of TT52CAR19 for the induction of molecular remission in children with relapsed /refractory CD19-positive B-cell acute lymphoblastic leukaemia (B-ALL) within 28 days, ahead of planned allogeneic haematopoietic stem cell transplantation (allo-SCT). Assessments include time to remission, duration of remission, disease-free survival and overall survival. Expansion, persistence and elimination of TT52CAR19 cells and tracking of immune recovery after allo-SCT is monitored. Recording of complications and toxicities, including possible genotoxic side effects from CRISPR/Cas9 modification provides safety profile information.Eligibility, infusion and outcomesThe study plans to treat 10 children aged between 6 months and < 18 years with CD19+ B-ALL quantified at >10 -4 in marrow (by flow or PCR) who are ineligible for autologous therapy. To date 2/4 children screened were found eligible and proceeded to lymphodepletion comprising Fludarabine, Cyclophosphamide and Alemtuzumab followed by a single infusion of 0.8-2.0x10 6 CAR19 T cells and a maximum of 5x10 4/kg TCRαβ T cells. In both cases, there was no GVHD or CRS >grade 1 and recovery of neutrophil counts by d28. Molecular remission was achieved in one child, where TT52CAR19 cells persistence was tracked by chimerism and copy number until further conditioning and allo-SCT. This child remains in remission >6 months later.ConclusionsFeasibility of pre-manufacturing off-the-shelf CRISPR/Cas9 edited CAR19 T cells is demonstrated and the trial has provided first in human safety data and preliminary indications of potent anti-leukaemic activity in one of two subjects dosed. DisclosuresQasim: Autolus: Current equity holder in publicly-traded company; Novartis: Honoraria; Servier: Research Funding; Tessa: Membership on an entity's Board of Directors or advisory committees.

Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

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

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

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward.

Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life-threatening cytokine release syndrome (CRS) and neurotoxicity, B-cell aplasia-associated hypogammaglobulinemia and agammaglobulinemia, and the alloreactivity of allogeneic CAR-Ts. Furthermore, recent advances such as improvements in media design, the reduction of ex vivo culturing duration, and other phenotype-determining factors can still create room for a more effective CAR-T therapy in R/R B-ALL. Herein, we review preclinical and clinical strategies with a focus on novel studies aiming to address the mentioned hurdles and stepping further towards a milestone in CAR-T therapy of B-ALL.

Cytoplasmic CD79a is a promising biomarker for B lymphoblastic leukemia follow up post CD19 CAR-T therapy

Minimal residual disease (MRD) detection is an important prognostic parameter in patients with refractory or relapsed B-cell acute lymphoblastic leukemia (R/R B-ALL). CD79a has been reported to exhibit a high degree of linage-specificity for B-cell differentiation, with a specificity of 88% and a sensitivity of 100%. In this study, we investigated the efficiency and prognostic role of cytoplasmic CD79a (cCD79a) antibody-gated multicolor flow cytometry (MFC) in MRD detection in patients with B-ALL who received CD19-targeted chimeric antigen receptor (CAR) T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The retrospective analysis was carried on to 59 patients who accepted allo-HSCT after CD19-CAR-T infusion from June 2016 to May 2017. The MFC MRD statuses before and after allo-HSCT were both strongly correlated with the transplantation prognosis, the MFC panel with cCD79a gating can effectively monitor MRD after CD19 CAR T-cell therapy and predict the prognosis after allo-HSCT. Trial registration: ClinicalTrials#: ChiCTR-IIh-16008711.gov: NCT03173417. Registered 30 May 2017 – retrospectively registered, https://www.clinicaltrials.gov/

CAR T\u2009cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B\u2009cell acute lymphoblastic leukemia: a phase 1 trial

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

CAR T-cell Therapy in Indolent Lymphoma

Introduction CD19 directed chimeric antigen receptor (CAR) T-cell therapy has had a transformative impact on the natural history of chemotherapy refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL), inducing long-term remissions in 40–50% of patients.1–5 It does this, however, at the expense of both financial and clinical toxicity. But the cost and risk of care in the absence of CAR T-cells in these instances outweighs the risk of the therapy itself, and so it has broadly been accepted as a standard of care for these patients. Moving CD19 directed CAR T-cell therapy into the slower growing, but historically incurable, indolent B-NHLs has the potential to challenge this balance between risks and benefits. Will CAR T-cells offer definitive therapy for these otherwise incurable diseases? If not, will CAR T-cells positively affect long-term survival over alternative therapies? The answer to these questions will determine how oncologists weigh the financial and clinical costs against the therapeutic benefits.

A dream that came true: Poland’s first successful CAR-T cell therapy in child with refractory B-cell acute lymphoblastic leukemia (ALL)

When all of the usually applied treatment methods fail, we have to try something innovative. In this vignette, we present the history of the first in Poland CAR-T cell therapy in a child with refractory B-cell acute lymphoblastic leukemia (ALL). In more than 10 months observation time post infusion the patient remains MRD-free with a chance for long awaited clinical cure.

Effect of Renal and/or Hepatic Impairment on the Pharmacokinetics and Safety of Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

▪Introduction: Inotuzumab ozogamicin (InO) is an antibody drug conjugate targeting CD22 antigen linked to N-acetyl-g-calicheamicin dimethyl hydrazide, a potent cytotoxic antibiotic that induces double strand DNA breaks. The pharmacokinetics of InO has been characterized in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The primary objective of this analysis was to assess the pharmacokinetics and safety of InO in patients with renal and/or hepatic impairment.Methods: The effects of renal and hepatic impairment on the pharmacokinetics of InO clearance (CL) were evaluated in adult patients with relapsed or refractory ALL (n=234) following administration of 1.2-1.8 mg/m2 fractionated over 2 or 3 doses given weekly. For assessment of renal function, patients were stratified into 5 subgroups using baseline creatinine clearance (BCrCL): normal (≥90 mL/min), mild (60-89 mL/min), moderate (30-59 mL/min), severe (15-29 mL/min), and end-stage renal disease (<15 mL/min).For assessment of hepatic impairment, patients were stratified into 5 subgoups per criteria from the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), which categorizes impairment based on baseline total bilirubin (TB) and aspartate aminotransferase (AST): normal (TB and AST ≤ upper limit of normal [ULN]), mild B1 (TB ≤ ULN and AST > ULN), mild B2 (TB >1-1.5 x ULN, any AST), moderate (TB >1.5-3 x ULN, any AST), and severe (TB >3 x ULN, any AST).Data from adult patients with relapsed or refractory ALL (n=161) who received InO at a starting fractionated dose of 1.8 mg/m2 were used to evaluate the safety of InO in patients with some degree of renal and/or hepatic dysfunction. For each of the renal function and NCI ODWG hepatic impairment subgroups, the percentage of patients exhibiting Grade ≥3 for any adverse events and Grade ≥3 hepatoxicity adverse event, respectively, was reported. Severity of hepatoxicity was determined through standardized search criteria with Standard Medical Dictionary for Regulatory Activities queries (cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, noninfectious; and liver-related investigations, signs, and symptoms) and preferred terms (veno-occlusive liver disease or veno-occlusive disease; hepatic vein occlusion or thrombosis; portal vein thrombosis; Budd-Chiari syndrome; chronic graft versus host disease in liver; and acute graft versus host disease in liver).Results: For renal impairment, the median InO CL was 0.0394, 0.0403, 0.0308, and 0.0273 L/h, respectively, in individuals with normal (n=184), mild (n=32), moderate (n=17), and severe renal impairment (n=1). There were no patients with end-stage renal disease. Grade ≥3 adverse events were reported in 91.7% of patients with normal, 81.8% with mild, 100% with moderate, and 0% with severe or end-stage renal disease renal impairment.For hepatic impairment, the median InO clearance was 0.0363, 0.0520, 0.0382, and 0.0238 L/h, respectively, in individuals with normal (n=167), mild B1 (n=58), mild B2 (n=8), and moderate hepatic impairment (n=1). There were no patients with severe hepatic impairment. Hepatotoxicity Grade ≥3 adverse events were reported in 23.6% of patients with normal, 6.8% with mild B1, and 3.1% with mild B2 hepatic function; no such events occurred in patients with moderate or severe hepatic impairment.Conclusions: InO pharmacokinetics were not affected by renal or hepatic impairment status, and safety was similar regardless of renal and/or hepatic function. Therefore, no starting-dose adjustment is required for patients with relapsed or refractory ALL with pre-existing mild to severe renal dysfunction or mild hepatic impairment. DisclosuresGarrett:Pfizer: Employment. Kantarjian:Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. DeAngelo:Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

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

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

Management of Coagulopathy Associated with CTL019 CAR T-Cell Therapy

Introduction: CTL019 (tisagenlecleucel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has demonstrated high durable response rates and a manageable safety profile in pediatric/young adult patients (pts) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). CTL019-associated cytokine-release syndrome (CRS), a systemic inflammatory response caused by elevated serum cytokine levels, occurred in 81% of pts treated in 2 multicenter trials (Maude et al, Haematologica . 2017;120(s2): [abstract P517]). Coagulopathy has been associated with CRS and macrophage activation syndrome (MAS) in previous reports of CTL019 from a single-center US study, and similar coagulopathy has been reported in cases of MAS/hemophagocytic lymphohistiocytosis associated with other events such as infections or chemotherapy. Here, we outline the treatment guidelines established and US and global multicenter experience with CTL019-associated coagulopathy in 97 pts treated with CTL019.Methods: Pooled data from 2 single-arm, multicenter phase II trials of CTL019 in pediatric/young adult pts with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to further characterize coagulopathy during CTL019-associated CRS.Results: Maximal grades 1-2, 3, and 4 CRS occurred in 36, 19, and 24 pts, respectively. Median lowest fibrinogen levels were 3.5 g/L and 3.3 g/L in pts with maximal grade 1-2 and 3 CRS, respectively, while median lowest fibrinogen level in pts with maximal grade 4 CRS was 1.2 g/L. 3%, 11%, and 25% of pts with maximal grades 1-2, 3, and 4 CRS, respectively, had lowest reported fibrinogen levels of ≥ 1 to < 1.5 g/L. Very low fibrinogen levels (<1 g/L) were observed in 33% of pts with maximal grade 4 CRS, with 2 pts having unmeasurable levels of fibrinogen, but not in any pt with maximal grade 1-3 CRS. Very low fibrinogen levels (<1 g/L) could occur before maximal CRS grade (n=1), during maximal CRS grade (n=6), or at the time of CRS improvement (n=1). Near the time of very low fibrinogen levels (<1 g/L) onset, only 1 pt had concurrent grade 3 increased INR and aPTT; the other 7 pts had grade 0-2 increased INR and aPTT.Given that hypofibrinogenemia was the most notable coagulopathy, cryoprecipitate was the mainstay of treatment in the US. In addition, administration of large volumes of fresh frozen plasma can be problematic in pts with CRS, fluid overload, and capillary leak. Guidelines for fibrinogen concentrate (FC) use were developed for the ELIANA global trial for CTL019-associated coagulopathy since cryoprecipitate is not readily available in Japan and some European countries. FC was available at 7/25 sites and administered to 3/7 pts with grade 4 CRS, and none of 8 pts with grades 1-3 CRS, out of 20 infused pts. Cryoprecipitate was available in 18/25 sites and administered to 12/17 pts with grade 4 CRS, 2/15 pts with grade 3 CRS, and none of 32 pts with grades 1-2 CRS, out of 77 infused pts.In pediatric pts with r/r B-ALL, the risk of bleeding from CTL019-associated hypofibrinogenemia can be increased by co-morbid thrombocytopenia and the use of anticoagulants, including those used in veno-venous hemofiltration (CVVH). Within 1 day of onset of very low fibrinogen levels (<1 g/L), 5/8 pts had concurrent grade 3 or 4 decreased platelets. 1 fatal case (1/97 infused pts=1%) of intra-parenchymal cranial hemorrhage was seen during resolving CRS with grade 3 hypofibrinogenemia, ongoing thrombocytopenia, and CVVH with citrate.Conclusions: Clinical recommendations and guidelines were developed for the use of FC and cryoprecipitate for the treatment of CTL019-associated coagulopathy with hypofibrinogenemia. During CTL019-associated coagulopathy, fibrinogen levels were disproportionately low as compared with INR/PTT. Hypofibrinogenemia was observed more frequently in pts with higher CRS grades, could be seen either during or when CRS was improving or resolution, and was effectively managed by FC or cryoprecipitate replacement. Rarely, fatal bleeding can be seen. Frequent monitoring of fibrinogen, INR/PTT, platelets, and signs of clinical bleeding, as well as appropriate fibrinogen replacement are needed in pts with grade 3 and 4 CRS associated with CAR T-cell therapies. DisclosuresBüchner:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Hiramatsu:Novartis Pharmaceuticals Corporation: Other: Clinical trials . Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Yi:Novartis Pharmaceuticals Corporation: Employment.