scholarly journals Potential Impact of Treatment with Inotuzumab Ozogamicin on Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3824-3824
Author(s):  
Valeria Ceolin ◽  
Erica Brivio ◽  
Susan R. Rheingold ◽  
Allison Barz Leahy ◽  
Britta Julia Vormoor ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Bridging Therapy ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Significant Difference ◽  
Car T

Abstract Background: Chimeric Antigen Receptor T-cells targeting CD19 (CART-19) have shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The ELIANA trial leading to market authorization of tisagenlecleucel excluded prior therapy with monoclonal antibodies. Blinatumomab prior to CART-19 seems associated with a higher risk of early failure (Pillai, Blood Advances 2019). Inotuzumab ozogamicin (InO) is an anti-CD22 antibody conjugated to calicheamicin. InO as bridging therapy to CART-19 (n=11) was associated with a shorter overall survival (OS) (Dourthe, Leukemia 2021). InO given prior to leukapheresis might impact on the quality of T-cells collected and, when used as bridging, could result in insufficient CD19 positive (CD19+) antigen load and affect CAR T-cell expansion. We report on a cohort of children and young adults with R/R BCP-ALL treated with InO prior to CART-19 infusion. Methods: Data of patients (pts) treated with CART-19 after InO given at any time before and/or after apheresis, irrespective of other anti-leukemic treatments, were collected using a standardized Case Report Form. The study was approved by the ethics committee of the UMC Utrecht (MvdL/is/21/500393) Results: Thirty-nine pts were treated in 10 centers and received CART-19 between July 2016 and April 2021. Thirty-four received commercial tisagenlecleucel and 5 academic products. Median age was 13 years (range 1-23); 25 were male. Four pts (10.3%) had received a prior CART-19 infusion and 15 (38%) blinatumomab, 18 (46%) had been previously transplanted. All pts received at least two doses of InO (range 2-12); 12 before apheresis only (median time 48 days (range 13-560) between last InO dose and apheresis); 27 as bridging therapy (median time 52 days (range 16-257) from last InO dose to CART-19 infusion), including 5 who had also received InO before apheresis. At time of the infusion, 22 pts were in complete remission (CR) (<5% marrow blasts) including 10 with negative minimal residual disease (MRD; <0.01% by flow or <10 -4 by PCR). In all pts receiving InO prior to apheresis viable CART products were manufactured. One product was out-of-specification due to insufficient interferon-γ, but a subsequent production fulfilled release criteria. At day 28 (d28) post infusion 35/39 were in CR (89.7%), of whom 31 (88.6%) were also MRD negative. Four pts (10.3%) did not achieve CR: 3/4 were not in CR at the time of the infusion; all of them received InO as bridging within 2 months before the infusion. With a median follow-up of 12.5 months (range 1-50) after CART-19 infusion, 12-month event free survival (EFS) was 59% (95% confidence interval (CI) [42.0-76.0]) and OS was 79.5% (95% CI [64.6-94.4]). There was no significant difference in OS/EFS between pts who received blinatumomab and InO prior to CART-19 infusion (n=15) and those who received InO only (n=24) (p=0.61 and p=0.37, respectively). Sixteen pts (45.7%) relapsed at median 163 days (range 28-655) after CART-19 infusion; 7/16 (43.8%) had a CD19+ relapse (median 287 days; range 28-655), 8/16 (50.0%) had a CD19 negative (CD19-) relapse (median 163 days; range 136-273) (1 status unknown). There was no significant difference in 12-month OS/EFS between pts who received InO before apheresis or as bridging (OS 83.3% vs 77.8%, p=0.50; EFS 58.3% vs 59.3%, p=0.62); and no difference in d28 MRD response (p=0.57) or incidence of CD19+ or CD19- relapses (p=0.48) between the 2 groups. Twelve of the 35 pts in CR at d28 (34.2%) lost BCA, median 92 days after CART-19 infusion (range 29−294) (1 data not available); 7/12 relapsed, 5/7 with CD19+ relapse. Among the 35 responders, 5/12 pts who received InO before harvesting lost BCA (1 data not available) vs 7/23 pts who received InO as bridging. There was no significant difference in 12-month EFS between pts who received CART-19 with low CD19 burden at start of lymphodepletion chemotherapy (MRD <10 -4 and BCA, n=6) compared to the rest of the population (p=0.30). Conclusion: InO as a bridging strategy to CAR T-19 does not seem to result in inferior response when EFS/OS are compared to published data (Maude, NEJM 2018; Pasquini, Blood Adv, 2020). The ITCC/IntReALL-059 study will treat very high risk first relapsed BCP-ALL pts (very early relapse or presence of TP53 mutation and/or deletion, hypodiploidy, t(1;19)/t(17;19), KTM2A/AF4) with InO reinduction followed by CART, given the poor prognosis with current strategies. Disclosures O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Zwaan: SANOFI: Consultancy; NOVARTIS: Consultancy; ROCHE: Consultancy; INCYTE: Consultancy; PFIZER: Consultancy, Research Funding; JAZZ: Other: travel funding, Research Funding; BMS: Research Funding; Abbvie: Research Funding.

scholarly journals Pre-Clinical Activity of Allogeneic Anti-CD22 CAR-T Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 808-808
Author(s):  
Julia Wells ◽  
Tianyu Cai ◽  
Cécile Schiffer-Manniou ◽  
Stéphanie Filipe ◽  
Agnès Gouble ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Surface Expression ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Autologous T-cells engineered with chimeric antigen receptors (CARs) against CD19 are proving to be an efficacious immunotherapy for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). At present, CAR technology is administered through the custom-made manufacturing of therapeutic products from each patient's own T-cells. However, this patient-specific autologous paradigm is a significant limiting factor in the large-scale deployment of CAR technology. In this study, we utilized allogeneic "off-the-shelf" engineered CAR T-cells from third-party healthy donors. The CD22 surface antigen is commonly expressed in B-ALL patients as well as in healthy B-cells. Here, its potential as a CAR target was investigated using allogeneic off-the shelf engineered CAR T-cells against human CD22 (UCART22). UCART22 cells harbor surface expression of an anti-CD22 CAR (CD22 scFv-41BB-CD3z) and the RQR8 ligand, a safety feature rendering the T-cells sensitive to the monoclonal antibody rituximab. To reduce the potential for alloreactivity, the cell surface expression of the T-cell receptor (TCR) is abrogated through the inactivation of the TCRα constant (TRAC) gene using Cellectis' TALEN® gene-editing technology. The level of CD22 cell surface molecules was measured using BD Quantbrite beads for both patient peripheral blood samples and B-ALL cell lines. B-ALL cell lines (n=8) expressed a greater amount of CD22 molecules per cell than patient samples (n=14) (5,028 +/- 1,342 compared to 951 +/-160 molecules/cell, p=0.044), with highest expression of CD22 in two Ph-like B-ALL cell lines (MUTZ5, shown in Figure1A and MHH-CALL4). The in vitro cytotoxic activity of UCART22 cells was evaluated by co-culturing UCART22 or non-transduced CAR(-) TCRαβ(-) control T-cells (NTD) with B-ALL cell lines and primary human samples, at a maximum 10:1 effector to target ratio (represented in Figure1B). Using flow cytometry, significant antigen-specific cytotoxic activity of UCART22 cells was found compared to NTD controls and correlated with CD22 expression factored by the %kolmogorov-smirnov max difference in CD22-PE fluorescence compared to unstained controls (Pearson correlation r-squared for cell lines= 0.6850, p=0.0001 and r-squared for patient samples=0.6204, p=0.0008). Secretion of 13 cytokines was measured after 1:1 co-incubation of effector and target cells. UCART22 cells stimulated by CD22(+) B-ALL, but not NTD cells, secreted high levels of IFNγ, TNFα, IL-5, IL-17A and IL-17F in the culture supernatants, with cytokine levels being proportionate to CD22 abundance (represented in Figure1C). In addition, immune compromised mice engrafted with Daudi cells, a CD22(+) expressing Burkitt's lymphoma cell line, were treated with UCART22 cells. Treatment doses of 1-10x10^6 cells per mouse reduced disease burden (Figure 1D), measured by bioluminescence imaging, and extended survival in a dose-dependent fashion compared to saline or NTD treated controls. Additional PDX studies using B-ALL patient derived xenografts are ongoing and will be presented. Altogether, these results show supporting evidence for the future use of allogenic UCART22 in B-ALL immunotherapy. Disclosures Schiffer-Manniou: Cellectis SA: Employment. Filipe: Cellectis: Employment. Gouble: Cellectis SA: Employment. Galetto: Cellectis SA: Employment. Jain: ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Verastem: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour: Bristol-Myers Squibb: Consultancy. Smith: Cellectis Inc: Employment.

scholarly journals Results of the Compassionate Program of Inotuzumab Ozogamicin for Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia in Spain

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4392-4392
Author(s):  
Josep-Maria Ribera ◽  
Olga Garcia ◽  
Pau Montesinos ◽  
Rebeca Rodríguez-Veiga ◽  
María García-Fortes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Real Life ◽  
Early Death ◽  
Median Number ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Wbc Count

Abstract Background and objective. Inotuzumab ozogamicin (InO) was approved for patients (pts) with relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL) based on the results of INO-VATE trial (Kantarjian et al, 2016). There are scarce studies evaluating the results of InO therapy in real life in similar pts as those from the INO-VATE trial. Our objective was to analyze the outcomes of pts included in the compassionate program of InO in Spain (June 2013-April 2018) before definitive approval. Patients and Methods. Inclusion criteria were age >18 yrs., CD22+ ALL, R/R resistant to ≥2 previous lines, Ph+ ALL resistant/intolerant to TKI, ECOG ≤2 or >2 if due to ALL, Bilirubin <1.5 ULN, AST & ALT <2.5 ULN, Creatinine ≤ 1.5 ULN. Exclusion criteria included mature B ALL, active CNS leukemia, chemotherapy in the two previous weeks, HSCT in the previous 6 months, grade ≥2 aGVHD or cGVHD, acute or chronic hepatitis B or C, HIV infection, VOD/SOS and antecedent chronic liver disease. Cycles of InO (0.8 mg/m 2 IV d1, and 0.5mg/m 2 IV on d8 and d15) were given every 21 days. Main outcomes: early death, CR/CRi, CR duration, PFS, OS and HSCT realization after InO. Results. 34 pts were included in the trial, 21 males, median age 43 yrs (range 19-73), ECOG <2 22/26, WBC count 7.8 x10 9/L (0.3-388), pro B ALL 4/33, common 26/33, pre-B 3/33, Ph+ ALL 5/34 (15%), BM blast cells >50% 15/33 (45%). 25/34 (73%) of pts received >2 previous lines of therapy and 20 (59%) were previously transplanted. The duration of first CR remission before InO was <12 months in 16/33 pts (49%) and 16/34 pts were refractory to the last treatment before InO. The median number of InO cycles was 2 (1-6). One pt withdrew the study before evaluation, 5 (15%) dead during therapy and 21 (64%) achieved CR/CRi. Ten pts (29%) were transplanted. With a median follow-up for alive patients after InO start of 26 months, the medians (95%CI) of DR, PFS and OS were 4.7 months (2.4-7.0), 3.5 (2.0-5.0) and 4.0 months (1.9-6.1), respectively. CR duration, PFS and OS were significantly shorter in refractory ALL (Figure 1A), pts with first CR (CR1) duration <12 months (Figure 1B) and in those without previous HSCT. The number of previous lines of therapy did not show impact on outcome. The most frequent adverse events were hepatic (24%), infectious (18%), hematologic (15%) and gastrointestinal (9%). 3/10 transplanted patients showed grade 3-4 VOD/SOS. Grade 5 toxic events were hepatic (n=2), infection (n=2) and hemorrhage (n=1). Conclusion. The results in this series of compassionate use of InO for R/R ALL before approval for clinical use were slightly inferior to that of the INO-VATE trial. However, patients form this series had poorer risk factors than those included in that trial. The frequency and type of AE were similar to that of observed in the INO-VATE trial. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Overall survival according to ALL status at inotuzumab start (A) and to duration of first complete remission (B) Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Hernández-Rivas: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Polatuzumab Vedotin Use before Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Aggressive Lymphoma: A US Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3842-3842
Author(s):  
Arushi Khurana ◽  
Radhika Bansal ◽  
Matthew Hathcock ◽  
Adrienne Nedved ◽  
Yucai Wang ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Single Center ◽  
Infection Rates ◽  
Bridging Therapy ◽  
Advisory Committees ◽  
Single Center Experience ◽  
Significant Difference ◽  
Car T

Abstract Background: Polatuzumab vedotin (Pola), an antibody drug conjugate targeting CD79b received FDA approval in combination with bendamustine and rituximab (Pola-BR) in June 2019. With CAR-T as destination therapy, the option of Pola-BR appears appealing with its superior efficacy and lack of potential interference with CAR-T due to different target antigens. However, clinical concerns remain regarding prolonged lymphopenia associated with benda and CAR-T manufacturing if used before apheresis. We reviewed the single center experience of all patients with exposure to polatuzumab around CAR-T for R/R aggressive NHL treated at Mayo Clinic Rochester. Methods: A review of patients that received at least one dose of Pola with the intent to proceed to CAR-T between July 1, 2019 and March 31st, 2021 at Mayo Clinic, Rochester were included. Response to therapy was based on 2014 Lugano criteria. Overall survival (OS) was defined as the time from CAR-T infusion to death, and event-free survival (EFS) as the time from CAR-T infusion to disease progression, next treatment, or death. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results: A total of 22 patients were identified during the study period. Of these 18 (82%), made it to CAR-T infusion (17 axi-cel, and 1 -tisa cel). 3 patients died due to progressive disease (PD) before CAR-T and one achieved complete remission (CR). In the pre-CAR-T Pola cohort (n = 22), the median age was 65.5 years (39-73), 50% were males, 96% had advanced stage and IPI ≥ 3. Median prior lines of treatment were 4.5 (2-6), 73% had primary refractory disease and 50% had myc rearrangement. 19 (86%) patients received Pola as bridging therapy and 8 were exposed to Pola before T-cell apheresis. Bendamustine was included in the treatment for 79% (15/19) for bridging therapy and 63% (5/8) with exposure pre-apheresis. For those in the bridging group, the overall response rate (ORR) was 26% (5/19), with one patient achieving CR with Pola-BR. Disease control (defined as those in a partial response [PR] or stable disease [SD]) was seen in 47% (9/19) patients. One of the 8 patients with pre-apheresis exposure to Pola, required an additional attempt at CAR-T manufacturing after the initial failure. At a median follow up of 48 weeks, the EFS and OS in 18 patient cohort with pre-CAR-T Pola exposure were 6.7 weeks (95% CI, 4.3-not reached [NR]) and 15 weeks (95% CI, 9.7-NR), respectively. At the data cut off (7/25/2021), 78% patients had died. As traditional chemo for bridging is a particularly poor prognostic group, we compared Pola-BR bridging group (n = 15), to other traditional chemo bridge group (n = 16) in our CAR-T database. Both groups had comparable baseline characteristics as shown in Table 1 except for higher proportion of patients with B-symptoms in the Pola-BR group at time of CAR-T. There was also no difference in the inflammatory markers (CRP and ferritin) at LD or peak level after CAR-T. Table 2 shows outcomes between the 2 groups with comparable any grade CRS, neurotoxicity, pre and post CAR-T infection rates. Best response ORR to CAR-T was higher in the other chemo group vs. Pola BR (81.2% vs. 33%, p = 0.027). There was a significant difference in the 6-month OS rate (other 81.3% [95%CI, 54.5-96] vs. pola 33.3% [95%CI, 11.8- 61.6], p = 0.007) but no significant difference in the 6-month EFS rate (other 37.5% [95%CI, 15.2-64.6%] vs. pola 13.3% [95%CI, 1.7-40.5%] p = 0.12) between the 2 groups (figure 1). On univariate analysis within the chemo type bridging cohort (Pola-BR + other traditional chemo, n = 31), presence of B-symptoms (HR 4.72, p = 0.002), ECOG PS > 2 at CAR-T (HR 6.75, p = 0.0008), and type of bridge therapy (pola HR 6.57, p = 0.009) were associated with worse OS whereas a response to bridge (PR+SD, HR 0.39, 0.031) was favorable. On MVA, association was maintained for bridge type (pola, p <0.001) and response to bridge (p <0.001). Discussion: Pola based bridge was feasible in this US based cohort without significant issues with CAR-T manufacturing or increased infection rates. However, in this retrospective analysis, use of Pola-BR was associated with inferior outcomes compared to other traditional chemotherapy options. Future studies are required to elucidate whether these difference in outcomes stem from a biological basis versus bias in patient selection. Figure 1 Figure 1. Disclosures Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; InnoCare: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Legend: Consultancy; Sorrento: Consultancy.

Weekly Inotuzumab Ozogamicin (InO) In Adult Patients With Relapsed Or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3906-3906 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Wendy Stock ◽  
Andrei R. Shustov ◽  
Michaela Liedtke ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Dose Escalation ◽  
Research Funding ◽  
Graft Failure ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees

Abstract Background InO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on a majority of B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Cancer. 2013 Aug 1;119(15):2728-36). Aims To optimize the InO dose and weekly schedule, and evaluate safety and efficacy in CD22+ relapsed/refractory ALL. Methods This phase 1, dose-escalation and expansion study enrolled pts aged ≥18 y with CD22+ refractory/relapsed ALL and no central nervous system disease. InO was administered in 28-d cycles (Table), up to 6 cycles. The final dose was to be determined based on dose-limiting toxicities (DLT) and efficacy, using the MDACC EffTox V2.10 software. Adverse event (AE) severity was assessed per CTCAE V3. DLTs included the following InO -related events in Cycle 1: gr ≥4 nonhematologic AE; prolonged myelosuppression; gr 3 nonhematologic AE >7 d; any AE resulting in permanent InO discontinuation. Complete response (CR) was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease; CRi defined as CR without ANC or platelet recovery. Results We report data for 37 pts: median age was 56 y (23-75 y); 65% were male; 17 (46%) pts were in salvage 1, 9 (24%) in salvage 2, and 10 (27%) in salvage ≥3; 7 (19%) pts had prior allogeneic stem cell transplant (SCT); 6 (16%) pts were Ph+; CD22 found on a median of 98% blasts (31.1-100%); median WBC was 5.18×103/mm3 (0.5-67.2×103/mm3). The expansion cohort (n=13) was comprised of pts with higher peripheral blast counts (PBC) and higher risk cytogenetics as compared to the dose escalation group (n=24): median PBC of 4158/µL (0-38,976/µL) and 18/µL (0-10,189/µL), respectively; aberrant baseline cytogenetics were reported in 10/13 (77%) expansion pts including 2 pts Ph+ and 2 pts t(4;11) and 11/24 (46%) escalation pts. Median follow-up in surviving pts was 4.1 mo (1-12.6 mo). Thirty-two pts discontinued InO: 14 due to PD, relapse or resistant disease, 11 proceeded to SCT, 6 due to AEs (1 pt each: gr 3 acute renal failure, gr 2 ascites, gr 2 increased gamma-glutamyl transpeptidase (GGT), gr 5 graft failure, gr 2 constitutional symptoms and gr 2 veno-occlusive disease (VOD)) and 1 to receive maintenance therapy. InO-related ≥gr 3 AEs (≥10% of pts) were thrombocytopenia (30%) and neutropenia (19%). Other ≥gr 3 hepatic AEs included increased ALT (5.4%) and increased GGT (3%). Gr 2 AEs include ascites (2 pts) and VOD (2 pts). Sixteen deaths were reported: ALL (n=11), sepsis following SCT (n=3), graft failure (n=1) and gut GVHD and liver dysfunction (n=1). The RP2D was determined as 1.8 mg/m2/cycle based on efficacy and safety in the dose escalation patients (1 DLT; 89% CR+CRi rate; all remissions were minimal residual disease (MRD) negative (<1 blast out of 104 mononuclear cells by flow cytometry) with a dose reduction to 1.6 mg/m2/cycle upon achievement of CR/CRi. The dose reduction was recommended due to AEs leading to discontinuation and the observation of increased InO exposure with successive cycles in prior studies. The remission rate (CR+CRi) for the dose escalation pts (n=24) was 79% (95% CI: 58, 93) and 46% (95% CI: 19, 75) for the dose expansion pts (n=13); 18/19 (95%) escalation pts with CR/CRi and 4/6 (67%) expansion pts with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 29 d (20-85d) and 34 d (22-141d), respectively. Minimum InO concentrations in responders were higher than in pts failing treatment. Summary/Conclusion The RP2D was confirmed as 1.8 mg/m2/cycle, InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this relapsed/refractory population; preliminary efficacy results appear dynamically related to exposure and circulating blasts. Further exploration in CD22+ ALL is ongoing. Disclosures: DeAngelo: Pfizer Inc: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ acute lymphoblastic leukemia; this drug is investigational and is not approved for use in any indication in any country. Stock:Pfizer Inc: Research Funding. Liedtke:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Schiffer:Amgen Inc: Research Funding; Pfizer Inc: Research Funding. Ananthakrishnan:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Liau:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Advani:Pfizer Inc: Research Funding.

scholarly journals Automated Manufacture of Matched Donor-Derived Allogeneic CD19 CAR T-Cells for Relapsed/Refractory B-ALL Following Allogeneic Stem Cell Transplantation: Toxicity, Efficacy and the Important Role of Lymphodepletion

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 776-776
Author(s):  
Claire Roddie ◽  
Maeve A O'Reilly ◽  
Maria A V Marzolini ◽  
Leigh Wood ◽  
Juliana Dias Alves Pinto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Peak Car ◽  
Matched Donor

Introduction: 2nd generation CD19 CAR T cells show unprecedented efficacy in B-ALL, but several challenges remain: (1) scaling manufacture to meet patient need and (2) feasibility of generating products from lymphopenic patients post allogeneic stem cell transplant (allo-SCT). To overcome these issues we propose: (1) use of the CliniMACS Prodigy (Miltenyi Biotec), a semi-automated cGMP platform that simplifies CAR T cell manufacture and (2) the use of matched donor T cells to overcome the challenge posed by patient lymphopenia, albeit this may come with a heightened risk of graft versus host disease (GvHD). CARD (NCT02893189) is a Phase I study of matched donor derived CD19 CAR T cells generated on the CliniMACS Prodigy in 14 adult patients with relapsed/refractory (r/r) B ALL following allo-SCT. We additionally explore the requirement for lymphodepletion (LD) in the allogeneic CAR T cell setting and report on the incidence of GvHD with this therapy. Methods: Manufacturing: CARD utilises non-mobilised matched donor leucapheresate to manufacture 2nd generation CD19CAR T cells using a closed CliniMACS® Prodigy/ TransACTTM process. Study design: Eligible subjects are aged 16-70y with r/r B ALL following allo SCT. Study endpoints include feasibility of CD19CAR T cell manufacture from allo-SCT donors on the CliniMACS Prodigy and assessments of engraftment and safety including GvHD. To assess the requirement for LD prior to CD19CAR T cells in lymphopenic post-allo-SCT patients, the study is split into Cohort 1 (no LD) and Cohort 2 (fludarabine (30 mg/m2 x3) and cyclophosphamide (300mg/m2 x3)). To mitigate for the potential GvHD risk, cell dosing on study mirrors conventional donor lymphocyte infusion (DLI) schedules and is based on total CD3+ (not CAR T) cell numbers: Dose 1=1x106/kg CD3+ T cells; Dose 2= 3x106/kg CD3+ T cells; Dose 3= 1x107/kg CD3+ T cells. Results: As of 26 July 2019, 17 matched allo SCT donors were leukapheresed and 16 products were successfully manufactured and QP released. Patient demographics are as follows: (1) median patient age was 43y (range 19-64y); (2) 4/17 had prior blinatumomab and 5/17 prior inotuzumab ozogamicin; (3) 7/17 had myeloablative allo SCT and 10/17 reduced intensity allo SCT of which 6/17 were sibling donors and 12/17 were matched unrelated donors. No patients with haploidentical transplant were enrolled. To date, 12/16 patients have received at least 1 dose of CD19CAR T cells: 7/16 on Cohort 1 and 5/16 on Cohort 2 (2/16 are pending infusion on Cohort 2 and 2/16 died of fungal infection prior to infusion). Median follow-up for all 12 patients is 22.9 months (IQR 2.9-25.9; range 0.7 - 25.9). At the time of CAR T cell infusion, 7/12 patients were in morphological relapse with &gt;5% leukemic blasts. Despite this, CD19CAR T cells were administered safely: only 2/12 patients experienced Grade 3 CRS (UPenn criteria), both in Cohort 1, which fully resolved with Tocilizumab and corticosteroids. No patients experienced ≥Grade 3 neurotoxicity and importantly, no patients experienced clinically significant GvHD. In Cohort 1 (7 patients), median peak CAR expansion by flow was 87 CD19CAR/uL blood whereas in Cohort 2 (5 patients to date), median peak CAR expansion was 1309 CD19CAR/uL blood. This difference is likely to reflect the use of LD in Cohort 2. CAR T cell persistence by qPCR in Cohort 1 is short, with demonstrable CAR in only 2/7 treated patients at Month 2. Data for Cohort 2 is immature, but this will also be reported at the meeting in addition to potential mechanisms underlying the short persistence observed in Cohort 1. Of the 10 response evaluable patients (2/12 pending marrow assessment), 9/10 (90%) achieved flow/molecular MRD negative CR at 6 weeks. 2/9 responders experienced CD19 negative relapse (one at M3, one at M5) and 3/9 responders experienced CD19+ relapse (one at M3, one at M9, one at M12). 4/10 (40%) response evaluable patients remain on study and continue in flow/molecular MRD negative remission at a median follow up of 11.9 months (range 2.9-25.9). Conclusions: Donor-derived matched allogeneic CD19 CAR T cells are straightforward to manufacture using the CliniMACS Prodigy and deliver excellent early remission rates, with 90% MRD negative CR observed at Week 6 in the absence of severe CAR associated toxicity or GvHD. Peak CAR expansion appears to be compromised by the absence of LD and this may lead to a higher relapse rate. Updated results from Cohorts 1 and 2 will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Qasim:Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; UCLB: Other: revenue share eligibility; Servier: Research Funding; Bellicum: Research Funding; CellMedica: Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 779-779 ◽  
Author(s):  
Zinaida Good ◽  
Jay Y. Spiegel ◽  
Bita Sahaf ◽  
Meena B. Malipatlolla ◽  
Matthew J. Frank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Car T Cells ◽  
Scientific Advisory Board ◽  
Car T ◽  
Scientific Advisory

Axicabtagene ciloleucel (Axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the ZUMA-1 phase 1-2 clinical trial showed that ~40% of Axi-cel patients remained progression-free at 2 years (Locke et al., Lancet Oncology 2019). Those patients who achieved a complete response (CR) at 6 months generally remained progression-free long-term. The biological basis for achieving a durable CR in patients receiving Axi-cel remains poorly understood. Here, we sought to identify CAR T-cell intrinsic features associated with CR at 6 months in DLBCL patients receiving commercial Axi-cel at our institution. Using mass cytometry, we assessed expression of 33 surface or intracellular proteins relevant to T-cell function on blood collected before CAR T cell infusion, on day 7 (peak expansion), and on day 21 (late expansion) post-infusion. To identify cell features that distinguish patients with durable CR (n = 11) from those who developed progressive disease (PD, n = 14) by 6 months following Axi-cel infusion, we performed differential abundance analysis of multiparametric protein expression on CAR T cells. This unsupervised analysis identified populations on day 7 associated with persistent CR or PD at 6 months. Using 10-fold cross-validation, we next fitted a least absolute shrinkage and selection operator (lasso) model that identified two clusters of CD4+ CAR T cells on day 7 as potentially predictive of clinical outcome. The first cluster identified by our model was associated with CR at 6 months and had high expression of CD45RO, CD57, PD1, and T-bet transcription factor. Analysis of protein co-expression in this cluster enabled us to define a simple gating scheme based on high expression of CD57 and T-bet, which captured a population of CD4+ CAR T cells on day 7 with greater expansion in patients experiencing a durable CR (mean±s.e.m. CR: 26.13%±2.59%, PD: 10.99%±2.53%, P = 0.0014). In contrast, the second cluster was associated with PD at 6 months and had high expression of CD25, TIGIT, and Helios transcription factor with no CD57. A CD57-negative Helios-positive gate captured a population of CD4+ CAR T cells was enriched on day 7 in patients who experienced progression (CR: 9.75%±2.70%, PD: 20.93%±3.70%, P = 0.016). Co-expression of CD4, CD25, and Helios on these CAR T cells highlights their similarity to regulatory T cells, which could provide a basis for their detrimental effects. In this exploratory analysis of 25 patients treated with Axi-cel, we identified two populations of CD4+ CAR T cells on day 7 that were highly associated with clinical outcome at 6 months. Ongoing analyses are underway to fully characterize this dataset, to explore the biological activity of the populations identified, and to assess the presence of other populations that may be associated with CAR-T expansion or neurotoxicity. This work demonstrates how multidimensional correlative studies can enhance our understanding of CAR T-cell biology and uncover populations associated with clinical outcome in CAR T cell therapies. This work was supported by the Parker Institute for Cancer Immunotherapy. Figure Disclosures Muffly: Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Miklos:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. Mackall:Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board.

scholarly journals Human CD83 Targeted Chimeric Antigen Receptor T Cell for the Prevention of Graft Versus Host Disease and Treatment of Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 196-196
Author(s):  
Bishwas Shrestha ◽  
Kelly Walton ◽  
Jordan Reff ◽  
Elizabeth M. Sagatys ◽  
Nhan Tu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Fund Research

Distinct from pharmacologic immunosuppression, we designed a programmed cytolytic effector T cell that prevents graft versus host disease (GVHD). CD83 is expressed on allo-activated conventional T cells (Tconv) and pro-inflammatory dendritic cells (DCs), which are implicated in GVHD pathogenesis. Therefore we developed a novel human CD83 targeted chimeric antigen receptor (CAR) T cell for GVHD prophylaxis. Here we demonstrate that human CD83 CAR T cells eradicate cell mediators of GVHD, significantly increase the ratio of regulatory T cells (Treg) to allo-activated Tconv, and provide lasting protection from xenogeneic GVHD. Further, we show human, acute myeloid leukemia (AML) expresses CD83 and can be targeted by CD83 CAR T cells. A 2nd generation CD83 CAR was generated with CD3ζ and 41BB costimulatory domain that was retrovirally transduced in human T cells to generate CD83 CAR T cells. The CD83 CAR construct exhibited a high degree of transduction efficiency of about 60%. The CD83 CAR T cells demonstrated robust IFN-γ and IL-2 production, killing, and proliferation when cultured with CD83+ target cells. To test whether human CD83 CAR T cells reduce alloreactivity in vitro, we investigated their suppressive function in allogeneic mixed leukocyte reactions (alloMLR). CD83 CAR T cells were added to 5-day alloMLRs consisting of autologous T cells and allogeneic monocyte-derived DCs at ratios ranging from 3:1 to 1:10. The CD83 CAR T cells potently reduced alloreactive T cell proliferation compared to mock transduced and CD19 CAR T cells. We identified that CD83 is differentially expressed on alloreactive Tconv, compared to Tregs. Moreover, the CD83 CAR T cell efficiently depletes CD83+ Tconv and proinflammatory DCs with 48 hours of engagement. To test the efficacy of human CD83 CAR T cells in vivo, we used an established xenogeneic GVHD model, where mice were inoculated with human PBMCs (25x106) and autologous CD83 CAR (1-10x106) or mock transduced T cells. The CD83 CAR T cells were well tolerated by the mice, and significantly improved survival compared to mock transduced T cells (Figure 1A). Mice treated with CD83 CAR T cells exhibited negligible GVHD target organ damage at day +21 (Figure 1B). Mice inoculated with CD83 CAR T cells demonstrated significantly fewer CD1c+, CD83+ DCs (1.7x106 v 6.2x105, P=0.002), CD4+, CD83+ T cells (4.8x103 v 5.8x102, P=0.005), and pathogenic Th1 cells (3.1x105 v 1.1x102, P=0.005) at day +21, compared to mice treated with mock transduced T cells. Moreover, the ratio of Treg to alloreactive Tconv (CD25+ non-Treg) was significantly increased among mice treated with CD83 CAR T cells (78 v 346, P=0.02), compared to mice injected with mock transduced T cells. Further, CD83 appears to be a promising candidate to target myeloid malignancies. We observed CD83 expression on malignant myeloid K562, Thp-1, U937, and MOLM-13 cells. Moreover, the CD83 CAR T cells effectively killed AML cell lines. Many AML antigens are expressed on progenitor stem cells. Thus, we evaluated for stem cell killing in human colony forming unit (CFU) assays, which demonstrated negligible on-target, off-tumor toxicity. Therefore, the human CD83 CAR T cell is an innovative cell-based approach to prevent GVHD, while providing direct anti-tumor activity against myeloid malignancies. Figure Disclosures Blazar: Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; Alpine Immune Sciences, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Fate Therapeutics, Inc.: Research Funding; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Davila:Atara: Research Funding; Celgene: Research Funding; Precision Biosciences: Consultancy; Bellicum: Consultancy; GlaxoSmithKline: Consultancy; Adaptive: Consultancy; Anixa: Consultancy; Novartis: Research Funding.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

scholarly journals Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3816-3816 ◽  
Author(s):  
Ryan J. Daley ◽  
Sridevi Rajeeve ◽  
Charlene C. Kabel ◽  
Jeremy J. Pappacena ◽  
Sarah E. Stump ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hypersensitivity Reactions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

Easix As Prediction Score before CAR-T Cells Vs Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Relapsed/Refractory (r/r) Large B Cell Lymphoma (LBCL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Felix Korell ◽  
Thomas Luft ◽  
Michael Schmitt ◽  
Sascha Dietrich ◽  
Anita Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Tumor Board ◽  
Advisory Committees ◽  
Educational Activities ◽  
Bulky Disease ◽  
Car T Cells ◽  
Car T

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

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