- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Imbruvica (ibrutinib) / AbbVie, J&J
Ibrutinib Treatment in CLL Patients Improves T Cell Function and Blinatumomab Redirected Cytotoxicity (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1853;
CLL patients’ T cells post ibrutinib treatment demonstrated superior cytotoxicity against autologous leukemia cells compared to T cells from treatment baseline . Moreover, we show that increased T cell activity is not solely due to ibrutinib-related Treg depletion .
- |||||||||| SENL-B19 / Hebei Senlang Biotechnology, Blincyto (blinatumomab) / Astellas, Amgen, fludarabine / Generic mfg.
Analysis of Factors Predicting Treatment Response of 254 Patients Who Received CD19-Targeted CAR-T Cell Therapy for Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) (Tangerine 3 (WF3-4), Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1591;
P1, P1/2
The CR rate of patients who received prior either CAR-T or blinatumomab treatment was lower than those who had not (50% vs. 91.53%, p=0.01)...There were no differences in CR between patients age 1-14 yr and >14 yr, patients with or without extramedullary disease (EMD), or patients receiving different chemotherapies between enrollment and CAR-T cells infusion on top of fludarabine and cyclophosphamide (FC) conditioning regimen...Patients who developed severe neurotoxicity (grade 2-4) post CAR-T had higher odds of achieving CR compared to patients with grade 0-1 neurotoxicity [OR=34.796(95%CI 3.232-374.659)]. Conclusions In this analysis, we have observed that significant risk factors for not achieving CR after CD-19 CAR-T therapy include female gender, BM blasts more than 20%, a positive TP53 mutation, treatment with CD28 co-stimulatory domain vs 4-1BB CAR-T product, and mild as opposed to severe CAR-T related neurotoxicity.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal, IO Biomarker: CD47/SIRPα blocking enhances CD19/CD3-bispecific T cell engager antibody-mediated lysis of B cell malignancies. (Pubmed Central) - Nov 6, 2019
T cell immunotherapies are promising options in leukemia, among which the CD19/CD3-bispecific T cell engager antibody blinatumomab (MT103) has shown high response rates at very low doses in patients with lymphoma...These antibodies enhanced the therapeutic efficacy through mechanisms combining both innate and adaptive immune responses by induction of phagocytosis and T cell cytotoxicity. The combination strategy in this study might be applicable to many other cancers.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Expanding Horizons for Immunotherapy in Pediatric Leukemia (W230, Level 2 (Orange County Convention Center)) - Oct 27, 2019 - Abstract #ASH2019ASH_288;
Rebecca Gardner will discuss predictive clinical biomarkers of response and resistance in children with B-ALL treated with antibody-based or cellular immunotherapies . She will then describe new approaches to overcome immunotherapeutic resistance via enhanced CAR constructs, bispecific antigen targeting, combination therapies, and the role of subsequent hematopoietic stem cell transplantation.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Expanding Horizons for Immunotherapy in Pediatric Leukemia (Tangerine 1 (WF1), Level 2 (Orange County Convention Center)) - Oct 27, 2019 - Abstract #ASH2019ASH_284;
Rebecca Gardner will discuss predictive clinical biomarkers of response and resistance in children with B-ALL treated with antibody-based or cellular immunotherapies . She will then describe new approaches to overcome immunotherapeutic resistance via enhanced CAR constructs, bispecific antigen targeting, combination therapies, and the role of subsequent hematopoietic stem cell transplantation.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Acute Lymphoblastic Leukemia: Aiming High to Keep MRD Low, or Even Better, Negative (Valencia BC (W415BC), Level 4 (Orange County Convention Center)) - Oct 27, 2019 - Abstract #ASH2019ASH_261;
Dr . Adele Fielding will review the promising results with second and third generation TKIs in combination with chemotherapy for Ph+ ALL and the controversies surrounding the question of allogeneic hematopoietic stem cell transplant for these patients.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Acute Lymphoblastic Leukemia: Aiming High to Keep MRD Low, or Even Better, Negative (Chapin Theater (W320), Level 3 (Orange County Convention Center)) - Oct 27, 2019 - Abstract #ASH2019ASH_260;
Dr . Adele Fielding will review the promising results with second and third generation TKIs in combination with chemotherapy for Ph+ ALL and the controversies surrounding the question of allogeneic hematopoietic stem cell transplant for these patients.
- |||||||||| Novel therapy for relapsed childhood acute lymphoblastic leukemia () - Oct 23, 2019 - Abstract #EHOC2019EHOC_7;
Since bcl-2 pathway prevents apoptosis, the efficacy of bcl-2 inhibitors, Navitoclax and Venetoclax, in ALL is being investigated...Palbociclib, CDK6 inhibitor, is used as monotherapy in KMT2A-r acute leukemia...Immunotherapy Antibody-based immunotherapy Blinatumomab: It is an antibody capable of binding to CD19 and CD3 and transmitting T-cell cytotoxicity to lymphoblasts presenting CD19...Denintuzumab mafodatin: It is a humanized CD19 antibody bound with monomethyl auristatin F (MMAF)...ADCT-402: It is a humanized anti-CD19 antibody conjugated with Pyrrolobenzodiazepine dimer cytotoxin...DT2219: It is a bispecific, recombinant, diphtheria toxin-based immunotoxin that recognizes CD19 and CD22-presenting cells...Inotuzumab ozogamicin: It is a novel monoclonal antibody against CD22 conjugated to the toxin Calicheamicin...Epratuzumab: It is a humanized monoclonal anti-CD22 antibody...Rituximab: It is a chimeric monoclonal CD20 antibody...Ofatumumab: It is a humanized anti-CD20 antibody...Obinutuzumab: It a type II humanized anti-CD20 monoclonal antibody...Etanercept (anti-TNF) and Tociluzumab (anti IL-6) can be used in the treatment of cytokine release syndrome. There are many marching studies on CAR-T cell therapy.
- |||||||||| Scemblix (asciminib) / Novartis, Blincyto (blinatumomab) / Astellas, Amgen
Trial primary completion date, Combination therapy: ABL001 + Dasatinib + Prednisone + Blinatumomab in BCR-ABL+ B-ALL or CML (clinicaltrials.gov) - Oct 17, 2019
P1, N=34, Recruiting,
A validation of results on larger cohorts of pts will be performed. Trial primary completion date: Nov 2019 --> Nov 2021
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Clinical, Journal: Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia. (Pubmed Central) - Oct 11, 2019
The incorporation of new monoclonal antibodies and other targeted approaches into frontline regimens is showing promising results. If confirmed, such strategies may increase the cure rates in adults to levels achieved in pediatric ALL and reduce the need for intensive and prolonged chemotherapy.
- |||||||||| Rituxan (rituximab) / Roche, Biogen
Review, Journal: Antibodies in hematology by the example of acute lymphatic leukemia (Pubmed Central) - Oct 8, 2019
Although the antibodies have improved the treatment of patients with ALL, it still holds true that the therapy of patients can only be successfully carried out with a strategy that integrates different, mutually complementary schemes. The improvement of therapy can only be achieved through clinical studies with clearly defined protocols.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal: Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold. (Pubmed Central) - Oct 4, 2019
Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia...Rather than a tandem of c-type immunoglobulin folds predicted from the amino acid sequence, the extracellular domain of CD19 exhibits an elongated β-sandwich formed by two immunoglobulin folds by swapping their C-terminal halves. This is the first structure of CD19, which has no sequence homologs.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Novel humanized CD3ε mouse model for evaluation of bi-specific T-cell engager antibodies (Prince George's Exhibition Halls AB) - Oct 2, 2019 - Abstract #SITC2019SITC_1143;
Taken together, Biocytogen's B-hCD3ε mice are validated and exhibit expected T cell profile, robust in vitro activity, and efficacious in vivo response to anti-human CD3 antibody and anti-human CD3 bispecific antibody. These humanized B-hCD3ε mice present a useful model for accelerated in vivo evaluation of anti-human CD3 therapeutics.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
A next generation bispecific antibody platform for effective tumor cell killing with minimal cytokine release (Prince George's Exhibition Halls AB) - Oct 2, 2019 - Abstract #SITC2019SITC_1059;
Evidence from clinical data of Blinatumomab, the only FDA approved bispecific antibody, suggests that T-BsAbs are associated with cytokine release syndrome (CRS), similar to other T cell targeting therapies such as Muromonab or CAR-T, thus warranting a newer generation of bispecific antibodies which can limit CRS... This next generation of T-BsAbs thus shows promise as an effective therapy against multiple cancer indications.
- |||||||||| Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL) (clinicaltrials.gov) - Oct 1, 2019
P3, N=111, Active, not recruiting,
Flow cytometry provides a robust method to directly measure T, NK, and complement-dependent killing of cancer cells in human whole blood. Recruiting --> Active, not recruiting | N=202 --> 111 | Trial completion date: Jul 2023 --> Oct 2022 | Trial primary completion date: Sep 2020 --> Dec 2019
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB, Gazyva (obinutuzumab) / Biogen, Roche
Antibody modification: is it even better? (Hall A3) - Sep 30, 2019 - Abstract #DGHO2019DGHO_456;
Therefore, strategies in improving these effector functions by Fc-engineering have been evaluated and with obinutuzumab were clinically translated in lymphoma therapy...With the approval of blinatumomab in ALL, especially T cell-engaging bispecific antibodies have regained great attention, but also alternative antibody formats designed to potently activate NK cells via engagement of FcγRIIIa or NKG2D may represent promising agents...With inotuzumab-ozogamicin a prototypic antibody drug conjugate has recently been approved in ALL treatment and a variety of next generation agents entered clinical development...In conclusion, a large panel of antibody engineering strategies have been developed allowing the rational design of next generation antibodies with tailor-made unique effector functions. Established and emerging antibody engineering concepts will be presented and discussed.
- |||||||||| mosunetuzumab (BTCT4465A) / Roche
Managing Cytokine Release Syndrome and Neurotoxicity with Step-Up Dosing of Mosunetuzumab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (Aggressive B-Cell Lymphoma) - Sep 26, 2019 - Abstract #SOHO2019SOHO_425;
P1
In these patients, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL patients.Conclusions Step-up dosing has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile.Acknowledgements Funding from F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, directed by Nancy Bartlett, was provided by Louise Profit and Russell Craddock of Gardiner-Caldwell Communications, and funded by F. Hoffmann-La Roche Ltd.
- |||||||||| Ph+ ALL: How Can We Optimize Treatment for All Patients? () - Sep 26, 2019 - Abstract #SOHO2019SOHO_267;
Studies have used imatinib, dasatinib and, more rarely, nilotinib as TKI therapy, together with or following induction treatment...Similar to the MDACC trial, toxicity was a concern, since 35 adverse events related to ponatinib were recorded (26 serious and 13 likely to be related to the drug itself).37 Taken together, these results indicate that the upfront use of ponatinib is highly effective.Emerging approaches are based on the combination of TKIs with novel therapeutic strategies: in this setting, GIMEMA has recently closed enrollment to the LAL2116 (alias D-ALBA) trial in which, after an induction with dasatinib (and steroids), patients (n=63) received at least 2 cycles of blinatumomab (2 cycles were mandatory, 3 additional cycles left to investigator choice)...Even with short median follow-up (10 months, range: 0-21.1), results are extremely promising with OS and DFS of 94.8% and 87.8%, respectively.38 Efforts are ongoing to evaluate the impact of genetic features.In conclusion, MRD evaluation, ABL1 mutational screening, the search for additional genomic screening and the use of novel targeted agents (both TKIs and immunotherapeutic compounds) are refining the current management of Ph+ ALL patients. These improvements should be incorporated into clinical practice in order to stratify patients to specific risk groups and, more importantly, to drive therapeutic strategies, including transplantation.
- |||||||||| Rituxan (rituximab) / Roche, Biogen
Debate: Is Transplant Still Necessary in the Era of Targeted Cellular Therapy for ALL? CON () - Sep 26, 2019 - Abstract #SOHO2019SOHO_265;
At the same time, the addition of tyrosine kinase inhibitors (TKIs), CD20 antibodies such as rituximab, and intensive risk-directed therapy has led to continued improvements in up-front cure of patients with chemotherapy...In addition, tisagenlecleucel and other 4-1BB-based CAR T-cell approaches have induced remissions that in some cases are exceeding 6 years, showing that cures can occur without HCT in a high percentage of patients. Approaches aimed at optimizing CAR T-cell expansion and persistence along with targeting of multiple antigens are likely to lead to additional improvements in survival after CAR T-cells alone, further diminishing to role for HCT in this disease.
- |||||||||| Darzalex IV (daratumumab) / J&J
Childhood Acute Lymphoblastic Leukemia: How to Cure the Very High Risk? () - Sep 26, 2019 - Abstract #SOHO2019SOHO_242;
In a recent global study of 75 patients with relapsed or refractory B-ALL treated with tisagenlecleucel, the overall complete remission rate within 3 months was 81%, and the 12-month event-free and overall survival rates were 50% and 76%, respectively.31 Although these immunotherapy and adoptive cellular therapies have been used in the relapse or refractory setting, they are being brought forward to newly diagnosed B-ALL patients and promise to improve the outcome of these patients...Nonetheless, preclinical studies have shown efficacy with the anti-CD38 monoclonal antibody daratumumab and with CAR-T cells targeting several antigens, including CD2, CD5, and CD7 in T-ALL.32,33 In a recent Children’s Oncology Group trial AALL0434 for T-ALL, patients randomized to receive nelarabine have excellent treatment outcome.34 Since the vast majority of the patients received prophylactic cranial irradiation, additional studies are needed to determine if nelarabine can by itself improve CNS disease control.Conclusions Improved genomic sequencing and biologic understanding of ALL as well as integration of novel molecular, immunological and cellular therapy should continue to advance the cure rate for B-ALL. For T-ALL, better methods to identify patients at risk of relapse and more effective personalized therapies are needed.Funding Supported in part by National Cancer Institute grants CA21765, CA36401, CA176063 and P50 GM115279; and the American Lebanese and Syrian Associated Charities (ALSAC).
- |||||||||| Management of Advanced Phase Chronic Myeloid Leukemia () - Sep 26, 2019 - Abstract #SOHO2019SOHO_241;
Patients with accelerated phase (CML-AP) or blast phase (CML-BP) may receive initial therapy with TKIs (newer generation TKIs like dasatinib or ponatinib preferred over imatinib) to reduce the CML burden, and be considered for early allogeneic stem cell transplantation (allo-SCT)...Venetoclax in combination with TKI is currently being tested in early CML-CP and CML-BP disease.Both the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin and the CD3-CD19 bispecific T-cell engager blinatumomab have single-agent activity in relapsed or refractory Philadelphia-negative and Philadelphia-positive ALL...Patients with de-novo CML-AP are treated with frontline second generation TKI infinitely if an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is achieved within 6 months of therapy. All other patients in CML-AP are treated with second/third generation TKI followed by allo-SCT.
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