- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Opdivo (nivolumab) / Ono Pharma, BMS
Trial completion date, Trial primary completion date, Combination therapy, Checkpoint inhibition: AALL1821: A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL) (clinicaltrials.gov) - Jun 30, 2021
P2, N=550, Recruiting,
Trial primary completion date: Jun 2021 --> Jun 2022 Trial completion date: Dec 2023 --> Jun 2028 | Trial primary completion date: Dec 2023 --> Jun 2028
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Enrollment open: Blinatumomab After TCR Alpha Beta/CD19 Depleted HCT (clinicaltrials.gov) - Jun 25, 2021
P2, N=25, Recruiting,
Trial completion date: Dec 2023 --> Jun 2028 | Trial primary completion date: Dec 2023 --> Jun 2028 Not yet recruiting --> Recruiting
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Review, Journal: Immunotherapy for the Treatment of Acute Lymphoblastic Leukemia. (Pubmed Central) - Jun 22, 2021
The biologic and clinical contexts in which immunotherapies have advanced the treatment of ALL confer optimism that more patients will achieve durable remissions. Immunotherapy treatments in ALL will expand through rationally targeted approaches alongside advances in CAR T cell therapy design and clinical experience.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Arranon (nelarabine) / Novartis, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Review, Journal: Recent Advances in the Management of Acute Lymphoblastic Leukaemia. (Pubmed Central) - Jun 16, 2021
Nelarabine represents an advance, but there remains a pressing need to develop new therapies with efficacy against T-ALL, especially in the relapse setting.Outcomes for younger adults have improved with the adoption of paediatric-like regimens, with a focus on dose intensity and heavy use of pegylated asparaginase...In elderly patients with ALL, the introduction of tyrosine kinase inhibitors (TKIs) and reduction in standard chemotherapy intensity (especially for those with Philadelphia-positive disease) have significantly reduced treatment-associated mortality and resulted in durable remissions with good quality of life.Bone marrow transplantation remains a key therapy in adult ALL, and is still the treatment of choice for relapsed disease. The mortality associated with a myeloablative approach can be substantially lowered by reduced intensity conditioning, without an apparently significant reduction in efficacy.
- |||||||||| glofitamab (RG6026) / Roche, Blincyto (blinatumomab) / Astellas, Amgen, mosunetuzumab (BTCT4465A) / Roche
Journal: Bispecific antibodies for the treatment of lymphomas: Promises and challenges. (Pubmed Central) - Jun 16, 2021
The recent demonstration that chimeric antigen receptor (CAR) modified T cells can achieve very durable remissions in some patients with relapsed or refractory B-cell lymphomas, as well as the potential efficacy of bispecific antibodies in CAR T cell failures, has rekindled interested in bispecific antibodies as a T cell-mediated therapeutic approach. We review the early results of phase 1 clinical trials of bispecific antibodies targeting CD20 on B cells and engaging T cells via CD3 in 1:1 or 2:1 CD20:CD3 Fab formats for treatment of relapsed or refractory B-cell lymphomas.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Blincyto (blinatumomab) / Astellas, Amgen
Journal: TKI-BiTE Combo Produces CMRs in Most with ALL. (Pubmed Central) - Jun 13, 2021
We review the early results of phase 1 clinical trials of bispecific antibodies targeting CD20 on B cells and engaging T cells via CD3 in 1:1 or 2:1 CD20:CD3 Fab formats for treatment of relapsed or refractory B-cell lymphomas. Early results from a phase II clinical trial show that the third-generation tyrosine kinase inhibitor ponatinib plus the bispecific T-cell engager blinatumomab can produce complete molecular remissions in most patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
[VIRTUAL] T-CELL SUBSET COMPOSITION AND FUNCTIONALITY IN PATIENTS WITH WALDENSTRÖM'S MACROGLOBULINEMIA () - Jun 11, 2021 - Abstract #ICML2021ICML_567;
The qualitative and quantitative changes in the immune system seen in CLL are not found in WM; T-cell numbers, distribution and functionality seem mostly preserved even in pretreated patients. These findings are encouraging for application of T-cell directed immunotherapy in WM, especially for relapsed/refractory WM.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Yervoy (ipilimumab) / Ono Pharma, BMS
Review, Journal: Neurological complications of cancer immunotherapy. (Pubmed Central) - Jun 8, 2021
The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors...Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal: Bispecific antibodies in acute lymphoblastic leukemia therapy. (Pubmed Central) - Jun 5, 2021
Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Blincyto (blinatumomab) / Astellas, Amgen
#ASCO21 #leusm Short: Ponatinib + Blinatumomab for Ph+ALL (20 front-line, 10 R/R, 5 CML-LBP), 96% CR/CRp, 79% CMR, 1 death in F/L cohort likely related to Ponat, but all others surviving. (Twitter) - Jun 4, 2021
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal: Drug Combo May Obviate Chemotherapy in ALL. (Pubmed Central) - Jun 4, 2021
A phase II trial shows that a chemotherapy-free regimen of dasatinib and blinatumomab produces molecular responses in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. The study found that 60% of patients had molecular responses after two cycles of blinatumomab and 71% had molecular responses after five cycles.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, blinatumomab subcutaneous / Amgen
Trial completion date, Trial primary completion date: A Study of Subcutaneous Blinatumomab Administration in Acute Lymphoblastic Leukemia (ALL) Patients (clinicaltrials.gov) - Jun 3, 2021
P1b, N=35, Recruiting,
The study found that 60% of patients had molecular responses after two cycles of blinatumomab and 71% had molecular responses after five cycles. Trial completion date: Sep 2023 --> Jun 2024 | Trial primary completion date: May 2023 --> Feb 2024
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal: Single-arm trials with historical controls: Study designs to avoid time-related biases. (Pubmed Central) - Jun 1, 2021
Nevertheless, long-term effectiveness data are needed to validate the several assumptions that were necessary for this model. While single-arm trials with external historical controls are gaining recognition, a proper understanding of time-related sources of bias is essential if such trials will be used to provide valid evidence for drug approval from regulatory agencies.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Review, Journal: The landscape of bispecific T cell engager in cancer treatment. (Pubmed Central) - May 28, 2021
BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies...In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Review, Journal, IO biomarker: The BiTE (Bispecific T-Cell engager) platform: development and future potential of a targeted immuno-oncology therapy across Tumor Types. (Pubmed Central) - May 21, 2021
Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms...BiTE molecules with an extended half-life relative to the canonical BiTE molecules are also being developed. Advances in immuno-oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments.
- |||||||||| Arzerra (ofatumumab) / Novartis, Genmab, Opdivo (nivolumab) / Ono Pharma, BMS
[VIRTUAL] Approaches to Therapy of Richter Syndrome (LEVEL 4, GRAND BALLROOM G-L) - May 20, 2021 - Abstract #SOHO2021SOHO_170;
P2
Conclusions Relapsed/refractory patients with CLL on novel agents are a new high-risk prognostic group with an extremely adverse outcome upon transformation. An international and common effort in developing preclinical models, prognosticators, biobanks, and databases should be pursued to improve outcomes in patients with RS.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
[VIRTUAL] Measurable Residual Disease in Acute Lymphoblastic Leukemia: Optimization and Innovation in 2021 and Beyond () - May 20, 2021 - Abstract #SOHO2021SOHO_92;
Society guidelines and expert consensus documents include assessment of MRD as the standard of care following induction therapy, consolidation therapy, and at additional time points, depending on the treatment regimen administered.1–3 Further, the approval of blinatumomab for MRD+ B-ALL has advanced the concept of MRD response as a clinical endpoint in ALL...The foundation for MRD was developed in ALL; MRD assessment is now a cornerstone of disease management. Ongoing innovations and well-designed clinical studies will aid in the further optimization and broader implementation of this critical tool.
- |||||||||| Arzerra (ofatumumab) / Novartis, Genmab
[VIRTUAL] Hyper-CVAD in 2021: Lessons Learned and New Approaches () - May 20, 2021 - Abstract #SOHO2021SOHO_90;
Hyper-fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate (MTX) and cytarabine for a total of an 8-intensive- course regimen, developed at MD Anderson Cancer Center in 1992,1,2 was inspired by a Burkitt lymphoma regimen developed in the 1980s by the pediatric oncology group at St...These changes, which include modifying maintenance and intensification therapy, incorporating novel monoclonal antibodies, BCR-ABL1 tyrosine kinase inhibitors (TKIs), and the use of growth factors, have resulted in improved complete remission rates, overall survival, and decreased induction mortality.4–9 In order to improve its tolerability across all age groups, several modifications were implemented.10 These include: 1) decreasing the dose of high-dose methotrexate from 1 g/m2 to 750 mg/m2 and high-dose cytarabine from 3 g/m2 to 2 grams/m2 per dose during even courses; 2) adjustment of the cytarabine dose based on renal function, particularly after clearance of methotrexate; 3) reversing the administration of intrathecal methotrexate and cytarabine during the even courses (Courses 2, 4, 6 and 8) to avoid simultaneous systemic and intrathecal methotrexate [which has been associated with rare cases of central nervous system (CNS) demyelination and neurotoxicity]; 4) prophylactic use of antibiotics, growth factors, and antifungal therapy; 5) interruption of azoles around the use of vincristine, which is capped at 2 milligrams as a flat dose (we have noted occasionally referred patients who had been given vincristine 2 mg/m2 erroneously and who developed severe neurotoxicity); and 6) early assessment of minimal/measurable residual disease (MRD) status [at complete response (CR) and after every cycle until it is undetectable and every 3 months thereafter].11 We recently reported the results of the hyper-CVAD and ofatumumab study in 69 adults with Philadelphia (Ph)-negative ALL with a median age of 41 years (range, 32–50 years).12 The overall response rate was 98%, the MRD negativity rate was 93%, and the induction mortality was 1%...A landmark analysis performed at 6 months showed a trend toward better OS in patients who did not undergo ASCT in first remission (5-year OS rate of 66% for patients who underwent ASCT compared to 83% for patients who did not [P=0.07]).18 A propensity score matching analysis comparing the efficacy of hyper-CVAD-ponatinib with hyper- CVAD-dasatinib showed a superior outcome with ponatinib: the 3-month CMR rates were 82% versus 65% (P=0.03); the 3-year event-EFS and OS rates were 69% versus 46% (P=0.04) and 83% versus 56% (P=0.03), respectively.19 The combination of blinatumomab with TKi(mainly ponatinib) has been shown to be safe and effective in a small case series of 15 patients from MDACC with 50% CR rate and 75% molecular response.20 The GIMEMA group has recently published the results of the D-ALBA trial, the first trial investigating the sequential use of TKI/steroid (in induction) and blinatumomab (in consolidation).21 Sixty-three patients were with this regimen of prednisone, dasatinib, and blinatumomab...Clinical experience with this intensive regimen and awareness of its modifications and the anticipated toxicities are necessary for the successful administration of hyper-CVAD. New strategies to increase the MRD negativity rates and to allow a reduction in intensity and duration of chemotherapy, including the incorporation of inotuzumab ozogamicin, blinatumomab, and venetoclax in frontline ALL, may further improve the outcomes in ALL across all age groups.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
[VIRTUAL] Novel Transplant and Post-Transplant Options in ALL () - May 20, 2021 - Abstract #SOHO2021SOHO_8;
Previous widely accepted indicators for transplantation may now be approached with non-transplant therapy – i.e., Ph+ B-ALL treated with front-line hyperCVAD and ponatinib.1 Other genetic subgroups in the heterogeneous family of Ph-negative ALLs have become better understood, and identifying relapse predictors, such as Ph-like kinase activating translocations and mutations, has, for the time being at least, made it somewhat easier to identify patients likely to benefit from transplant early in their course of therapy.2 For the remainder of adults with intermediate-risk genotypes, it is increasingly becoming the standard of care to base decisions about whether to proceed to allo-HCT on MRD status after induction or, if not then, then after no more than 2–3 cycles of chemotherapy, depending on the regimen used.3,4 Within this strategy lies the ultimate conundrum, however: Patients who go into allo-HCT MRD-negative have the most favorable outcomes,5,6 but do all patients who achieve MRD negativity actually require allo-HCT?...This continues to be important in the era of blinatumomab prior to allo-HCT since this agent may have some vulnerabilities to extramedullary relapse.16 Nevertheless, non-TBibased regimens have importantly been developed with a specific focus on ALL, such as clofarabine/ busulfan, but randomized comparisons with TBihave not been conducted.17 Post-Transplant Strategies for ALL As allo-HCT remains our most powerful weapon against high-risk and relapsed ALL, it is imperative to have methods for assessing the response to transplant and verifying the achievement and maintenance of deep remissions...Nevertheless, as the potent novel agents blinatumomab and inotuzumab ozogamicin are increasingly likely to move to front-line therapy, it will become more difficult to determine who should undergo allo-HCT in first remission...The challenge for the field is to develop better methods for identifying patients with leukemias unlikely to remain in remission without allo-HCT while also striving to achieve higher levels of GVHD-free relapse-free survival in the high-risk patients who do proceed to transplant. Consequently, it will be critically important to further explore the utility of using highly sensitive, serial MRD monitoring to identify patients at risk of relapse and identify more effective strategies to eliminate MRD, hopefully obviating the need for allo-HCT in some, while also using these same techniques to identify patients at risk for post-transplant relapse to enable meaningful and timely interventions.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
[VIRTUAL] Lumit™ Immunoassays for Simple and Rapid Determination of Cytokine Release from Cell Culture Models () - May 19, 2021 - Abstract #IMMUNOLOGY2021IMMUNOLOGY_1441;
P=N/A
In a mix of purified CD8+ T cells and target Raji B cells treated with the bispecific T-cell engager Blincyto®, IL-2, IFN-γ, and TNF-α release was observed with an EC50 of ~0.2 ng/ml and max S/B ratios of 82-, 168-, and 31-fold, respectively...An alternative to the no-transfer assay method, split-sample analysis, can be performed to easily determine the levels of multiple cytokines released in the same cell well. The implementation of this novel detection chemistry will enable simple and rapid assay of cytokine release from cells for both low- and high-throughput applications, including quantitative assessments of T cell activation and differentiation.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
[VIRTUAL] IL-12 abrogates mechanisms of immune suppression by B-ALL () - May 19, 2021 - Abstract #IMMUNOLOGY2021IMMUNOLOGY_1370;
Impressively, IL-12 augmented the efficacy of Blinatumomab resulting in more T-cell mediated killing of leukemia cells. Our results demonstrate the therapeutic potential of IL-12 as a treatment for ALL.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
[VIRTUAL] IL-12 abrogates mechanisms of immune suppression by B-ALL () - May 19, 2021 - Abstract #IMMUNOLOGY2021IMMUNOLOGY_1154;
Impressively, IL-12 augmented the efficacy of Blinatumomab resulting in more T-cell mediated killing of leukemia cells. Our results demonstrate the therapeutic potential of IL-12 as a treatment for ALL.
- |||||||||| Journal: Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. (Pubmed Central) - May 15, 2021
In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Journal, IO biomarker: Blinatumomab-induced T cell activation at single cell transcriptome resolution. (Pubmed Central) - May 15, 2021
We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions. These results reveal a target cell-dependent mechanism of T-cell activation by blinatumomab and suggest that TNFSF4 may be responsible for the resistant mechanism and a potential target for combination therapy with blinatumomab, to treat B-ALL or other B-cell malignancies.
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