Besponsa (inotuzumab ozogamicin)

Here we report the case of a child with DS who was diagnosed with a second relapse of BCP-ALL and has maintained complete remission through regular single-agent InO therapy. Single-agent maintenance using InO can be a good option to avoid subsequent relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to allo-HCT and require less-toxic treatments.

Incorporation of blinatumomab and/or inotuzumab in CR1 may mitigate the negative prognostic significance of MRD, however it is unclear if intensity of standard post-remission therapy can be safely reduced without compromising outcomes...We designed a phase I clinical trial to determine safety and tolerability of UCD19 CAR-T cell therapy for adults with B-ALL in MRD+ CR1 who are at high risk for relapse.Methods : Eligible patients include adults (≥18yo) with B-ALL in CR1 after induction therapy, with MRD positivity by either flow cytometry or NGS (Clonoseq)...Longer follow-up is needed to determine if remissions remain durable, and to determine the relationship between functional persistence (as measured by B-cell aplasia) and remission durability. Enrollment is ongoing at DL2.

Blinatumomab, a CD19/CD3 bispecific T-cell engager; inotuzumab ozogamicin (INO), a CD22 antibody drug conjugate; and chimeric-antigen receptor (CAR) T-cell constructs are novel immune-therapeutic options for treatment of acute lymphoblastic leukemia (ALL). Herein, we discuss strategies to address the unique adverse effects of blinatumomab and ways to optimize its administration and integration into the treatment backbone of B-ALL. We outline our approach to combining and sequencing blinatumomab with other immunotherapies, such as INO and CD19 CAR T-cells, and provide recommendations for the management of toxicities and dose-optimization of blinatumomab therapy in clinical practice.

P=N/A, N=1, Active, not recruiting, Pfizer | Not yet recruiting --> Active, not recruiting

"Introduction : Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)...No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel...Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative."

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)...The survival outcomes are encouraging and need to be validated in a larger number of patients. Currently, post-transplant cyclophosphamide has been implemented to lessen the risk of GVHD.

Because of the above, further research is needed to explore whether using upfront immunotherapy like inotuzumab ozogamicin or blinatumomab in the upfront setting, as well as administering allogeneic transplant early in the treatment course of muTP53-ALL would decrease the risk of relapse and improve long-term survival. Although muTP53 ALL achieved a higher MRD-FC negative response compared to wtTP53 ALL, this did not translate into long-term survival in the muTP53 ALL. Whether using NGS for B-cell and T-cell receptors as a method for MRD testing, like clonoSEQ®, would provide a better prognostic tool is currently unknown.

Frontline therapy was hyper-CVAD-based ± immunotherapy (e.g. inotuzumab ozogamicin and/or blinatumomab) in 43% (n=69), mini-hyper-CVD-based ± immunotherapy in 28% (n=45), and chemotherapy-free in 29% (n=47, all of whom were Ph+). Importantly, no relapses were observed in pts with HR cytogenetic/molecular features who achieved early NGS MRD negativity, suggesting that early MRD dynamics should be included in ALL risk stratification systems. Pts with HR Ph- ALL who achieve deep MRD negativity within the first 6 months of frontline therapy do not appear to benefit from allogeneic SCT.

Case presentation: Herein, we present the case of a 23-month-old girl with high-risk B-ALL who experienced very early isolated medullary relapse; following the failure of conventional chemotherapy according to the ALL-IC REL 2016 protocol, she went on to receive the bispecific T-cell engager (BiTE) blinatumomab and subsequently, due to refractory disease, the combination of fludarabine, cytarabine, and the proteasome inhibitor bortezomib without achieving remission. The minimal residual disease (MRD) was 0.08% on day 28, and InO was continued, thus achieving MRD negativity; the patient successfully underwent an allogeneic stem cell transplantation from a matched family donor. Our case highlights the efficacy and safety of InO as a salvage treatment in the setting of relapsed B-ALL refractory not only to conventional chemotherapy but also to novel treatments, such as blinatumomab and bortezomib.

P2, N=10, Terminated, M.D. Anderson Cancer Center | N=78 --> 10 | Trial completion date: Dec 2036 --> Oct 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2035 --> Oct 2024; PI Request. Slow accrual and lack of clinical interest

Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

P2, N=78, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P=N/A, N=421, Completed, Pfizer | Active, not recruiting --> Completed | N=200 --> 421

P=N/A, N=1, Not yet recruiting, Pfizer | N=29 --> 1 | Initiation date: Jul 2024 --> Dec 2024

She was treated with modified Ph-negative EWALL induction (Vincristine, Idarubicin, dexamethasone) and achieved a complete remission. However, she subsequently experienced an early relapse and was refractory to targeted therapy with blinatumomab. After treatment with inotuzumab ozogamicin, she achieved a second complete remission...It demonstrates that patients with ostensibly favourable prognostic factors may experience poor response rates to traditional chemotherapy as well as targeted salvage agents. It also illustrates the challenges of treating B-ALL in the elderly population.

In Japan, 4 drugs are approved as ADCs for leukemia and lymphoma: gemtuzumab ozogamicin(GO)consists of an anti-CD33 monoclonal antibody bound to calicheamicin via a linker, approved for relapsed/refractory acute myeloid leukemia. Brentuximab vedotin (BV)has anti-CD30 antibodies bound to MMAE via a linker and is approved for CD30-positive Hodgkin's lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma...Inotuzumab ozogamicin(IO)has an anti-CD22 antibody bound to calicheamicin via a linker, approved for relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia...Polatuzumab vedotin(PV)has an anti-CD79b monoclonal antibody bounds to MMAE via a linker, approved for diffuse large B-cell lymphoma(DLBCL). In DLBCL patients with an international prognostic index score(IPI score)of 2 or higher, the combination of PV plus rituximab, cyclophosphamide, doxorubicin, and prednisone(PV+R-CHP)extended PFS at 2 years compared with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which has long been the standard of care. As shown, ADCs exhibit high therapeutic efficacy in leukemia and lymphoma treatment, but many aspects of their resistance mechanisms remain unclear and require further research.

He underwent cord blood transplantation with the conditioning regimen of total body irradiation plus cyclophosphamide and cytarabine with granulocyte-colony stimulating factor priming. Prophylaxis for graft versus host disease was performed with short-term methotrexate and cyclosporin...At that time, he was treated with inotuzumab ozogamicin because the blasts expressed CD22 (75.4%), but this was ineffective. He was next administered blinatumomab with dexamethasone pretreatment, resulting in a complete remission (CR)...He has still maintained a CR for 12 months. Blinatumomab might be a promising treatment and a bridge to stem cell transplantation even in relapsed/refractory CD19-expressing MPAL-B/T.

P2, N=20, Recruiting, First Affiliated Hospital of Zhejiang University

P1, N=26, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jul 2024 --> Dec 2024

Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

P2, N=128, Not yet recruiting, St. Jude Children's Research Hospital

P2, N=25, Recruiting, University of Chicago | Trial completion date: May 2026 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Mar 2025

P2, N=21, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P1/2, N=44, Recruiting, Leland Metheny | Trial primary completion date: May 2024 --> Nov 2024

The third-generation TKI olverembatinib has been proven to be effective in CML patients with the T315I mutation, and it may also be effective in Ph+ acute lymphoblastic leukemia. Some new immune drugs have also shown improvement in the remission rate. Combination therapy with olverembatinib and Ino can achieve a complete molecular response in patients with relapsed and refractory Ph+ ALL with the T315I mutation.

P1/2, N=40, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

No abstract available

P=N/A, N=29, Not yet recruiting, Pfizer

P2, N=80, Recruiting, Children's Oncology Group | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Mar 2026

However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.

P2, N=21, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P2, N=80, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

Prior therapy included blinatumomab (94%), inotuzumab (88%), allo-SCT (24%)...Tocilizumab was needed in 15 pts (44%), dexamethasone 7 pts (21%), and 2 pts needed ICU care... Use of brexu-cel in pts with low tumor burden is associated with low rates of G3-4 CRS/ICANS. We noted CART expansion in pts with no morphologic disease prior to LD. Prospective trials are planned to assess role of CART in low tumor burden setting, including MRD+ and as consolidation strategy.

P2, N=80, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Further investigation of this combination is warranted. ClinicalTrials.gov Identifier: NCT03991884.

P2; Trial primary completion date: May 2028 --> May 2025

P2, N=53, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P3, N=310, Suspended, Alliance for Clinical Trials in Oncology | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

This trial was registered at www.clinicaltrials.gov as no. NCT01564784.

P=N/A, N=158, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Not yet recruiting --> Recruiting

Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL...More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin...These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

P2, N=80, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting