Besponsa (inotuzumab ozogamicin)

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

Our findings highlight the importance of defining the basis of CD22 escape, and eradication of residual disease prior to HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss, and provide opportunities to improve therapeutic approaches and overcome resistance.

P=N/A, N=160, Active, not recruiting, Pfizer | N=100 --> 160

Several ongoing trials in older patients with newly diagnosed ALL have yielded encouraging data with inotuzumab ozogamicin in induction alone and in combination with low-intensity chemotherapy. In this podcast, the authors summarize and highlight some of the recent findings on the use of inotuzumab ozogamicin as induction therapy for older adults with newly diagnosed ALL.

P3, N=4997, Recruiting, Children's Oncology Group | Trial completion date: Jun 2029 --> Mar 2030 | Trial primary completion date: Jun 2029 --> Mar 2030

P1/2, N=44, Recruiting, Leland Metheny | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Dec 2023 --> May 2024

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

One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.

P=N/A, N=200, Active, not recruiting, Pfizer | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: May 2024 --> Sep 2024

P2, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P=N/A, N=158, Not yet recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | N=250 --> 158 | Trial completion date: Jun 2024 --> Nov 2024 | Initiation date: Nov 2023 --> Feb 2024 | Trial primary completion date: Jun 2024 --> Nov 2024

Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.

InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (two 5-day blocks, then amended), and intrathecal therapy. This combination showed an response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose. #NTR5736.

After the initial induction chemotherapy, her disease remained refractory, and the patient received salvage immunotherapy with blinatumomab and inotuzumab ozogamicin. We present this case to highlight the potential of KMT2A-rearranged B-ALL to undergo lineage switch following B-cell targeted therapy. Patients with this kind of B-ALL should therefore be closely monitored to capture potential changes in the nature of the disease and prompt appropriate treatment.

P2, N=32, Recruiting, St. Jude Children's Research Hospital

P=N/A, N=100, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=160 --> 100

Significance Statement Several in vitro and in vivo stability studies of ABBV-011, a calicheamicin-based ADC, identified circulating metabolites and catabolites and suggested that disulfide cleavage may be a key liability for the conjugated linker-payload. These observations may be relevant to other disulfide-linked ADCs, such as Mylotarg and Besponsa, both of which have reported similar half-lives that possibly indicate instability.

He began maintenance BCNU/cytoxan, then several cycles 6-MP/MTX/vincristine. On day +554 after diagnosis, he relapsed and started decitabine/venetoclax, then decadron + dasatinib, then MVP, followed by 3 cycles of inotuzumab...As his condition worsened he was put on ponatinib, then asciminib before expiring on day +940...On day +447 he started blinatumomab + IT MTX + nilotinib...The patient underwent leukapheresis and started HiDAC + mitoxantrone + etoposide + dasatinib...Likewise, many undocumented adults are the parents of US citizen minors who would benefit economically from their survival. For consideration we will explore cost analysis to further elucidate the potential benefit of allowing coverage of HSCT.

Introduction Anti-CD19 chimeric antigen receptor (CAR) autologous T-cell therapy tisagenlecleucel (CTL019) has shown efficacy in pivotal trials and real-world data in relapsed/refractory pediatric B-cell precursor acute lymphoblastic leukemia (r/r B-ALL)...5%), using inotuzumab in 1 patient...5%) consisted on fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 2 days...Our experience suggests the efficacy of its use as a bridge to consolidative HSCT. Nevertheless, a larger number of patients in the context of a clinical trial would be necessary.

This study aimed to investigate the efficacy and safety of Inotuzumab Ozogamicin (InO) combined with reduce dose R-GDP as a salvage therapy in patients with relapsed/refractory (R/R) B-NLH...All patients received Rituximab (R) 375mg/m 2 intravenously (IV) on day -1, and InO 0...Then Gemcitabine (G) 500-1000mg/m 2(IV), Dexamethasone (D) 40 mg/day (IV) on day 1-4 and Cisplatin (P) 40-75mg/m 2 (IV) on day 1 of each 21-day cycle (±2 days)... Seven patients with R/R B-NLH received 1-2 cycles of InO combined with reduce dose R-GDP therapy. Three patients did not respond to anti-CD19 and CD22 CAR-T cell therapy or their disease progressed again. The other four patients did not respond to more than 3 lines of combined immunochemotherapy and never achieved Partial response (PR) or CR.

B-ALL pt received Dasatinib, Inotuzumab and CNS prophylaxis. Preparative conditioning regimen for these 4 patients were: Fludarabine-Cyclophosphamide (n=1), with Rituximab (n=2) and Rituximab with Nivolumab (n=1)... Reinfusion of varnimcabtagene autoleucel (IMN-003A) is feasible, safe and well tolerated. Preparative conditioning regimen for reinfusion needs personalization guided by CAR persistence, disease biology (CD20, PDL1 expression) and haematological reserve. After reinfusion, prolonged B cell aplasia was observed with 100% ORR at D+28 in evaluable pts.

Background Clinical outcomes for B-cell Acute Lymphoblastic Leukemia (B-ALL) have significantly improved in the last decade, owing to the Introduction of newer agents such as inotuzumab ozogamicin (INO) and blinatumomab. Further work is needed to evaluate the role of CD58 as a predictive marker for other therapies in B-ALL. These data suggest that INO is likely to remain an effective option for these patients, regardless of the intensity of CD58 expression.

Recently, such pts have new hope with the wide application of a novel third-generation TKI Olverembatinib developed in China and Blinatumomab（CD19 antibody,BITE）and INOTUZUMAB OZOGAMICIN(CD22 antibody,Ino. For heavily treated RR ABL1+B ALL pts,including those after treatment with ponatinib and other TKICART and HSCT, Olverembatinib combined with monoclonal antibodies is effective and safe. In my cases, it is particularly noteworthy that one pts ,Ph like ALL with ABL1 FG, received Olverembatinib combination BITE and achieved a surprising response, so Olverembatinib may also be effective and safe for such pts. In addition, venetoclax may be used as a sensitizer for TKI or other antitumor drugs.

This would be because the PARP inhibitors were still effective in inhibiting the DNA repair in Reh-IO-R cells where the DNA repair function was not augmented. [Conclusion]The combination of IO with PARP inhibitors synergized the antileukemic effect of IO by inhibiting DNA strand break repair in CD22-positive ALL cell lines and IO-resistant ALL cells, suggesting that these results may contribute to overcoming the IO resistance mechanisms.

One regimen that is commonly used is a combination of targeted therapies along with reduced intensity chemotherapy (inotuzumab ozogamicin, rituximab (if CD20+), blinatumomab and mini hyper fractionated cyclophosphamide, vincristine, and dexamethasone [Mini-HCVD]), which has demonstrated both improvements in survival while reducing treatment related toxicity. This retrospective single institute study demonstrates that the clinical outcomes of Mini-HCVD plus immunotherapeutic agents in older adults with Ph- ALL are similar to modified BFM backbone with reduced incidence of toxicity. While limited by small numbers, these results suggest that reduced intensity chemotherapy in combination with novel targeted agents could represent a new standard of care regimen in this historically difficult to treat patient population.

The patients received a 7-day pre-treatment VCP regimen consisting of intravenous infusions of cyclophosphamide 800 mg/m 2 on day 1, vindesine 3 mg/m 2 on day 1, prednisone 1-2 mg/kg on days 1 to 7 (VCP regimen), followed by 28 days of treatment with blinatumomab at 5µg/m 2/day on the first 1 to 7 days and 15 µg/m 2/day on the next 8 to 28 days...Blinatumomab was administered to 5 patients in the induction remission period, and for 2 patients, blinatumomab was administered in consolidation after inotuzumab ozogamicin (INO)...Blinatumomab consolidation therapy was also effective in patients pretreated with INO. Blinatumomab consolidation after induction therapy could be a new and effective strategy for the treatment of patients with newly diagnosed B-ALL.

One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis...Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze)... The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

Eight patients had received an allogenic hematopoietic stem cell transplant (alloHSCT) and 6 patients had received inotuzumab, a CD22 antibody-drug conjugate, prior to blinatumomab salvage. These groups of patients however represent very-high risk groups with inferior survival outcomes. Novel treatments and better sequencing of treatments may improve outcomes of these patients.

While many therapies are under investigation including the addition of a tyrosine kinase inhibitor or ruxolitinib to conventional chemotherapy, a standardized and molecularly-based approach to treating patients with Ph-like ALL is not yet defined. There also remain questions about the efficacy of integrating inotuzumab ozogamicin or blinatumomab into first-line therapy for these patients...1 patient received Car T cell therapy with Brexucabtagene autoleucel following relapse after allogeneic stem cell transplant... We identified 9 patients who met inclusion criteria. All 9 patients self-identified as either ‘American Indian or Alaska Native’ or ‘Hispanic or Latino. ‘ The median age at diagnosis was 34 and the mean BMI at diagnosis was 34.

P4, N=39, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

The fludarabine, cyclophosphamide, and alemtuzumab (FCA) LD regimen was also shown to extend host lymphocyte suppression and improve UCART22 expansion versus fludarabine and cyclophosphamide (FC) alone (Boissel N, et al...Cytokine release syndrome (CRS) occurred in 2/3 (67%) pts, with one G1 that resolved without treatment and one G2 that resolved after tocilizumab x1...Pt 3 was refractory to treatment, however this pt received bridging therapy with dasatinib for his ABL2 fusion, and on Day -1, only 47% of the leukemic cells expressed CD22 (down from 88% at screening)... As of 01 July 2023, 3 pts were enrolled into the first UCART22 P2 cohort at DL2. Pt 1 is a 17yo female with B-ALL with a hypodiploid karyotype and a germline TP53 mutation whose disease had previously failed to respond to multiagent chemotherapy, blinatumomab (blina), inotuzumab (ino), venetoclax (ven), allogeneic hematopoietic stem cell transplantation (HSCT), and autologous CD19 CAR T-cell therapy (CAR19) x2. Pt 2 is a 68yo female with Ph-negative B-ALL who relapsed with CD19-low disease after multiagent chemotherapy, ino, and blina.

Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2)...One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab...Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%)...Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors