A tango of antibody and inhibitor

In this issue of Blood, Kirchhoff et al provide in vivo evidence that the combination of inotuzumab ozogamicin, dexamethasone, and the BCL2 inhibitor venetoclax is synergistic in inducing apoptosis in primary acute lymphoblastic leukemia (ALL) samples.¹ 

Importantly, in 3 murine patient-derived xenografts, there was disease eradication and long-term leukemia-free survival (LFS), which was not achieved with inotuzumab ozogamicin or venetoclax-dexamethasone alone. Of note, 2 xenografts were derived from patients with different chimeric Transcription factor 3 (TCF3) fusions, including t(17;19)(q22;p13)/TCF3-HLF, which is usually felt to make ALL incurable with standard chemotherapy.²  One of 5 mice with this fusion gene had long-term LFS with the triple combination of drugs. Recent data suggest that ALL patients with this specific fusion may respond to blinatumomab, and sensitivity to venetoclax has also been reported.^3,4 

The availability of novel antibodies for treating ALL is a major breakthrough. For decades, treatment advances consisted of implementing risk group stratification based on minimal residual disease and risk-adapted treatment. Children benefitted to a greater extent than adults from this approach, and prognosis still declines with increasing age. Younger adults often benefit from pediatric-inspired protocols, but outcomes in elderly ALL patients remain poor.

Rituximab was the first antibody to show a benefit in adult CD20⁺ ALL when added to chemotherapy.⁵  Blinatumomab, a bispecifc T-cell–engaging antibody, is mainly effective in eradicating minimal residual disease in CD19⁺ disease, whereas inotuzumab ozogamicin (an anti-CD22–directed antibody drug conjugate) is able to induce remissions in heavily pretreated CD22⁺ patients and in patients with high tumor load. Both drugs were superior to standard-of-care chemotherapy in the high-risk adults included in the clinical trials. Recent randomized pediatric studies showed that blinatumomab consolidation was superior to chemotherapy in the first relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and high remission rates were reported with inotuzumab ozogamicin in pediatric patients with multiply relapsed BCP-ALL.^6,7 

Inotuzumab ozogamicin has been studied in combination with regular chemotherapy in adults, for example, in mini-hyper cyclophosphamide, vincristine, and dexamethasone (CVD) courses (at reduced dosages).⁸  The next step by the MD Anderson Cancer Center group was adding blinatumomab for a total of 8 courses as consolidation and maintenance therapy. Of interest, treatment-related mortality outweighed leukemia relapse with this combined antibody-chemotherapy approach. Thus, the number of inotuzumab ozogamicin-chemotherapy cycles and the inotuzumab ozogamicin cumulative dose (to 2.7 mg/m² given as fractionated doses) were reduced.⁹  By using this approach, the survival in elderly patients with ALL has now increased to 50% at 4 years. The goal is to eliminate or reduce chemotherapy as much as possible for the oldest and most frail patients. This combination was also evaluated at relapse, resulting in a 3-year overall survival rate of 33%, which compares favorably to data from inotuzumab ozogamicin single-agent therapy.

The ongoing ITCC-059 study in children is assessing the combination of inotuzumab ozogamicin with the UK ALLR3 relapsed ALL protocol reinduction chemotherapy block as a substitute for mitoxantrone as a safe combination that can be used as reinduction therapy at first relapse.⁷  In addition, inotuzumab ozogamicin and blinatumomab have been introduced in protocols for newly diagnosed BCP-ALL, mainly as single-agent blocks in consolidation. Reducing long-term adverse effects in children with ALL is an important goal, given the current high cure rates. However, the long-term adverse effects of these new treatment options have not yet been characterized and will require careful follow-up. Moreover, their potential impact on the outcome of chimeric antigen receptor T-cell therapy as potentially definitive therapy replacing stem-cell transplantation needs to be determined. Ultimately, short- and long-term toxicity need to be minimized while retaining efficacy.

Another important consideration is the activity of the new antibody regimens in ALL patients with high-risk genetic abnormalities. KMT2A-rearranged ALL often has low CD22 expression and may be less responsive to inotuzumab ozogamicin. A study in infant KMT2A-rearranged ALL with blinatumomab is ongoing (NL5993 trial). Adult patients with relapsed ALL with low hyperdiploidy and/or TP53-mutant ALL had disappointing response rates with the dual antibody-chemotherapy approach, as mentioned above. Foà et al¹⁰  recently reported their short-term experience with blinatumomab and dasatinib in adult Philadelphia chromosome–positive ALL, a regimen being developed as a chemotherapy-free induction/consolidation regimen. Venetoclax has so far been tested only in a limited number of B-cell ALL patients, and most of the initial development has been in T-cell ALL patients. However, there is also evidence that venetoclax may be of benefit in various subsets of high-risk cytogenetic BCP-ALL, as recently reviewed by Pui.² 

Therefore, combining venetoclax-dexamethasone with antibody therapy seems warranted to help develop combinations that may be active in specific subsets of patients with poor-risk characteristics. The study by Kirchhoff et al provides further rationale which can be rapidly explored in an early-phase clinical trial. Broader screening of genetic subsets may provide more information regarding which subsets might benefit most. Moreover, the role of steroids in this triple combination needs to be further clarified, because it was not addressed specifically by the authors.