*4.2.14 Liposomal drug formulations*

*Advances in Hematologic Malignancies*

*4.2.12 Inotuzumab ozogamicin (InO)*

CD22+ B ALL [170].

InO is a monoclonal antibody against CD22 and conjugated to calicheamicin, a potent cytotoxic compound which binds to the DNA in the leukemic blasts, resulting in double-stranded DNA breaks and cell death via apoptosis [165]. It was FDA approved in August, 2017 for use in r/r ALL. In a phase II study in r/r ALL in the age group of 6–80 years, Kantarijian et al. demonstrated ORR of 57% with median OS of 6.7 months [166]. In phase III INO-VATE trial in relapsed adult B ALL, single agent InO showed superior outcome compared to standard chemotherapy with CR (81%) and 1-year OS (78%) [167] However, its use in pediatric population continues in development. A retrospective French study in children <18 years with r/r B-ALL showed promising results (CR 72%), with hepatic and hematologic toxicities [168]. Bhojwani et al. in r/r pediatric ALL showed high CR rate (67%) with MRD negativity, independent of cytogenetic subtype or prior lines of therapy [169]. The AALL1621 phase II randomized trial in the age group 1-21 years is evaluating the role of InO in children and young adults with r/r

*4.2.13 CAR T-cell therapy: the new driving force for relapsed ALL*

transplant, with a potential to ultimately replace SCT.

Relapsed or refractory ALL is one of the leading causes of childhood cancer mortality. Refractory ALL in particular has a dismal prognosis with significant chemotherapy resistance in the leukemic clone. The advent of CAR T-cell therapy has brought a paradigm shift in the management of children with highly resistant disease. Rosenberg et al. at the NCI pioneered the CAR T-cell therapy and demonstrated successful treatment of cancer using CAR T-cells. This attractive therapy harnesses the immune system of the host to eradicate the leukemic clone. Adoptive T-cell therapy involves engineering T-cell receptors (TCRs) to bind to specific antigens present on tumor cells. These modified TCRs, known as CARs, allow the immune system to specifically target and destroy tumor cells in an MHC independent manner, bypassing the immune escape mechanisms of downregulation of MHC class I antigens and altered antigen processing by tumor cells [171]. These modified T cells have the capacity to expand and proliferate in the host, produce cytokines to kill tumor cells, as well as cross blood-brain barrier as shown by Maude et al. [172]. Early results from ongoing trials have shown promising and durable responses. Current complete remission rate of 90% have been reported as per the CHP959 phase I study [172]. The ELIANA [173] and ENSIGN [174] trials in r/r B ALL showed high CR rates of 90%, significantly higher than salvage rates of 30% attained with chemotherapy [26, 175]. This led to the FDA approval of CD19 4-1BB CAR T-cell therapy in August 2017 for children and young adults up to the age of 25 years. Maude et al. showed durable remission and survival in children treated with CD19 CAR T cell therapy with EFS (50%) and OS (76%) at 12 months of follow-up [176]. Success from pediatric CAR T-cell therapy trials is driving research programs across ages and disease types worldwide. The advantage of this therapy is that it can be offered to patients who are ineligible for transplant or have relapsed post-

Tumor lysis syndrome, cytokine release syndrome and neurotoxicity are known complications of this therapy [177]. Another off-target toxicity is the development of B-cell aplasia, a surrogate for CAR T-cell persistence, results in agammaglobulinemia, and requires long-term immunoglobulin replacement [172]. With the use of CD19 directed CART cells, there is a risk of CD19 negative relapse [177]. Trials are underway to study the efficacy of CD22 CART cells as well as the use of dual CARS

**42**

(CD19 + CD22).

The outcomes for pediatric ALL have significantly improved over the past five decades, and the focus is now on minimizing the toxicity and the late effects of chemotherapy. Liposomal doxorubicin has shown remarkably low non-hematological toxicity, although the infection rates may be significant due to severe myelosuppression [178, 179]. In an attempt to decrease the toxicity of therapy, TACL 2012-002 trial is testing the use of liposomal vincristine in children and AYA with relapsed ALL [180]. This study attempts to study the feasibility and safety of liposomal formulation of vincristine sulphate over standard vincristine in first, second or third relapse of B or T ALL.
