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H. Inaba and C.G. Mullighan
nucleotide levels as long as daily doses were administered at the same time of day.120
Central nervous system-directed therapy
Because of the high risk of late neurocognitive sequelae, endocrinopathy, and secondary cancers, cranial irradiation has been largely replaced by intrathecal chemotherapy, in addition to systemic chemotherapy that has CNS effects (e.g., dexamethasone, high-dose methotrexate, and asparaginase). In an international meta-analysis, cranial irradiation decreased the incidence of isolated CNS relapse in patients with overt CNS involvement at diagno- sis (CNS 3) but the cumulative incidences of any event and the OS were similar to those in patients who did not receive cranial irradiation.121
The St. Jude Total XVI study used intensified intrathecal therapy during induction therapy and obtained a remark- able reduction in 5-year cumulative isolated and combined CNS relapses to 1.3% and 1.5%, respectively, without cra- nial irradiation (Table 1).9 In addition to CNS 3 at diagno- sis, CNS 2 status (<5 WBC/mL and blasts) at diagnosis is associated with worse outcomes and greater risk of CNS relapse, and augmented intrathecal chemotherapy is required.122 Traumatic lumbar puncture at diagnosis can introduce circulating ALL blasts into the cerebrospinal fluid (CSF) and is also associated with worse outcomes. Delaying the first intrathecal therapy until circulating blasts had disappeared improved the control of CNS dis- ease.123
Acute lymphoblastic leukemia blasts are typically detected in CSF by morphologic evaluation of cytospin samples. Flow cytometric analysis of CSF improved ALL blast detection, and positive results were associated with a higher incidence of any relapse,124 although another study failed to show such an association.125
Molecularly targeted agents
With the increased understanding of genetic alterations in ALL, approaches targeting the driving genetic mutation and/or the associated signaling pathway are emerging (Table 2). Such an approach is attractive as it can augment or replace conventional chemotherapy with fewer off-tar- get effects. In pediatric Ph-positive ALL, adding an ABL1 tyrosine kinase inhibitor, imatinib mesylate (340 mg/m2/day), to intensive post-induction chemotherapy resulted in outcomes similar to those in patients who received HCT.126 Newer generations of tyrosine kinase inhibitors are available, and a randomized study showed that pediatric patients who received chemotherapy with 80 mg/m2/day of dasatinib, a dual ABL/SRC inhibitor with more potent activity against BCR-ABL1 and better CNS penetration than imatinib, had better EFS, OS, and CNS disease control when compared to patients who received imatinib (300 mg/m2/day).127 Ponatinib has potent activity in both wild-type and mutant BCR-ABL1 ALL, including cells harboring the gatekeeper ABL1 T315I mutation. Combination chemotherapy with ponatinib and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternat- ing with high-dose methotrexate and cytarabine resulted in excellent 2-year EFS in adults with newly diagnosed Ph-positive ALL.128 Because of the potential adverse effects, such as thrombosis and pancreatitis, the safety of ponatinib in combination with pediatric regimens should be evaluated.
For patients with Ph-like ALL and ABL-class gene fusions (ABL1, ABL2, CSF1R, LYN, PDGFRA, or PDGFRB), ABL1 inhibitors can be combined with chemotherapy.129,130 For those patients with alterations that activate the JAK- STAT signaling pathway, such as rearrangements or a mutation of CRLF2 (IGH-CRLF2, P2RY8-CRLF2, or CRLF2 F232C), rearrangements of JAK2, EPOR, or TYK2, or mutations/deletions of IL7R, SH2B3, JAK1, JAK3, TYK2, or IL2RB, clinical trials of a JAK inhibitor, ruxolitinib, are ongoing.
Venetoclax inhibits the anti-apoptotic regulator BCL-2. Deregulated cell death pathways contribute to treatment failure in ALL.131 Preclinical studies have identified activi- ties of venetoclax against high-risk leukemias such as ETP ALL, KMT2A-rearranged ALL, TCF3-HLF-positive ALL, and hypodiploid ALL (Table 2).132,133 Proteasome and mTOR inhibitors have shown efficacy in relapsed ALL.134,135 DOT1L, bromodomain, menin, and histone deacetylate inhibitors have shown promise in preclinical studies as therapies targeting unique molecular character- istics of KMT2A-rearranged ALL.136
Immunotherapy
Immunotherapy can be given as antibody-based thera- py (e.g., blinatumomab or inotuzumab ozogamicin) or T- cell-based therapy (chimeric antigen receptor T [CAR T] cells, e.g., tisagenlecleucel), which have improved the response rate and outcomes in patients with relapsed/refractory B-ALL (Figure 4).137 Antibodies (e.g., daratumumab directed against CD38) and CAR T cells (e.g., targeting CD1a, CD5, and CD7) against T-ALL are also under investigation.
Blinatumomab has two different single-chain Fv frag- ments: one binds the CD3 antigen and activates T-cell cyto- toxicity, and the other binds the B-cell antigen CD19, which is expressed on most B-ALL cells.138-140 In a randomized study of adults with refractory/relapsed B-ALL, patients who received blinatumomab had a better complete remission rate and survival than those who received the standard-of- care chemotherapy,138 and blinatumomab was effective in eradicating MRD.139 Patients aged 1-30 years with interme- diate- or high-risk relapsed B-ALL were randomized to receive either two blocks of intensive chemotherapy or two 4-week blocks of blinatumomab after receiving re-induction chemotherapy.140 The blinatumomab arm had better 2-year DFS, OS, and MRD clearance and lower incidences of febrile neutropenia, infection, and sepsis when compared with the chemotherapy arm. Cytokine release syndrome and neuro- toxicity are adverse effects of blinatumomab, and their inci- dence and severity can be reduced by decreasing the disease burden before treatment.
Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin.141-143 A randomized study in adults with refractory/relapsed B- ALL showed that patients who received inotuzumab had a better remission rate and survival than did patients who received standard chemotherapy.141 In a pediatric ino- tuzumab compassionate-use program, complete remis- sion was seen in 67% of 51 children with relapsed/refrac- tory ALL.142 Inotuzumab is associated with sinusoidal obstruction syndrome, especially after HCT.141-143 Fractionated use of low-dose inotuzumab and a longer interval between inotuzumab treatment and HCT can reduce the incidence of this syndrome.
Chimeric antigen receptor T cells express a synthetic
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haematologica | 2020; 105(11)