Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Amy Y. Wang, MD, MPH; Lori S. Muffly, MD, MS; Wendy Stock, MD

Disclosures

J Oncol Pract. 2020;16(5):231-238. 

In This Article

Treatment of Relapsed Disease

Antibody-based and cellular therapies have become a new standard in the treatment of relapsed and/or refractory (R/R) B-cell ALL, greatly bolstering the armamentarium of therapeutic options. Current immunotherapies specifically target cell surface antigens CD19, CD20, and CD22, which are expressed at a high level in pre-B ALL blast cells.[36] The antibody-based agents blinatumomab and IO can serve as effective bridges to hematopoietic cell transplantation (HCT), whereas the role of chimeric antigen receptor (CAR) T-cell therapy in relation to HCT remains less well defined.

Antibody-based Therapies

Blinatumomab has demonstrated remarkable efficacy in clinical trials. In addition to being approved by the FDA for MRD-positive disease as discussed above, blinatumomab is also approved for use in the R/R setting. The FDA approval was based on results from the international phase III TOWER study in 405 patients with R/R Ph-negative ALL comparing blinatumomab versus standard salvage chemotherapy. The study reported superior remission rates (45% v 25%, respectively; P < .001) and median OS of 7.7 versus 4.0 months, respectively (hazard ratio [HR], 0.71; P = .01).[37] Remission rates were comparable among the age 18 to 35 years subgroup. The most notable toxicities of blinatumomab are cytokine release syndrome and neurologic changes. The risk of cytokine release syndrome is higher with greater tumor burden, but this can be mitigated through several approaches, including administering a lower dose of blinatumomab during the first week, pretreatment with steroids, lowering the disease burden before treatment, and holding additional doses or administering tocilizumab when symptoms arise.[38]

FDA approval of IO for R/R B-cell ALL was based on the pivotal phase III INOVATE trial comparing IO versus standard salvage chemotherapy in 326 patients with R/R ALL. This study demonstrated a significantly higher remission rate (80.7% v 29.4%; P < .001), longer progression-free survival of 5.0 versus 1.8 months (HR, 0.45; P < .001), and longer OS of 7.7 versus 6.7 months (HR, 0.77; P = .04) with IO.[39] Veno-occlusive disease was a unique adverse event that occurred in 11% of IO-treated patients, as compared with 1% of patients treated with standard therapy.[39]

Chimeric Antigen Receptor T-cell Therapy

The development of cell-based therapies has become an exciting and intense area of research across multiple hematologic malignancies. Tisagenlecleucel was the first CAR T-cell targeting CD19 approved by the FDA for the treatment of R/R B-cell ALL in patients up to age 25 years. Approval of this agent was based on the phase II ELIANA trial of pediatric and young adult patients with CD19+ R/R B-cell ALL, which reported on survival outcomes of 75 patients receiving CAR-T cell infusion. In the seminal publication, the overall remission rate for patients receiving the CAR-T infusion was 81% (95% CI, 71% to 89%); 95% of those in remission were MRD negative by 28 days post–CAR-T. Six-month EFS and OS were 73% and 90%, respectively.[40] Cytokine release syndrome and neurotoxicity were common adverse events, occurring in 77% and 40% of patients, respectively; grade 3 or 4 cytokine release syndrome occurred in 45%, grade 3 neurotoxicity occurred in 13%, and there were no cases of grade 4 neurotoxicity.[40] Notably, the risk of severe cytokine release syndrome and neurotoxic effects was increased with a higher disease burden.[41]

CAR T cells are a potent therapy with the potential for durable remission, but several issues are worth noting. The complexities and length of time required for CAR T-cell manufacturing, the cost, the toxicity profile, and the need for an experienced treatment team are factors to consider when selecting therapy in the R/R setting.[10,38,42] Relative to CAR T-cell therapy, the antibody agents blinatumomab and IO may be limited by shorter duration of response and survival outcomes, and currently HCT remains necessary for curative-intent treatment in the relapsed setting.[38] However, the role of allogeneic HCT has come under question in the CAR T-cell era. Long-term persistence of CAR T cells has been noted in some patients, mitigating the need for immediate HCT.[40,42] Moreover, in a smaller analysis of adult patients with ALL undergoing CD19-directed CAR T-cell therapy at a single institution, Park et al[41] found no significant survival benefit associated with HCT after CAR T-cell therapy, so the question of whether HCT can be avoided in certain patients remains an area of debate. More recent data do suggest a role for consolidative HCT after CAR T-cell therapy in patients with a short duration of B-cell aplasia (≤ 63 days), which is associated with increased risk of relapse.[43] Last, surface antigen loss or downregulation of either CD19 or CD22 is a major mechanism of resistance and relapse for both antibody-based and CAR T-cell therapy, and novel bicistronic CD19/CD22 CARs have been developed in response.[44] Early results of a phase I study using CD19/CD22 CAR T cells in four pediatric patients with R/R ALL demonstrated safety and tolerability of the bispecific CAR as well as 100% remission rate with 75% MRD negativity.[45] Through better management of toxicities and greater understanding of the mechanisms behind CAR T-cell persistence and antigen loss, the next generation of therapies will include safer and more durable CAR T cells that will allow this strategy to be moved earlier into the course of ALL treatment.

HCT

The optimal use of HCT continues to evolve with improving diagnostics, more precise prognostication, and more effective nontransplantation therapies. In 2019, HCT remains an important modality in curing Ph-negative ALL and is currently offered to patients in their second complete remission and beyond. The role of HCT in first remission (CR1) in young adult ALL is evolving. Although the international ECOG E2993 randomized trial demonstrated a clear survival benefit associated with consolidative allogeneic HCT for young adults with standard-risk ALL in CR1,[46,47] this study was conducted using a standard adult front-line ALL regimen and in an era where MRD was not routinely assessed and HCT was only offered to patients with matched donors. More recent retrospective data suggest that the use of a pediatric-inspired ALL regimen confers an overall survival benefit over HCT in CR1.[48] Results of the C10403 study provided preliminary prospective evidence in support of this non-HCT approach, reporting superior DFS and OS, despite only performing transplantation in 7.6% (20 of 263) of high-risk patients in CR1.[21] Currently, HCT is most commonly considered in AYAs in first remission with low-level MRD (typically after 10 to 16 weeks of intensive multi-agent chemotherapy) as well as those with high-risk biologic features, such as early T-cell precursor ALL or certain subsets of Ph-like ALL. AYAs without high-risk features who are in MRD-negative remission should receive consolidative pediatric-inspired chemotherapy. As mentioned earlier, recent reports of durable remissions after CAR T cells[42,49] have called into question whether cure may be obtained after ALL relapse without allogeneic HCT, and clinical trials are planned to test this hypothesis.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....