ALL treatment: Current settings, future goals
Significant advancements in the treatment of acute lymphocytic leukaemia (ALL) in children have improved their outcomes. However, ALL treatment and eradication remain a major challenge in adults. In a recent webinar, two specialists from the US discussed current ALL treatment strategies and goals of future regimens.
Immunotherapy in ALL: A leap forward
Multiple discoveries in the past decade have reshaped ALL treatment, said Professor Elias Jabbour from the MD Anderson Cancer Center (MDACC) in Houston, Texas, US. These included the CD22 monoclonal antibody inotuzumab and CD19 bispecific antibody blinatumomab, the eradication of minimal residual disease (MRD), and chimeric antigen receptor (CAR) T-cell therapy.
In Burkitt leukaemia for instance, adding rituximab to chemotherapy increased the 3–4-year survival rate from about 50 percent to 77–79 percent, said Jabbour. A randomized trial demonstrated significant improvements in event-free survival (EFS) and overall survival (OS) with the addition of rituximab to chemotherapy vs chemotherapy alone (p=0.046 and p=0.024, respectively). [Blood 2012;120:685]
Adding ofatumumab to hyper-CVAD* produced an overall response rate (ORR) of 98 percent and a 4-year OS rate of 68 percent which appeared better in patients aged 18–39 years (74 percent). [Lancet Haematol 2020;7:e523-e533]
In the TOWER trial, blinatumomab in relapsed/refractory (R/R)-ALL improved survival (HR, 0.71; p=0.01 vs chemotherapy) and complete response (CR) with full, partial, or incomplete haematologic recovery (44 percent vs 25 percent; p<0.001). [N Engl J Med 2017;376:836-847] Likewise, the INO-VATE ALL trial improved CR (80.7 percent vs 29.4 percent [chemotherapy]; p<0.001) and OS outcomes (HR, 0.77; p=0.04). [N Engl J Med 2016;375:740-753]
Importance of early MRD eradication
Regardless of treatment regimen, a major factor driving survival is early elimination of MRD, said Jabbour.
A study of 214 hyper-CVAD-treated patients showed that those who achieved MRD-negativity at CR had better 5-year EFS and OS rates (56 and 68 percent, respectively) than MRD-positive patients (≤0.1 percent; 31 and 46 percent, respectively). Similarly, a 307-patient study showed 5-year OS rates of 38 and 55 percent among those who did and did not undergo transplant, respectively, which was even higher (90 percent) in patients with MRD <0.01 at mid-consolidation CR.
A small study (n=34) of hyper-CVAD and blinatumomab-treated patients demonstrated overall MRD-negativity and CR rates of 97 and 87 percent, respectively, with a 2-year OS rate of 86 percent. “We are hopeful that this type of regimen will allow us to deliver less chemotherapy, less need for transplant, and eradicate MRD-positivity,” Jabbour said.
“Transplant does not negate the impact of MRD, and it does not improve the outcome to the level seen in patients who are MRD-negative. Therefore, we must eradicate MRD before transplant,” he pointed out.
Tackling ALL in the elderly
According to Jabbour, survival outcomes are worse in elderly patients, with OS ranging from a median 15 months as per MDACC data to 4–10 months as per SEER** and Medicare data.
A study of 70 older patients (27 aged ≥70 years) treated with mini-HCVD*** and inotuzumab with or without blinatumomab showed a 98 percent response rate, with only one non-responder. There were no early deaths. MRD-negativity was 96 percent overall and 80 percent at day 21. These findings speak to the potency of inotuzumab and blinatumomab, said Jabbour.
Three-year OS was 56 percent (median 45 months) overall, with patients aged 60–69 years having better OS than those aged >70 years (65 percent vs 44 percent [median not reached vs 34 months]; p=0.06).
Improving outcomes remains a goal in the treatment of elderly patients. An important question is the necessity of chemotherapy, which has led to explorations of chemotherapy-free regimens (eg, inotuzumab plus blinatumomab), said Jabbour.
Allogeneic stem cell transplant (SCT) may also not always be necessary. Allogeneic SCT used to be standard of care (SoC) for MRD-positive disease which is now managed with blinatumomab-inotuzumab, he noted.
The role of CAR T-cell therapy
Despite effective immunotherapies such as blinatumomab and inotuzumab, median OS in the relapse setting is about 8 months, said Dr Jae H Park, director of the Adult ALL Leukemia Program at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, US.
Many patients on these treatments may still require transplant. Therefore, there is incentive to develop more effective therapies, he said. “One single infusion of CAR T-cells may be able to achieve a long, durable remission, and hopefully a cure in patients with ALL.”
The phase II ELIANA study, the most advanced to date, assessed a single dose of the CD19-directed CAR T-cell immunotherapy tisagenlecleucel in 92 children and young adults (age 3–21 years) with R/R B-ALL who had undergone lymphodepletion with fludarabine and cyclophosphamide. Three-month ORR was 81 percent, OS was 90 and 76 percent at 6 and 12 months, respectively, and EFS 73 and 50 percent, respectively. [N Engl J Med 2018;378:439-448]
Despite potential early relapse, most remissions were durable beyond 10 months, said Park. “[A]bout 50 percent … are able to get durable remissions [and] very few [about 10 percent] … proceeded to bone marrow transplant after receiving CAR T-cell therapy.” These findings led to FDA approval of tisagenlecleucel in patients aged ≤25 years with R/R B-ALL.
An MSKCC study of 52 CAR-T–treated adults showed that overall CR was 84.6 percent, with an MRD-CR rate of 66.6 percent. However, survival was inferior to that of the paediatric population, with most patients experiencing relapse, said Park.
According to Park, low disease burden appears to predict better long-term outcomes and a lower relapse rate following CAR-T therapy in adults. Targeting multiple pathways may also help reduce relapse risk. The need for bone marrow transplant after CAR T-cell therapy should be approached on a case-by-case basis.
Where are we headed?
In the US, patients with first relapse following induction, consolidation, or maintenance chemotherapy currently receive blinatumomab or inotuzumab as SoC, with CAR-T therapy administered after another relapse. In the future, we hope that CAR-T therapy can be introduced earlier in the treatment setting, said Park.
Future ALL treatment would be inotuzumab-blinatumomab followed by CAR-T therapy, with CAR-T therapy replacing allogeneic transplant, said Jabbour. The optimal regimen would involve less chemotherapy or a more targeted approach such as with subcutaneous blinatumomab. However, the removal of chemotherapy raises questions on the need for more central nervous system prophylaxis. The optimal number of blinatumomab courses also needs to be established, he said.
“It is plausible that incorporating active monoclonal antibodies/CAR T-cell therapy into frontline adult ALL therapy, in a concomitant or sequential fashion, may induce higher rates of MRD-negativity and increase cure rates to levels achieved in paediatric ALL. [This] may reduce the need for allogeneic SCT and intensive and prolonged chemotherapy schedules,” Jabbour said. “The future of ALL is being reshaped today and will hopefully cure adult ALL,” he concluded.