The UKALL14 misses the primary end point of improvement in event-free survival in patients with acute lymphoblastic leukemia.
Standard of care plus 4 doses of rituximab (Rituxan) did not significantly improve event-free survival (EFS) over standard of care for treatment of patients with acute lymphoblastic leukemia (ALL), missing the primary end point of the phase 3 UKALL14 study (NCT01085617).1
Although the 3-year EFS with the addition of rituximab to standard chemotherapy was not significant, UKALL14 showed that the combination was safe, even in patients for whom allogeneic hematopoietic stem-cell transplantation was a subsequent therapy. Moreover, risk of relapse and non-relapse mortality were reduced with the addition of rituximab and there was no apparent difference in graft-versus-host disease rates between the rituximab combination and chemotherapy-alone arms.
UKALL14 is randomized phase 3 study, which examined the standard chemotherapy to see how well it worked when given with or without rituximab and with or without nelarabine in patients with newly-diagnosed ALL.
“Four doses of rituximab added to standard-of-care chemotherapy during induction treatment for all adults aged 25-65 years, regardless of CD20 expression or BCR-ABL1 status, gave an event-free survival HR of 0.85 [95% CI, 0.69-1.06], which was greater than the 0.71 the study was powered to detect and hence did not meet the primary end point,” wrote the study authors led by David I Marks, MBBS, PhD FRCPath of Department of Hematology at University Hospitals Bristol and Amy A Kirkwood, MSc, Cancer Research UK & UCL Cancer Trials Center, University College London.
The randomized UKALL14 trial examined patients aged 25-65 years of age with newly diagnosed and previously untreated de-novo BCR-ABL1-negative ALL who had a pre-phase treatment of 5-7 days prior to registration. Patients with de-novo BCR-ABL1-positive ALL were eligible if they were aged 19-65 years.2
Other requirements included having HLA-compatible sibling or unrelated donor, having no blast transformation of chronic myeloid leukemia, no mature B-cell leukemia, and no known HIV infection.
Participants were randomly assigned 1:1 to standard-of-care induction therapy or standard-of-care induction therapy plus 4 doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Further, randomization used minimization and was stratified by sex, age, and white blood cell count.
A total of 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n = 294). Nine patients were excluded from the final analysis due to misdiagnosis including 4 in the standard-of-care arm and 5 in the standard-of-care plus rituximab arm.
The primary end point of the trial was EFS and safety was assessed within all participants who started trial treatment. Secondary end points consisted of anti-asparaginase antibodies in patients treated with monoclonal antibody therapy, overall survival (OS), complete remission (CR) rate, relapse rate, death in CR, toxicity, minimal-residual disease quantification after first phase of induction and post transplantation, and mucositis score in patients treated with palifermin.
Within the standard-of-care group, the median age was 45 years, 55% of participants were male (n = 159), 44% were female (n = 128), and 1 was intersex. There were 143 (59%) of 244 participants who had high-risk cytogenetics. In the standard-of-care plus rituximab group, the median age was 46 years with 55% of the participants being male (n = 159), 45% female (n = 130), and 140 (60%) of 235 participants having high-risk cytogenetics.
Findings revealed that after a median follow-up of 53.7 months, the 3-year EFS was 43.7% (95% CI, 37.8 – 49.5) for standard-of-care versus 51.4% (45.4-57.1) for standard-of-care plus rituximab (HR, 0.85; 95% CI 0.69-1.06; P =0.14).
In regard to safety, the most common adverse events (AEs) were infections and cytopenias. There were no differences in the rates of AEs between each group. Grade 5 AEs were fatal in 11 (4%) patients in induction phases 1 and 2 within the standard-of-care group and in 13 (5%) patients in the standard-of-care plus rituximab group. Further, 3-year non-relapse mortality was 23.7% (95% CI, 19.0 -29.4) in the standard-of-care group versus 20.6% (16.2- 25.9) in the standard-of-care plus rituximab group (HR, 0.88; 95% CI, 0.62-1.26; P =0.49).
“The UKALL14 B-cell randomization in which 4 doses of rituximab were added to standard of care did not show a statistically significant improvement in event-free survival. The full benefit of rituximab in patients with acute lymphoblastic leukemia is likely to require more prolonged administration of rituximab, as demonstrated by the GRAALL [NCT00327678] randomized controlled trial,” wrote Marks et al.