Rituximab Does Not Improve EFS Over Standard Chemotherapy as Treatment of ALL

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.


  1. Marks DI, Kirkwood AA, Rowntree CJ, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukemia (UKALL14): a phase 3, multicentre, randomized controlled trial. Lancet Haematol. 2022;9(4):e262-e275. doi:10.1016/S2352-3026(22)00038-2
  2. Standard Chemotherapy With or Without Nelarabine or Rituximab in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia (UKALL14). Clinicaltrials.gov. Accessed April 12, 2022. https://clinicaltrials.gov/ct2/show/NCT01085617
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