Rituximab Offers No Extra Benefit to Induction Chemo in ALL

Liam Davenport

May 08, 2020

Adding the anti-CD20 monoclonal antibody rituximab (various brands) to induction chemotherapy in patients with B-precursor acute lymphoblastic leukaemia (B-ALL) does not improve outcomes, UK researchers have found in a primary analysis of phase 3 trial data.

However, a separate examination of findings from the same study may nevertheless point to an update to the genetic classification for the disease that could help in creating an overall combined clinical and genetic risk score.

The research was published as an abstract from the British Society for Haematology 60th Annual Scientific Meeting, which was cancelled due to the COVID-19 pandemic.

Trial Details

UKALL14 involved patients with B-ALL aged 25–65 years, regardless of Philadelphia chromosome (Ph) status or CD20 expression, who were randomised to standard induction chemotherapy (SOC) with or without 4 doses of rituximab (SOC+R).

Focusing on patients recruited after an amendment to the SOC regimen in April 2012, the team conducted an intention-to-treat analysis in 288 SOC patients and 289 given SOC+R, of whom 95.5% received all 4 doses of the immunotherapy.

Adele Fielding, professor of haematology at University College London Cancer Institute, London, and colleagues report that complete remission rates, at 92.7% with SOC and 94.8% with SOC+R, were similar in the two treatment arms.

There was also no difference in minimal residual disease (MRD) rates, with 42.2% and 41.8%, respectively, negative for residual disease.

Adverse, including severe, event rates were similar between the two cohorts, and there was no difference in non-relapse mortality.

After a median follow-up of 50.5 months, the researchers calculate that the 3-year event-free survival (EFS) for patients given SOC was 41.9% versus 48.7% for those receiving SOC+R, at a hazard ratio of 0.88 (p=0.28).

Contrast With French Study

This contrasts with the French GRAALL-2005/R study, in which adults aged 18–59 years with CD20-positive, Ph–negative ALL were randomised to chemotherapy with or without rituximab, with a total of 16 to 18 infusions given across all treatment phases.

Their results indicated that adding rituximab to the ALL chemotherapy protocol improved outcomes, increasing EFS by 33% versus chemotherapy alone (p=0.04).

Prof Fielding told Medscape News UK that, for UKALL14, they had "hypothesised that giving rituximab early would make the difference, namely in helping to eliminate MRD early on".

"We were anxious not to give too much in case of toxicity from infections. It turned out that it is not toxic and doesn’t seem to work to eliminate MRD early on."

She added that, in fact, "the French data showed that too," which prompts her to wonder at the mechanism of action of rituximab in B-ALL.

"Maybe you need more doses at times when patients have functional neutrophils or macrophages, or natural killer cells."

Prof Fielding also pointed out that, in the French study, they focused on patients with Ph-negative disease and in those in whom more than 20% of blasts expressed CD20.

"An important finding from our work…is that the level of CD20 expression does not correlate with response to rituximab."

'Interesting Research'

Approached for comment, Rachel Kahn, research communications manager at Blood Cancer UK, said that, "the immunotherapy drug rituximab remains a vital treatment for many types of blood cancer".

She told Medscape News UK, however, that "this interesting research suggests that there may not be any additional benefit of taking this drug for people with ALL".

She highlighted that the results nevertheless suggested that patients who underwent myeloablative allogeneic stem cell transplant (MAallaSCT) appeared to derive a significant benefit from adding rituximab to SOC.

Three-year EFS was 50.7% among MAallaSCT patients given SOC alone versus 72.2% in those receiving SOC+R, at a hazard ratio of 0.47 (p=0.03), which was related to a reduction in relapse risk.

This effect was not seen in patients given reduced intensity allogeneic stem cell transplantation or in maintenance groups, prompting Rachel Kahn to call for further research to identify which patients with ALL "may benefit from taking rituximab".

Prof Fielding said that, as they "do not have any plausible biological explanation" for the finding, the team is "going to be cautious about interpreting" it.

Overall, she feels that, as rituximab is "safe, it’s probably better to give it to everyone", as "our ability to do that is greater than our ability to do proper flow cytometry in local centres to accurately quantify CD20".

'Chromosomal Abnormalities'

In a separate analysis, Prof Fielding and colleagues looked at all 653 patients who started treatment both before and after the SOC regimen amendment, of whom 49% were found to have high-risk chromosomal abnormalities.

These included 31% with BCR-ABL1, 8% with KMT2A-AFF1, 9% with HoL and 5% with CK abnormalities.

CK and HoL patients had lower 3-year overall survival than the overall cohort, at 24% and 19%, respectively, versus 52%, while patients with KMT2A-AFF1 fusion had an overall survival of 44% and BCR-ABL1 patients had a similar survival to the overall group.

The team also identified a series of other chromosomal abnormalities, including 1.3% with ABL-class fusions and the same proportion with JAK-STAT abnormalities, the latter had reduced 3-year overall survival, at 35%.

In contrast, among the 3% of patients with ZNF384 fusions, only two relapsed and none died.

Having found that secondary copy number alterations affecting key genes had no impact on outcomes, the team proposed "an amendment to the genetic risk classification for adult ALL", consisting of:

  1. very high risk: CK, HoL or JAK-STAT abnormalities

  2. high risk: all KMT2A fusions

  3. tyrosine kinase sensitive: BCR-ABL1 and ABL-class fusions

  4. low-risk: ZNF384 fusions

  5. standard risk: all other patients

The team writes: "The integration of these primary genetic risk factors with other risk factors such as age, white cell count and MRD into an overall risk score is a key goal of our current work."

Prof Fielding said that the "immediate goal" of the team is "evaluating an overall risk score in our next trial, UKALL15, which has been submitted to Cancer Research UK for funding".

Rachel Kahn commented that "this research is a key example of how important it is to continue developing risk scores based on the make-up of the cancer, which can help clinicians understand how likely someone is to respond to treatment".

"This study shows that further clues can be found based on changes to a patient’s chromosomes."

She continued: "The more we know about how abnormalities influence how risky a cancer is thought to be, the closer we get to being able to personalise treatment to each individual to give them the most effective treatments and the best possible chance of survival."

The study was funded by Cancer Research UK.

No conflicts of interest declared.

[However, Fielding declared to ASH : Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

BSH 2020: Abstracts BSH2020-OR-001 & BSH2020-OR-004

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