Blood cancers

‘Better than expected’ survival after reduced-intensity HSCT in ALL

Data from the UKALL14 trial shows “better than expected” survival results with reduced-intensity conditioned allogeneic HSCT in patients with high-risk acute lymphoblastic leukaemia (ALL), and separately that adding four doses of rituximab to ALL induction therapy is unlikely to be of benefit.

The UKALL group, led by Chief Investigator Professor Adele Fielding, explored whether two different strategies could improve outcomes of patients with ALL: adding the anti-CD20 monoclonal antibody rituximab to standard induction therapy in adults aged 25–65 years with precursor B-cell ALL; and use of in-vivo T-cell depleted reduced intensity allogeneic (HSCT) in first remission for patients aged 41 years and older or for those younger unable to undergo a myeloablative allograft.

This HSCT arm of the study, published in The Lancet Haematology, included 249 patients with B-cell or T-cell ALL who underwent reduced-intensity conditioned HSCT with fludarabine, melphalan, and alemtuzumab at 46 acute haematology centres in the UK.

Results showed that after four years, event-free survival (EFS) and overall survival (OS) rates were 46.8% and 54.8%, respectively, which was “better than expected”, the researchers said.

Moreover, these survival rates were achieved with relatively low rates of chronic graft-versus-host disease (GVHD; 22%) and transplant-related mortality (TRM; 19%), according to the study, which was led by Professor David Marks, a Consultant Haematologist at the University Hospital Bristol NHS Trust.

The research also revealed that patients who were MRD-positive at the end of induction “had more than double the risk of relapse” (hazard ratio [HR] 2.41) while those with unrelated donors had half the risk of relapse compared too those with sibling donors (0.47).

The researchers concluded that the findings provide “practice-informing evidence for the role of reduced-intensity conditioned allogeneic HSCT in older adults with acute lymphoblastic leukaemia in first complete remission”, given that “outcomes in this high-risk group exceeded those that would have been expected with chemotherapy alone”.

In an accompanying comment, Dr Anjali Advani, of the Cleveland Clinic Taussig Cancer Institute in Ohio, said few trials to date had systemically studied non-myeloablative transplantation prospectively and in a large scale fashion.

The trial, which “was impressive given the number of patients and sites, follow-up, and results,” gave encouraging results, he said, but also noted that “given the novel agents available in both Philadelphia-chromosome-negative and Philadelphia-chromosome-positive B-cell acute lymphoblastic leukaemia, better results might be shown with these therapies compared with transplantation in some patient populations”.

Rituximab: “less is not more”

A separate arm of the trial, also published in The Lancet Haematology, explored whether the addition of a short course of rituximab to induction chemotherapy would improve EFS in adults, given that CD20 is expressed on the cell surface of 40% of B-cell ALLs.

However, the researchers found no significant survival benefit with this regimen; 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, resulted in an EFS HR of 0.85, “which was greater than the 0.71 the study was powered to detect and hence did not meet the primary endpoint,” they noted.

This contrasts with findings of a study by the GRAALL group (Group for Research on Adult Acute Lymphoblastic Leukemia) that the addition of 16–18 doses of rituximab in patients aged 18–59 years of age with CD20-positive, Philadelphia-chromosome-negative B-cell ALL led to a significantly higher EFS compared to standard therapy (65% vs 52%, respectively).

“This suggests that that the number of doses is key; less is not more,” Dr David Taussig, study author and Consultant Haematologist at The Royal Marsden Hospital, told the limbic.

Taken together these findings are relevant to clinical practice as they indicate that “patients with acute lymphoblastic leukaemia whose leukaemia cells have CD20 on the surface of the cells benefit from 16 doses of rituximab”, a strategy approved by NICE in October last year, he added.

The research did show that adding rituximab to induction therapy was safe, as there was no increase in short-term adverse events, no issues with long-term neutropenia, and no difference in non-relapse or on-therapy mortality between the groups, the authors said.

Also, of note, there was surprise that a preplanned analysis of data on the effect of rituximab on allogeneic HSCT outcomes inexplicably showed that only patients who received myeloablative conditioned allogeneic HSCT had a significantly greater event-free survival if treated with standard of care plus rituximab, with an HR of 0.47 — this effect was not observed in patients who received reduced-intensity conditioned allogeneic HSCT.

“We could not find a single explanation — both relapse rate and non-relapse mortality were reduced by the same magnitude and there was no apparent difference in GVHD rates,” the authors noted.

All-in-all, Dr Advani concluded that both of the trial reports “represent a substantial advance in the scientific community.”

“We are hopeful that outcomes will continue to improve for patients as additional molecular profiling, incorporation of MRD, and the incorporation of novel agents are implemented,” she added.

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