19 December 2022

A series of studies chart a path for “gentler” care of blood cancers, questioning long-standing assumptions, the conference of the American Society of Hematology (ASH) has heard.

Dr Mikkael Sekeres, from the University of Miami, representing ASH, said: “As researchers in haematology, we look at it as our duty to question the standard approaches that we use to treat patients, even those that we thought of as tried-and-true.

“These abstracts challenge some of those standards and in fact reveal that in many cases, giving less therapy and being less restrictive is actually better for patients, or at least no worse.”

One UK-based study found that children with acute lymphoblastic leukaemia (ALL) or lymphoblastic leukaemia (LBL), who are initially treated with high-dose methotrexate, may not need to have a maintenance therapy of dexamethasone and vincristine pulses. This was an “unexpected” yet “significant finding”, researchers say.

Researchers from Great Ormond Street Hospital (GOSH), presenting at the American Society of Hematology (ASH) Annual Meeting, say their findings answer some questions – and raise new ones – about the optimal treatment strategy for children and young adults with ALL or LBL.

The UKALL 2011 randomised study is the first to test if a shorter, higher-dose course of dexamethasone during the first phase of cancer treatment is associated with reduced toxicity.

The researchers also analysed the effects of a higher dose of methotrexate and omitting pulses of dexamethasone along with vincristine monthly following initial treatment.

They found an initial course of a daily higher dose (10mg/m2) of dexamethasone over two weeks did not reduce toxicity compared to the standard four-week regimen of 6mg/m2.

When given with the standard dexamethasone regimen, high-dose methotrexate reduces the risk of bone marrow but not central nervous system relapse for some ALL sub-groups. Also, pulses of dexamethasone and vincristine may not have added benefit in patients who have received high dose methotrexate.

Dr Ajay Vora, of GOSH, said: “Based on our results, if you give high-dose methotrexate after standard dexamethasone in the induction phase, omission of pulses may not reduce the chance of cure, although that conclusion should be considered tentative given the confounding interactions.”

Initial study findings indicated that pulses were associated with an increased risk of behaviour change, muscle weakness, and high blood sugar. The team is now analysing the data further to assess the effect of the pulses on quality of life.

The trial had two main phases and examined three main questions.

In the first phase, they randomised 1,902 patients to receive either a two-week higher-dose course or a four-week course of dexamethasone during initial treatment. The results for that phase, reported in 2017, indicated the short course of steroids brought no reduction in toxicity and may be slightly less effective.

In the second phase, 1,570 patients were randomised to four groups: high-dose methotrexate plus dexamethasone and vincristine pulses; high-dose methotrexate without pulses; standard-dose methotrexate with pulses; and standard-dose methotrexate without pulses.

Some patients were enrolled in both phases of the trial while others only participated in one phase or the other.

Overall, the results suggested that steroid pulses could be safely omitted without adversely affecting bone marrow relapse. However, omitting the pulses was associated with a decrease in event-free-survival overall.

This effect was smaller in those treated with four-week dexamethasone and high dose methotrexate, suggesting it may be possible to omit pulses with this treatment schedule.

Dr Vora said: “We found that the interactions are highly significant, which is something nobody expected.

“In addition, we were surprised that high-dose methotrexate seems to bring a benefit with respect to relapses primarily in the bone marrow and not the central nervous system, and we don’t have a biologically plausible explanation for that finding.”

A second study, presented to the conference, found that people with acute myeloid leukaemia (AML) whose disease relapsed or did not respond to initial chemotherapy had similar outcomes when they were treated first with an allogeneic stem cell transplant compared with those who underwent intensive “salvage” chemotherapy to achieve complete remission first.

The findings from the German ASAP trial are opposite to the common practice of offering stem cell transplantation only to patients who are in complete remission, researchers say. They suggest many patients can skip the additional step of salvage chemotherapy before receiving a transplant.

Professor Dr Johannes Schetelig, of the University of Dresden, said: “Allogeneic stem cell transplantation is a very potent strategy which is curative for many patients.

“Our study suggests that the international standard of bringing patients into remission first should be questioned, as it proves that allotransplant should be considered a standard treatment option even for patients with active disease.”

This new study is the first randomised trial to assess if salvage chemotherapy makes a difference in long-term outcomes after a stem cell transplant.

Delegates also heard from a new trial of the European MCL Network, which concluded that people with mantle cell lymphoma (MCL) who were prescribed ibrutinib had similar rates of progression-free survival and overall survival to those on the current standard of care – high-dose immunochemotherapy followed by autologous stem cell transplantation.

Dr Martin Dreyling, of LMU University Hospital Munich in Germany, said: “We have to wait for the full results; so far, we don’t see any difference between these two ibrutinib curves for progression-free survival and overall survival, but already both curves are numerically superior to the old standard, autologous transplant only.

“I think clinicians will interpret these results as suggesting you may essentially substitute autologous transplant with ibrutinib to avoid its well-known long-term toxicities.”

Finally, the conference heard from an Italian study, which found people undergoing a stem cell transplant for cancer do not benefit from sticking to a restrictive ‘low-microbial’ diet that is commonly prescribed to prevent infections.

The diet only allows foods that have been cooked to 80°C and forbids fresh fruits and vegetables. However, Dr Federico Stella, of the Università degli Studi di Milano – Istituto Nazionale dei Tumori in Milan, said it did not have significantly lower rates of infection compared to a standard hospital-prepared non-restrictive diet.

He said: “A protective diet is an unnecessary burden for our patients because it impairs quality of life without reducing infection incidence. I think our results can be practice-changing in the context of autologous stem cell transplantation.”

Source: ASH December 2022


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