Audio Journal of Oncology, February 14 2023, Reporting from the American Society of Hematology Annual Meeting (ASH), December 2022
An interview with Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK
Interviewer: Peter M Goodwin
TITLE: Options Identified for in Acute Lymphoblastic Leukemia
NEW ORLEANS, USA—A big study conducted over an extended period of time has shown that there is scope for reducing the intensity of chemotherapy for patients with acute lymphoblastic leukema (ALL) and (the rarer) lymphoblastic lymphoma (LBL). Modifications to standard protocols offer scope for sparing many children the potential toxicity of full-does standard regimens without compromising cure rates.
Amy Kirkwood, Chief Statistician from University College, London tells the Audio Journal of Oncology (AJO) about her group’s findings from the randomized phase three UKALL 2011 study, reported (at the American Society of Hematology (ASH) 2022 Annual Meeting), showing that adjustments to current multi-agent chemotherapy regimens brought changes in outcome. She concludes that more gentle treatments may be possible for many patients while maintaining or improving efficacy for those at high risk.
The treatment of ALL had improved hugely in the last 50 years, first author Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK, told the AJO after giving her report at ASH. “We now have about 95 percent survival. About 15 percent of children will relapse. But we know that 50 years ago we were curing about 50 per cent of people with half the treatment. So, we know that we are overtreating large numbers of children,” she said.
So, trials were now looking at treatment reductions, and at trying to identify high-risk patients to design new ways of improving efficacy for that group only, she said. “We want to try and decrease treatment for the majority who will do well,” Kirkwood noted.
Specifically, the trial found that using high-dose methotrexate (HDM) did not improve central nervous system (CNS) relapse—contrary to some expectations. According to the UKALL 2011 study findings, it may have improved bone marrow relapse for some sub-groups of patients with B-lineage disease, however.
The trial also found that with some chemotherapy regimens the addition of monthly “pulses” of vincristine and dexamethasone (in the maintenance phase of treatment) had been un-necessary. They proved to be “non-inferior” for bone marrow relapse—compared with the standard practice of including such pulses. This suggested that pulse-free treatment could potentially be an option for some patients.
The UKALL 2011 study allocated patients to study arms in accordance with their risks, as stratified by National Cancer Institute (NCI) risk, cytogenetics and “end of induction minimum residual disease” (MRD). The aim was to assess whether elements of treatment could potentially be de-escalated without loss of efficacy. Randomizations were allocated within the several different standard “blocks” of chemotherapy.
Firstly, in the “induction” block of chemotherapy (aiming to get rid of most of the disease) there was a randomization between two different dose schedules of dexamethasone. A short (higher) dose schedule was compared with standard dexamethasone dosing. The aim had been to look at whether steroid dose could influence the incidence of side effects. This was followed by the “consolidation” block all in which all patients were treated the same.
Kirkwood said they saw no difference from steroid dosing schedule changes. “We were hoping to see a difference in steroid-related morbidity and mortality, so that randomization [was] closed,” she said. And, there had also been some “worrying trends” that maybe the patients treated with a shorter dexamethasone schedule (higher dose) were relapsing more often, she commented.
The second randomization (in the “interim maintenance” phase of treatment) was between standard and high-dose methotrexate. Although this was looking primarily for any impact of methotrexate dose on CNS relapse (and had found: “No difference at all”) Kirkwood noted there had been an effect of methotrexate dose on bone-marrow relapse. “Overall, we didn’t see a difference. But we found an interaction between the first randomization (the short versus standard dexamethasone) and the high methotrexate dose randomization.” The results were different depending on which steroid dose a patient had received initially. “If you had short dexamethasone up-front, then the high-dose methotrexate didn’t improve your bone marrow relapse risk. But if you had the standard dexamethasone up front, it looked like it might improve your bone marrow relapse risk. And we don’t know what caused this,” she said.
After the next block of treatment (called “delayed intensification” in which all patients had the same therapy) the third randomization was during the “maintenance” treatment. Patients either did, or did not, receive the monthly “pulses” of vincristine and dexamethasone. Primarily, the aim had been to see if the pulses had any effect on the bone marrow relapse rate. “[It] was non-inferior. We saw a small decrease. But it was within our pre-specified margin of five percent,” said Kirkwood. The team concluded it had been safe to remove the pulses. “However, we did see a ‘bit of a decrease’ in terms of event-free survival—over the five percent limit,” she said.
In terms of practical recommendations coming out of the UKALL 2011 study Kirkwood noted that knowledge about safe and effective options for changing methotrexate dose had been clarified. “We found that the patients who had standard dexamethasone, standard interim maintenance, didn’t have high [methotrexate] dose, and then went on to have pulses, had very similar outcomes to those that had the high-dose methotrexate. So that may be a trade-off: that you give the high-dose, you don’t give the pulses. Or, you give our standard [dose and] you still give the pulses.”
“The removal of pulses is probably safe in some groups of patients, but we still need to do further analysis,” she said. “The vast majority of children will be cured with front-line therapy. And our protocols are now working hard to try and pull out those small groups patients that are going to do badly and make sure they get the treatment that is best for them.”
ASH ABSTRACT DETAILS:
High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011
Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Clinical Trials
Hematology Disease Topics & Pathways:
Non-Biological therapies, Chemotherapy, Combination therapy, Therapies
Saturday, December 10, 2022: 2:45 PM
Amy A. Kirkwood, MSc1*, Nicholas Goulden, MD, PhD, MRCPath2*, John Moppett, PhD FRCPath3*, Sujith Samarasinghe, PhD, FRCPath4*, Jon Mee5*, Rachael Hough, MD FRCPath6*, Pamela R. Kearns, PhD, FRCPC7*, Sarah Lawson, MBBS FRCPath8*, Clare J. Rowntree, MBBS PhD9* and Ajay Vora, MD10
1Cancer Research UK & UCL Cancer Trials Centre, University College London, London, United Kingdom
2Great Ormond Street Hospital, London, United Kingdom
3Department of Haematology, Bristol Children’s Hospital, Bristol, United Kingdom
4Department of Paediatric Haematology, Great Ormond Street Hospital for Children, London, United Kingdom
5Cancer Clinical Trials Unit, Birmingham University, Birmingham, United Kingdom
6University College Hospital, University College of London, London, United Kingdom
7Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, United Kingdom
8Birmingham Children’s Hospital, Birmingham, United Kingdom
9Department of Haematology, University Hospital of Wales, Cardiff, United Kingdom
10Department of Haematology, Great Ormond Street Hospital for Children, London, United Kingdom
UKALL 2011 randomised children and young adults (up to 25) with Acute Lymphoblastic Leukaemia (ALL) or Lymphoblastic Lymphoma (LBL). The aims were to reduce induction toxicity (R1: Short [14 days] vs Standard [28 days] dexamethasone), CNS relapse risk (R2IM: HD MTX (HDM) vs standard interim maintenance (SIM)) and maintenance morbidity (R2pulses: Vincristine (VCR)/dexamethasone pulses or not). R1 results were presented at ASH 2017 and did not show a reduction in toxicity with short dexamethasone. Results of R2IM and R2pulses are reported here.
Patients and Methods
Patients were stratified by NCI risk, cytogenetics and end of induction MRD to receive Regimens A (NCI standard risk, MRD low risk), B (NCI high risk, MRD low risk) or C (Cytogenetic poor risk or MRD intermediate risk regardless of NCI risk). MRD high risk (end of consolidation MRD >0.5%, n=14) were not eligible for randomisation and received off protocol therapy. R2 was a factorial randomisation stratified by factors including NCI and MRD risk groups and resulted in 4 arms: HDM with pulses, HDM without pulses, standard interim maintenance (SIM) with pulses (standard of care) and SIM without pulses. SIM was for 2 months with oral mercaptopurine/MTX, monthly pulses and single IT MTX in Regimens A and B, and 5 doses of escalating IV MTX (Capizzi) + VCR + 2 doses of Pegylated asparaginase in Regimen C. HDM was given at a dose of 5g/m2 x 4 doses 2 weeks apart, low dose 6-MP and 2 doses of Pegylated asparaginase (Regimen C only). The primary endpoint for R2IM was the CNS relapse rate (CNSR) and for R2pulses was the bone marrow relapse rate (BMR) in ALL only; non-inferiority, 5% margin at 5 years. Event Free Survival (EFS) was considered a primary endpoint for both.
Of the 2750 patients registered on trial between April 2012 and December 2018, 1902 were randomised to R1 (closed April 2017) and 1570 to R2. Median age 5 years (IQR: 3-11), 83% B-ALL, 12% T-ALL, 1% B-LBL and 4% T-ABL, 43% NCI high risk. Median follow-up for R1 is 76 months and R1 or R2 is 72 months. Overall, we found no difference in CNSR (HR: 0.99 (0.65-1.51), p=0.97, 5-year rates: 5.6% and 5.6%), or any other endpoints for R2IM. However, there was an interaction between the R1 and R2IM randomisations (p=0.006 for EFS) with inferior outcomes for patients treated with short dexamethasone followed by HDM, particularly in those who did not receive pulses (Figure 1). Limiting analyses to patients treated with standard dexamethasone (N=995, including those that received it after closure of R1) there was a significant reduction in BMR rate with HDM (HR 0.62 (95% CI: 0.40 – 0.95) p = 0.029) and a trend for improvements in EFS and OS (HRs: 0.75 (95%CI: 0.53 – 1.04), p=0.087 and 0.61 (0.37 – 1.03), p=0.067) but no difference in CNSR. In subgroup analyses there were no significant interactions, but the effect appeared stronger for B-lineage, NCI high risk and MRD low risk patients (Figure 2). Overall, the BMR for R2pulses was non-inferior (+2.1% increase BMR at 5 years for ALL patients (95% CI: -1.4% to 4.7%), HR 1.22 (95%CI: 0.89 – 1.67). Considering all four R2 treatment arms in standard dexamethasone only, standard IM without pulses has a lower EFS, whilst there is no appreciable benefit of pulses in HDM treated patients; 5-year EFS difference: -2.8% (95% CI: -7.4% to 4.4%) and BMR (ALL): +0.4% (-6.7% to 4.3%).
HDM does not improve CNSR within a UKALL treatment backbone, but pre-specified analyses suggest it may improve BMR for some sub-groups of B-lineage patients when given following standard dexamethasone induction. Although the ‘no pulses’ arm was non-inferior overall for BMR, further sub-group and toxicity analyses are to be performed and will presented at the meeting.
Children with Cancer, Blood Cancer (grant ref 09042) and Cancer Research UK funded the trial.
Disclosures: Kirkwood: Kite: Consultancy, Honoraria. Rowntree: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Lilly: Membership on an entity’s Board of Directors or advisory committees; KITE pharma: Membership on an entity’s Board of Directors or advisory committees; Incyte: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees.
PRESS RELEASE 2022:
High-dose methotrexate may make post-treatment steroids unnecessary for some children with ALL or LBL
214: High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011
The results of a new study answer some questions and raise new ones about the optimal treatment strategy for children and young adults living with acute lymphoblastic leukemia (ALL) or lymphoblastic leukemia (LBL). The randomized study is the first to test whether the use of a shorter, higher-dose course of dexamethasone (a steroid) during the first phase of cancer treatment is associated with reduced toxicity. It also analyzed the effects of using a higher dose of the chemotherapy drug methotrexate and of omitting pulses of dexamethasone along with the chemotherapy drug vincristine monthly following initial treatment. Monthly pulses of vincristine and dexamethasone are commonly used as a “maintenance” strategy to help prevent cancer from coming back in the first few years following treatment.
The findings indicate that an initial course of daily higher dose dexamethasone (10mg/m2) spanning two weeks did not reduce toxicity compared to the standard regimen (6 mg/m2), which lasts four weeks. The results also indicate that, when given with the standard dexamethasone regimen, high-dose methotrexate reduces the risk of bone marrow but not central nervous system relapse for some sub-groups of ALL and that pulses of dexamethasone and vincristine may not have added benefit in patients who have received high dose methotrexate.
“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,” said Ajay Vora, MD, of the Great Ormond Street Hospital for Children in London.
According to initial study findings, pulses were associated with an increased risk of behavior change, muscle weakness, and high blood sugar; the researchers are currently analyzing 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. For the first phase, researchers randomized 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.
For the second phase, researchers randomized 1,570 patients 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.
Key endpoints for the second phase focused on whether the steroid pulses could be safely omitted without affecting bone marrow relapse or five-year event-free survival and whether the high-dose methotrexate could improve rates of relapse in the central nervous system. For high dose methotrexate, the results showed no significant differences overall for most endpoints. Researchers did find a significant interaction with the dexamethasone regimen given in the first phase, with patients treated with the four- week schedule showing improvements in bone marrow relapse rates when treated with high dose methotrexate. 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.
“We found that the interactions are highly significant, which is something nobody expected,” said Dr. Vora. “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.”
Going forward, researchers will be analyzing quality of life outcomes related to the dexamethasone- vincristine pulses for further insights into the possible benefits of skipping this added therapy. They will also study outcomes at longer follow-ups to ensure these results hold. In addition, they noted that other studies are underway to further illuminate optimal treatment strategies for different patient subgroups.
Amy Kirkwood, University College London, will present this study during an oral presentation on Saturday, December 10, 2022, at 2:45 p.m. Central time in room 265-268.