Page 28 - Haematologica Vol. 110 - January 2025

EDITORIAL
The real world of acute lymphoblastic leukemia
Mark R. Litzow
Division of Hematology, Mayo Clinic, Rochester, MN, USA
In this issue of Haematologica, Lazzarotto and colleagues describe the outcome of 421 adults between the ages of 18 and 80 years (median 42 years) with Philadelphia chro- mosome-negative acute lymphoblastic leukemia (Ph-ALL) who received treatment outside of a clinical trial from 39 centers who are part of the Campus ALL network in Italy.1 The treatment they received was according to the chemo- therapy regimen utilized in the GIMEMA LAL1913 protocol.2 The regimen is a BFM-style regimen with an induction course followed by 7 additional courses that include 3 courses of high-dose methotrexate and cytarabine and 4 additional courses of therapy similar to the induction cycle, followed by 24 months of maintenance therapy. Pegaspargase at a dose of 2000 IU/m2 was added to courses 1, 2, 5, and 6 for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Lazzarotto et al. compared their results to those of 203 patients treated on the LAL1913 protocol.2 They found that they achieved a higher complete remission (CR) rate in their patients at the end of induc- tion at 94% compared to 85% for the LAL1913 patients (P=0.004). However, rates of achievement of measurable residual disease (MRD) negativity by RT-PCR for immuno- globulin and T-cell receptor gene rearrangements at the end of induction and after course 3 of chemotherapy were significantly lower in their cohort compared to the LAL1913 patients (46% vs. 56%, P=0.04, and 72% vs. 80%, P=0.04, respectively). Despite this, the overall and disease-free survival (OS and DFS) rates in their cohort were nearly identical to those seen in the LAL1913 study (OS 67% vs. 67%, P=0.94 [Figure 1]; DFS 57% vs. 63%, P=0.17, respec- tively]. Propensity score matching was done between the two cohorts to balance varying risk factors, and with this weighting OS and DFS remained similar between the two cohorts. A major difference in outcome was the higher rate of pegaspargase-related hepatic toxicity ≥2 in the Campus ALL network cohort compared to the LAL1913 patients (25% vs. 12%, P=0.0003, respectively).
A common belief in the medical community is that patients treated on clinical trials have better outcomes than patients
who do not participate in clinical trials.3 The results of this Campus ALL network study would appear to counter this belief. The authors and clinicians caring for this cohort of patients are to be congratulated for the excellent results they have achieved in this study. This “real-life” study falls into the realm of the expanding field of “real-world evidence” (RWE) reports found in the literature. Real-world evidence is produced by analyzing data collected from routine clini- cal practice and can provide insights into multiple areas of clinical medicine including, but not limited to health eco- nomics, epidemiology, and the safety and effectiveness of treatment.4 In March of 2016, the United States Food and Drug Administration (FDA) indicated that they would use RWE in regulatory decision-making in a document entitled “Prescription Drug User Fee Act (PDUFA) for 2018-2022”. Legislation in the United States that same year, the 21st Century Cures Act, provided that RWE could be used in place of evidence from randomized clinical trials to support approval for new clinical agents if judged to be appropri- ate by the FDA. Since then, there has been a burgeoning literature on the topic of RWE with some inconsistencies in how the term is applied.5 And while the data provided in the report that is the subject of this editorial will not support any new drug approvals, it is an important proof of concept that RWE can confirm that the results seen in a controlled clinical trial can be applied in the community and achieve results similar to or better than those found in a clinical trial.
Of note, this report from the Campus ALL network and the LAL1913 trial did not incorporate the use of any immuno- therapeutic agents in the treatment regimen. Agents like blinatumomab, a bi-specific T-cell engager molecule, and inotuzumab ozogamicin, a CD22 antibody drug conjugate, are increasingly being utilized in the front-line setting in phase II, and more recently phase III, trials6-8 and have the potential to further improve outcomes. A recently reported randomized phase III trial conducted by the National Clin- ical Trials Network in the United States in patients with MRD negative Ph-ALL added 4 cycles of blinatumomab
Haematologica | 110 January 2025
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Correspondence: M.R. Litzow litzow.mark@mayo.edu
Received: Accepted: Early view:
August 19, 2024. August 23, 2024. September 5, 2024.
https://doi.org/10.3324/haematol.2024.286346
©2025 Ferrata Storti Foundation Published under a CC BY-NC license