Efficacy and tolerability of a modified pediatric‐inspired intensive regimen for acute lymphoblastic leukemia in older adults

Abstract Although acute lymphoblastic leukemia (ALL) is most common in pediatric and adolescent and young adult (AYA) patients, 20% of cases are diagnosed in patients ≥ 55 years old. Use of intensive pediatric regimens in AYA populations has demonstrated excellent tolerability and significant improvements in event‐free survival (EFS) and overall survival (OS). The backbone of pediatric regimens includes asparaginase and corticosteroids, both of which are associated with more toxicity in older patients and those with body mass index (BMI) ≥ 30 kg/m which leads to poor tolerance of these regimens. We tested the safety and efficacy of a dose‐modified The Cancer and Leukemia Group B 10403 regimen using reduced doses of pegylated (PEG)‐asparaginase (ASP) and corticosteroids (RD‐10403) in 30 patients with Philadelphia‐chromosome negative ALL who were ≥50‐year‐old and younger adults with significant metabolic or hepatic co‐morbidities. The complete remission rate on day 28 was 77%, 3‐year EFS was 54%, and estimated 3‐year OS was 55%. Grade 3+ toxicity was noted in 40% of patients during induction, and induction‐related mortality was 3%. Additional prospective evaluation of RD‐10403 is merited to determine efficacy and safety of this regimen and to serve as a framework for chemoimmunotherapy combination therapy.

TA B L E 1 A Comparison of peg-asparaginase and steroid dosing in the standard CALGB 10403 regimen and the reduced-dose regimen Prednisone 60 mg/m2/day PO or IV on days 1-28 * Equivalent to dexamethasone 252 mg/m 2 /induction course Dexamethasone 10 mg/m 2 PO or IV on days 1-7 and 15-21 * Can further reduce to 10 mg/m 2 on Days 1-7 alone
ALL. Compared to historical controls, there was a significant improvement in both event-free survival (EFS) and 3-year overall survival (OS). Median EFS was 78.1 months, and 3-year OS was 73% [3]. The backbone of the CALGB 10403 regimen included both pegylatedasparaginase (PEG-ASP) and corticosteroids. Previous analyses of AYA patients with ALL have demonstrated an improved EFS and OS associated with receipt of corticosteroids and asparaginase [4]. However, both agents also have serious toxicities that are known to increase with age and certain comorbid conditions including hyperglycemia, hepatic dysfunction, and thrombosis. When compared to patients with a body mass index (BMI) < 30 kg/m 2 , patients enrolled on CALGB 10403 with a BMI ≥ 30 kg/m 2 also had higher rates of toxicity and significantly worse survival [5]. Obesity has previously been identified as an independent risk factor for inferior OS in adults with ALL [5,6,3].
Due to the treatment-related AEs associated with intensive pediatric regimens, it has been difficult to establish a standard of care approach in adults ≥ 40 years old with newly-diagnosed ALL [7]. Low intensity pediatric inspired regimens have demonstrated poor longterm outcomes with survival rates < 20% in patients over the age of 60 years [8]. Unmodified pediatric inspired regimens, on the other hand, have not demonstrated improvement in the OS of older adults due to higher rates of induction-related deaths and deaths in first complete remission (CR) [9,10]. There are, however, emerging data suggesting that with some dosing modifications, pediatric regimens may be safely and effectively utilized in older patients with ALL [11][12][13].
Given our interest in exploring these issues, we tested the safety and efficacy of a modified CALGB 10403 regimen using reduced dosages of PEG-ASP and corticosteroids (RD-10403) in patients ≥ 50 years old and younger adults with significant metabolic or hepatic co-morbidities. We had previously demonstrated that adequate asparaginase activity levels with less toxicity can be achieved with reduced PEG-ASP dosing [14]. Here, we report on clinical characteristics and outcomes of patients with newly-diagnosed Ph-ALL treated on RD-10403.

METHODS
We performed a single-center retrospective analysis of adult patients with Ph-ALL who were treated per RD-10403 between August 2014 and April 2019. RD-10403 was adopted for use at our institution start-  cytogenetics, TP53 mutation detected on next-generation sequencing assay, and/or an early T-cell precursor ALL phenotype. Survival curves (EFS and OS) were constructed using the Kaplan-Meier method [15].
An event was defined as the first of these: failure to achieve CR, relapse after CR, or death.

Causes of treatment-related mortality beyond induction (n = 2)
Septic shock, n 1 Hepatic failure, n 1

Treatment-related AEs
At least one Grade 3+ non-hematologic AE was seen in 40% of patients during induction (hepatotoxicity in eight patients, thrombosis in four, pancreatitis in two). Regarding the four patients with thrombosis, all four patients developed upper extremity deep vein thrombosis (DVT).
One patient had proximal DVTs in both lower extremities as well.
All patients received therapeutic anticoagulation for a minimum of 6 months with interruptions of anticoagulation when platelet count was ≤50000/µl. There was one Grade 5 death due to septic shock (

DISCUSSION
Given that fewer than 20% of older adults with ALL are long-term survivors, improving upon the standard of care in this population is of essential importance [2]. A number of asparaginase free regimens have been studied in this patient population and have demonstrated high CR rates but poor long-term outcomes [16][17][18][19]. Overall these regimens were found to have toxicities in keeping with their respective components, with the achievement of some durable responses but with considerable room for improvement.
Recent data have demonstrated that asparaginase cannot only be safely incorporated into ALL treatment regimens for older adults, but that it may also lead to durable long-term outcomes [11,12,13]. In this study we show that the RD-10403 regimen is feasible both in older adults up to the age of 76 and in patients with metabolic and/or hepatic comorbidities. The day 28 CR rate was 77% with this regimen with an MRD-negativity rate of 77% in those that achieved a CR. Furthermore, estimated 3-year EFS was 54%, and estimated 3-year OS was 55% for the entire cohort, with only four patients receiving an allo-HCT in CR1.
This regimen was effective in patients with high-risk disease biology as well with a day 28 CR rate of 69% and an estimated 3-year OS of 58%.
This stands in contrast to findings from the GRAAL-2005 study, which found significantly worse survival and poor tolerability of a pediatricinspired protocol in patients aged 55-60 with newly-diagnosed ALL [10]. Estimated 3-year OS for patients with BMI ≥ 30 kg/m 2 was 46% while the estimated 3-year OS for patients with BMI < 30 kg/m 2 was 61%; however, the difference in OS was not statistically significant.
This is consistent with previous analyses, including the AYA patients enrolled on CALGB 10403, identifying obesity as a risk factor for poorer OS [3,5,6].
Despite the encouraging long-term outcomes seen in our high-risk cohort compared to historical data for similar patients, it is important to compare the toxicities of the RD-10403 with the toxicity data reported from the CALGB 10403 study upon which it was modeled.
Specific grade 3 of 4 AEs observed in the patients enrolled on CALGB 10403 included hyperglycemia (31%), alanine transaminase elevation (29%), febrile neutropenia (24%), hyperbilirubinemia (19%), aspartate transaminase elevation (13%), and thrombosis (5%) with a TRM of 2% during induction. In comparison, 40% percent of our RD-10403 patients had at least one Grade 3+ AE during induction with TRM of 3%. Nine of the 12 patients with Grade 3 of 4 AEs were able to receive additional PEG-ASP during post-remission therapy. Overall TRM attributable to RD-10403 was 10%, and two (6%) patients were not continued on the regimen due to toxicity. We did not find a significant difference in BMI or age between patients who had Grade 3+ AEs and those who did not. However, median day 11 asparaginase level was significantly higher in those with Grade 3+ AEs. Previous work by Derman et al and by others has demonstrated lower rates of Grade 3+ AEs in patients receiving a reduced dose of asparaginase in comparison to a standard dose, suggesting that dose reduction may be critical in allowing for safe administration of this regimen to older patients [14,20,21]. Adequate asparagine depletion has been demonstrated to improve outcomes in ALL and 83% of patients in our cohort achieved the recommended level of asparaginase activity during induction [22]. Furthermore, prospective data from the NOPHO ALL2008 trial in pediatric patients with ALL have demonstrated that lower doses of asparaginase can significantly reduce toxicity while preserving efficacy and survival outcomes [21]. Limitations of our study include its retrospective nature, the small sample size and the fact that this was a single-center experience. In addition, 5-year follow-up has not yet been achieved for the majority of this cohort.
It is also important to consider that the entire traditional therapeutic approach for treatment of ALL, particularly for older adults, is undergoing re-evaluation in new frontline trials and perhaps heralds a new era that introduces new agents in the frontline and minimizes exposure to the traditional chemotherapeutics that have been the backbone of the pediatric regimens. The FDA approvals of inotuzumab ozogamicin (InO) in relapsed or refractory (R/R) ALL and blinatumomab in R/R ALL and in MRD+ ALL have given clinicians targeted therapies with remarkable efficacy and tolerability [23][24][25].
These targeted therapies are being evaluated in the frontline setting as well. Phase II data on blinatumomab induction followed by there have also been two deaths in patients in first remission [28].
Longer follow-up of these novel reduced intensity or "chemotherapyfree" approaches are needed to ensure their efficacy and safety. In addition, the same resistance mechanisms reported with use of blinatumomab and InO in the relapsed and refractory setting (loss of CD19 or CD22 expression, lineage switch at relapse of disease, T-cell exhaustion) may be seen in the frontline setting and necessitate combination therapy approaches [29][30][31][32]. RD 10403 may be a backbone frontline therapy for non-AYA adults with ALL that either blinatumomab or InO can be layered onto similar to what is being tested in ongoing randomized frontline trials (NCT02003222, NCT03150693).
The feasibility of regimens similar to RD-10403 may be of particular relevance for the many regions of the world where access to new antibody therapies remains very limited and cost-prohibitive. In addition, the current treatment paradigm for T-ALL still lacks targeted therapies, although some new agents are being actively investigated in the R/R setting [33]. Therefore, given the efficacy that we report here in this older and high-risk population, the critical role of asparaginase and corticosteroids in improving survival of children and young adults with ALL, the ability to achieve therapeutic levels with lower doses of asparaginase and the poor outcomes of obese patients in the AYA population when full dose pediatric regimens are employed, we believe that there is still a strong rationale for prospective trials testing-modified pediatric intensive regimens with dose reduced asparaginase in these high-risk populations with ALL.

AUTHOR CONTRIBUTIONS
Anand Ashwin Patel designed the research study, analyzed data, and wrote the paper. Joseph Heng, Emily Dworkin, and Sarah Monick analyzed the data, helped to draft the paper, and provided critical revi-