Vincristine Dose Adjustments in Acute Lymphoblastic Leukemia: Impact on Treatment Outcomes and Neuropathy

Introduction

In recent years, the treatment of acute lymphoblastic leukemia (ALL) has changed with the use of pediatric-inspired regimens (PIR) containing higher vincristine doses. Clinical practice often involves adjusting vincristine dosage due to treatment-related side effects, but the impact of these adjustments is not well understood. This study aims to describe the frequency and impact of vincristine dose adjustments in ALL patients.

Methodology

This retrospective single-center analysis included adult patients diagnosed with ALL who achieved complete response and received at least two cycles of intensive chemotherapy that included vincristine. We analyzed the percentage of vincristine dose adjustments by treatment stage relative to the expected dose, according to the regimen, the causes of these adjustments, the reported frequency of significant neuropathy at the end of intensive treatment and the last follow-up, and leukemia-related outcomes (measurable residual disease (MRD), relapse-free survival (RFS), and overall survival (OS)).

Results

A total of 96 patients were included, with a median age of 29.5 years (17-68), 50% of whom were female. The majority (65.6%) received a PIR (modified CALGB 10403), followed by HCVAD (27.1%), and an institutional regimen in 7.3% (both adult regimens). Among these patients, 7.3% were Ph+. Only 20.8% received 100% of the expected vincristine dose. Vincristine dose adjustments were made in 28.4% of patients during induction, 55.2% during consolidation/intensification (cons/int), and 54.2% during maintenance. More than 80% of the expected dose was received by 81.1% of patients during induction, 70.8% during cons/int, and 69.4% during maintenance. Adjustments due to liver function test (LFT) abnormalities occurred in 21.1% of patients during induction, 30.2% during cons/int, and 22.7% during maintenance. Clinically significant neuropathy led to dose reductions in 2.1% of patients during induction, 18.8% during cons/int, and 30.7% during maintenance.

Comparing PIR to adult regimens, vincristine dose reductions were more frequent during intensive chemotherapy in PIR: induction (38.1% vs. 9.4%, p=0.004), cons/int (63.5% vs. 39.4%, p=0.031), but not during maintenance (55.8% vs. 50.0%, p=0.793). This difference was due to a higher rate of dose reduction for LFT abnormalities (induction 30.15% vs 3.12%, p=0.003, and cons/int 38.10% vs. 15.15%, p=0.021), but not related to neuropathy (induction 1.58% vs 3.12%, p=1, and cons/int 20.63% vs. 15.15%, p=0.592).

Neuropathy was reported by 35.1% of patients before maintenance and by 37% at the last follow-up. By the last follow-up, patients with neuropathy had received a greater reduction in vincristine dose, with a median of 80.6% of the expected dose vs. 93.2%, p=0.02. Factors associated with this neuropathy included age ≥30 years (56.8% vs. 16.7%, OR 6.56 (95% CI 2.20-19.55), p=0.001), diabetes (83.3% vs. 32.8%, OR 10.23 (95% CI 1.13-92.93), p=0.024) and an expected dose of vincristine greater than 53mg (46.7% vs. 21.4%, OR 3.21 (95% CI 1.09-9.41), p=0.045). There was no significant impact of vincristine dose reduction on MRD, RFS, or OS. A significant overall survival benefit was observed with PIR compared to adult regimens: expected 5-year OS of 59% vs. 31.5%, p=0.01 (HR 0.45, 95% CI 0.25-0.84, p=0.012). A sub-analysis of vincristine adjustments in the modified CALGB 10403 regimen showed no significant effect on MRD, RFS, and OS. A non-significant trend was seen in the 6-month landmark RFS analysis, with higher 3-year RFS in patients receiving adjustments resulting in <80% of the expected vincristine dose (77.1% vs. 55.4%, p=0.154).

Conclusions

A minority of adult patients with ALL receive the full vincristine dose as expected, primarily due to LFT abnormalities and peripheral neuropathy. With PIR, vincristine dose reductions are more likely due to LFT abnormalities. It seems that these changes do not affect the outcomes. Almost 40% of patients experience peripheral neuropathy during their last check-up, which may affect their quality of life. This emphasizes the importance of implementing proactive methods to identify and, if possible, prevent peripheral neuropathy at an early stage. It also suggests the need to reassess the best dose of vincristine in future research studies to achieve the best outcomes without compromising patients' quality of life.

Ontiveros-Austria:Servier: Speakers Bureau. Demichelis:Pfizer: Consultancy, Honoraria; AMGEN: Honoraria; Servier: Consultancy, Honoraria; TEVA: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria.