A retrospective cohort study describing chemotherapy-induced peripheral neuropathy in Non-Hodgkin lymphoma patients treated with EPOCH ± R: does HIV status matter?

Abstract

The frontline immuno-chemotherapy regimen for HIV-associated non-Hodgkin Lymphoma is dose-adjusted EPOCH ± R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). Chemotherapy-induced peripheral neuropathy (CIPN), caused by vincristine, is a common adverse effect of EPOCH ± R, negatively impacting long-term patient outcomes. The primary objective of this study was to determine the incidence of CIPN, stratified by HIV status, in patients treated with EPOCH ± R. A retrospective cohort study at a tertiary referral comprehensive cancer center evaluated patients treated with EPOCH ± R from 2011 to 2018. The final sample included 27 patients with HIV compared to 279 without HIV (total n = 306). Overall, the incidence of CIPN was 29.4% (n = 90), including 5 with HIV (18.5%) and 85 without HIV (30.5%). Propensity scores were used to match patients by HIV status. Although no relationship was found between HIV status and neuropathy, CIPN affects too many undergoing treatments for lymphoma, supporting future investigations to minimize toxicities.

Keywords:

• Chemotherapy-induced peripheral neuropathy
• lymphoma
• HIV
• EPOCH ± R
• vincristine

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive neurologic disorder characterized by numbness and tingling affecting the hands and feet and frequently associated with neuropathic pain, weakness, and loss of proprioception [1]. CIPN is associated with an increased risk of falls and injury and is directly linked with a negative impact on quality of life (QOL) [1]. Improving traditional treatment while minimizing toxic side effects, such as CIPN, is a research priority of the National Cancer Institute (NCI) [2].

Despite the absence of randomized clinical trials, infusional dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), with or without rituximab (R), became the widely accepted frontline treatment for aggressive non-Hodgkin’s lymphomas in people living with human immunodeficiency virus (HIV) following a pooled analysis of 1546 patients. EPOCH was associated with significantly better overall survival [3,4]. The Phase III Intergroup Trial Alliance/CALGB 50303 demonstrated more favorable results with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), noting a potential patient selection bias may preclude the generalizability of results, to specific high-risk subgroups [3]. Persons living with HIV (PLWH) were excluded from this trial. Peripheral neuropathy, caused by vincristine, is a common adverse effect of EPOCH chemotherapy. The pathophysiology is not entirely understood. Vincristine interferes with microtubule formation, critical components of nerve fiber axons, leading to mitotic arrest and cell death [1,5]. Other mechanisms include oxidative stress, altering the calcium homeostasis, and increased expression of serotonin receptors [6]. The phase III clinical trial reported CIPN in more than 80% of people receiving EPOCH ± R chemotherapy, with most cases grade 1/2 (65.4%, n = 155) [7,8].

PLWH are at an increased risk of developing peripheral neuropathy caused directly by HIV, inflammation, opportunistic infections, and neurotoxic consequences of antiretroviral drugs [9]. HIV is treated with combined antiretroviral therapy (cART), which may inhibit CYP3A4, the enzyme responsible for metabolizing vincristine. This interaction may lead to diminished clearance of vincristine, thereby potentially increasing neurotoxicity leading to a higher risk of CIPN. The National Comprehensive Cancer Network (NCCN) strongly recommends avoiding strong CYP3A4 inhibitors to minimize toxicities. Effective alternatives for cART are often available to avoid drug-drug interactions [10]. Antifungals, such as fluconazole, are often used for infection prophylaxis and may also inhibit CYP3A4, further increasing the risk of drug-drug interactions and CIPN [11]. There have been several reports of CIPN in PLWH receiving EPOCH ± R; Grade 3/4 CIPN was reported as 3-5% [12–14]. Ramos et al. [15] reported 8 of 12 PLWH developing a neurologic complication ≤ grade 2, although additional details were not provided [15]. More recently, Grade 1 and 2 CIPN was reported in 29% and 44%, respectively, of PLWH treated with EPOCH ± R (n = 86), with 4% reporting grade 3 [16].

We hypothesized that PLWH would be more likely to develop CIPN when treated with EPOCH+-R. Therefore, the primary objective of this study was to determine the incidence of CIPN in patients treated with EPOCH ± R chemotherapy, stratified by HIV status. Secondary objectives characterized factors associated with the development of CIPN.

Methods

A retrospective cohort study was conducted at the Ohio State University Arthur G. James Cancer Hospital, a large, tertiary NCI-designated Comprehensive Cancer Center, and was approved by the Institutional Review Board. Using the electronic medical record, people treated with EPOCH ± R chemotherapy between January 1, 2011, and October 1, 2018, were identified.

People were age 18 and older, with a diagnosis of NHL, and treated with EPOCH ± R chemotherapy. Prior to each treatment, the nurse performed a symptom assessment and documented this in the electronic medical record. CIPN was defined as a neuropathy grade > 0 using Clinical Terminology Criteria for Adverse Events (CTCAE) version 4. The presence of neuropathy was collected at baseline and before cycle 6. Patient-reported outcome measures were not available.

All statistical analyses were done using SAS version 9.4 for Windows. Statistical tests used a significance level of 0.05. For quantitative variables like age and BMI, means and standard deviations were used to describe central tendency and dispersion. For categorical variables like sex and CIPN grade, counts and percentages were used to describe the distribution of values. Exact Pearson chi-square tests were used to test for independence between pairs of categorical variables. For quantitative variables, differences between groups were assessed using t-tests.

Results

Eligible people had a diagnosis of NHL (n = 5565) and were treated with EPOCH ± R chemotherapy between January 1, 2011, and October 1, 2018 (n = 438). Exclusion criteria included age <18 years at their earliest encounter during the study period, incarceration, no vincristine cycle one, incomplete records, or prior chemotherapy. Bortezomib or high-dose methotrexate in addition to EPOCH were also excluded. The final sample consisted of 27 PLWH compared to 279 without HIV for a total sample of 306 individuals.

Overall, the sample was more likely to be male (n = 193, 63.1%), especially among PLWH (n = 25, 92.6%). PLWH were younger (mean age 44.9 ± 10.9 years compared to 62 ± 14.2 years) and less likely to be White (n = 17, 63% versus n = 258, 92.5%). Neuropathy at baseline was <5% overall (n = 11). A greater percentage of PLWH had a history of depression (n = 12, 44.4% compared to n = 69, 24.7%, p = 0.04), whereas a greater percentage of patients without HIV had a diagnosis of diabetes (n = 76, 27.2% compared to n = 2, 7.4%, p = 0.03). Baseline patient characteristics stratified by HIV status are outlined in Table 1. Table 1 also includes p values for tests of whether there are relationships between the characteristics and HIV status.

Table 1. Characteristics stratified by HIV status.

	HIV positive (n = 27)	HIV negative (n = 279)	Total sample (n = 306)	P value
Baseline characteristics
Mean age (standard deviation)	44.9 ± 10.9	62 ± 14.2	60.5 ± 14.8	<0.001
Male sex, n (%):	25 (92.6)	168 (60.2)	193 (63.1)	0.001
Race, n (%):White	17 (63)	258 (92.5)	275 (89.9)	<0.001
ECOG Performance Status, n (%): <2	20 (80)	188 (74.6)	208 (75.1)	0.64
>1	5 (20)	64 (25.4)	69 (24,9)
BMI, median (standard deviation)	27.6 ± 8.4	28.8 ± 6.6	28.7 ± 6.7	0.48
Neuropathy at Baselinen (%):	1 (3.7)	10 (3.6)	11 (3.6)	0.99
Diabetes, n (%):	2 (7.4)	76 (27.2)	78 (25.5)	0.03
Depression, n (%):	12 (44.4)	69 (24.7)	81 (26.5)	0.04
CIPN
CIPN, n (%):	5 (18.5)	85 (30.5)	90 (29.4)	0.27
CIPN Grade Cycle 6, n (%):				0.49
Grade 0	22 (81.5)	194 (69.5)	216 (70.6)
Grade 1	4 (14.8)	70 (25.1)	74 (24.2)
Grade > 1	1 (3.7)	15 (5.4)	16 (5.2)

HIV = Human Immunodeficiency Virus; ECOG = Eastern Cooperative Oncology Group; CIPN = Chemotherapy Induced Peripheral Neuropathy.

The incidence of CIPN was 29.4% (n = 90) overall, including 5 PLWH (18.5%) and 85 without HIV (30.5%) (p = 0.27). Most CIPN was grade one for both PLWH (n = 4, 80%) and persons without HIV (n = 70, 82.3%) (p = 0.49). White race was the only statistically significant baseline characteristic associated with developing CIPN (p = 0.04).

Because of the possibility that imbalances in the background characteristics of PLWH and those without HIV were affecting the relationship between CIPN and HIV status, the SAS procedure PSMATCH was used to compute HIV status propensity scores [17]. The scores were used to match patients in the PLWH group with similar patients in the HIV-negative group. It is a common practice to base propensity scores on characteristics related to both the exposure and the outcome [18]. Optimal propensity score pairing resulted in successfully matching the full sample of 27 PLWH with 27 patients without HIV. To that end, variables with p values no more than 0.20 in tests of relationships with HIV and neuropathy were selected for covariate balancing. The frequency of CIPN in the 27 patients with HIV was 18.5%, less than that of the full sample of HIV-negative patients, which was 30.5% (Table 2). McNemar’s test of whether the chance of CIPN depended on HIV status was not statistically significant, with a p-value of 0.58.

Table 2. Characteristics stratified by CIPN status.

	CIPN: Yes (n = 90)	CIPN: No (n = 216)	Total sample (n = 306)	P value
Baseline Characteristics
Mean age (standard deviation)	58.5 ± 15.7	61.3 ± 14.4	60.5 ± 14.8	0.16
Male sex, n (%):	51 (56.7)	142 (65.7)	193 (63.1)	0.15
Race, n (%): Caucasian	86 (95.6)	189 (87.5)	275 (89.9)	0.04
ECOG Performance Status, n (%):				0.77
<2	69 (76.7)	139 (74.3)	208 (75.1)
>1	21 (23.3)	48 (25.7)	69 (24.9)
BMI, median (standard deviation)	29.6 ± 7.4	28.3 ± 6.5	28.7 ± 6.7	0.14
Neuropathy at Baseline n (%):	6 (6.7)	5 (2.3)	11 (3.6)	0.09
Diabetes, n (%):	22 (24.4)	56 (25.9)	78 (25.5)	0.89
Depression, n (%):	22 (24.4)	59 (27.3)	81 (26.5)	0.67
HIV, n (%)	5 (5.6)	22 (10.2)	27 (8.8)	0.27

HIV = Human Immunodeficiency Virus; ECOG = Eastern Cooperative Oncology Group; CIPN = Chemotherapy Induced  Peripheral Neuropathy.

Discussion

This retrospective cohort study is the first to date assessing CIPN in people receiving EPOCH ± R, stratified by HIV status. Vincristine-induced peripheral neuropathy is a dose-limiting side effect that has not been well described in PLWH, especially in the modern cART era. Although PLWH have a greater risk for developing peripheral neuropathy, the incidence of CIPN in our sample was higher in individuals without HIV. There was no evidence that HIV increases the risk of neuropathy related to vincristine. Peripheral neuropathy is a well-known adverse event of EPOCH chemotherapy. Nearly one-third of our sample had CIPN at cycle 6 (n = 90, 29.4%), including 16 persons with grade 2 neuropathy, limiting their daily living activities.

In our sample, PLWH were more likely to be nonwhite, male, and younger, three patient-related factors that may influence the development of vincristine-induced peripheral neuropathy [19]. Race may influence the metabolism of vincristine via the distribution of the CYP enzymes [20]. White race was the only statistically significant demographic characteristic associated with CIPN (p = 0.04). Conflicting reports exist regarding the role of race and ethnicity, including black and African American women having an increased risk of CIPN related to taxanes, while research specific to vincristine suggests white race may experience increased neurotoxicity [21–24]. The role of race and vincristine-induced peripheral neuropathy is not well understood, and future research should include a more diverse sample [20].

Gender has been suggested as possibly impacting the development of CIPN [23]; Diouf et al. [21] indicate that female patients treated with vincristine had a greater risk of developing neuropathy. Results from a cohort study suggest females were more likely to develop paclitaxel- or oxaliplatin-induced CIPN (p = 0.01) [25]. A retrospective study in Saudi Arabia reported no association with gender and neuropathy in adult or pediatric patients receiving vincristine (n = 355) [26]. Similarly, in our study, there was no evidence of a relationship between gender and CIPN.

The association of age with CIPN varies across studies. Hershman et al. [27] identified 1,401 participants from phase II and III trials receiving paclitaxel using the Southwest Oncology Group database. Eighteen percent (n = 251) of participants had grade 2 or worse neuropathy. For every 1-year increase in age, the odds of neuropathy increased by 4% (p = 0.004). Mizrahi et al. [25] found an association between increasing age and CIPN severity in paclitaxel- and oxaliplatin-treated patients. Other studies have found no correlation between age and CIPN specifically with paclitaxel [28,29]. Most studies examining vincristine and neuropathy characteristics have focused on the pediatric population. Liew et al. [30] reported 43% (n = 12) of people with acute lymphoblastic leukemia experienced moderate to severe peripheral neuropathy symptoms, as measured by the Subjective Peripheral Neuropathy Screen. This was significantly higher in individuals ≥ age 40 (15.4% vs 66.7%, p = 0.006). Depression/anxiety and pain often occur together, with a bidirectional relationship and overlapping symptoms [31]. Bonhof et al. [32] reported a relationship between psychosocial distress, including depression and anxiety, and CIPN among colorectal cancer survivors. While gabapentin and pregabalin are often prescribed, duloxetine is the only agent recommended for the treatment of CIPN, based on a large randomized clinical trial of patients treated with paclitaxel or oxaliplatin [33,34]. A secondary data analysis showed emotional functioning predicted a response to duloxetine for painful neuropathy. Inferior emotional health (increased anxiety and depression) and painful CIPN may be part of a larger symptom cluster [35]. Although a greater percentage of PLWH (n = 12, 44.4%) having a history of depression, compared to those without HIV (n = 69, 24.7%)(p = 0.04), there was no evidence of a relationship between neuropathy and depression in our study.

Chemotherapy-induced peripheral neuropathy may occur with a single dose of vincristine; however, the occurrence is strongly dose-dependent and has led to the capping of vincristine at 2 mg by some, regardless of body surface area [6]. A small retrospective study by Weis et al. al. [36] suggests that capping the vincristine dose at 2 mg in EPOCH significantly reduces neurotoxicity while not sacrificing outcomes. They examined the overall incidence of ≥ grade 2 neuropathy in patients treated with dose-adjusted EPOCH with or without a 2 mg vincristine dose cap (n = 22 and n = 44, respectively) in a convenience sample from a single center [36]. The incidence of ≥ grade 2 neuropathy was significantly reduced with the dose cap (40.9% vs. 84.1%. p = 0.001).

The large, randomized Phase III Intergroup Trial Alliance/CALGB 50303, compared dose-adjusted EPOCH-R with R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) [7]. Eighty-four percent of patients (n = 199) receiving EPOCH- R experienced neuropathy, with 18.6% grade 3/4 (n = 44), compared to 50.6% of patients (n = 123) receiving R-CHOP (grade 3/4, n = 8, 3.3%). Bartlett, Wilson, & Leonard [7] believe optimizing first-line treatment for high-risk lymphomas is critical in the absence of definitive data on capping and recommend administering DA-EPOCH-R as it has been reported. Clinicians are urged to carefully assess for neurotoxicity symptoms and reduce the dose of vincristine earlier in the course of peripheral neuropathy [8]. It is unknown whether capping compromises efficacy, and salvage therapy often results in poor outcomes [7].

Our findings of CIPN are lower than many other reports in recent years, including the Intergroup Trial Alliance/CALGB 50303, discussed previously. This study excluded PLWH and reported CIPN in > 80% of people receiving EPOCH ± R [3]. A prospective multicenter phase 2 study published by Dunleavy et al. (2019) on dose-adjusted EPOCH-R (n = 53) included five PLWH [37]. Grade 2 and 3 sensory neurotoxicity occurred in 11 and 4 persons, respectively (n = 15, 28.3%). Roschewski et al. (2020) examined EPOCH-R and Burkitt’s Lymphoma in a multi-site trial (n = 111), including 28 individuals (25%) with HIV [38]. Five people experienced grade 3 or 4 sensory neurotoxicity (21). Our lower CIPN rates may be due to underreporting by clinicians outside of a clinical trial as well as the retrospective nature of our study. Table 3 compares the incidence of neurotoxicity reported recently with EPOCH chemotherapy.

Table 3. Vincristine neurotoxicity associated with EPOCH-R.

Study	Year	Sample	HIV (%)	Target population	VCR Capping	Neurotoxicty n (%)
Bartlett et al.	2019	237 Prospective Multi-site Phase III trial	0	DLBCL	No	Neuropathy: Grade 1/2: 155 (65.4) Grade 3/4: 44 (18.6)
Dunleavy et al.	2019	53 Prospective Multi-site	5 (9)	MYC rearrangement aggressive B-cell lymphomas	No	Sensory Neuropathy: Grade 2/3 n = 15 (28.3) Motor Neuropathy: Grade 2/3 n = 7 (13.2)
Ramos et al.	2018	12 Prospective Multi-site Phase I^1	12 (100)	Aggressive B-cell lymphomas	No	Neurotoxicity: ≤ Grade 3: n = 8 (66.7)
Ramos et al.	2020	86 Prospective Multi-site Phase II^1	86 (100)	Aggressive B-cell lymphomas	No	Peripheral Neuropathy: Grade 1: 29% Grade 2: 44% Grade 3: 4%
Roschewski et al.	2020	111 Prospective Multi-site	28 (25)	Burkitt’s Lymphoma	No	Sensory Neuropathy: Grade 3/4 n = 5 (5) Motor Neuropathy: Grade ≥ 2 n = 7 (6)
Weiss et al.	2020	44 Retrospective Convenience	6 (13.6)	Aggressive B-cell lymphomas	No	Neuropathy: Grade 2: 37 (84) Grade 3: 10 (22.7)
Weiss et al.	2020	22 Retrospective Convenience	5 (22.7)	Aggressive B-cell lymphomas	Yes	Neuropathy: Grade 2: 9 (41) Grade 3: 1 (4.5)

¹ EPOCH-R + Vorinostat.

Certain classes of antiretroviral agents, including the pharmacoenhancers ritonavir and cobicistat, among others, inhibit cytochrome P450. Hypothetically, interactions with cART could increase neurotoxicity even more. Ramos et al. (2020) amended their protocol to prohibit strong CYP3A4 inhibitors after the death of a patient with a regimen containing cobicistat [16]. As mentioned previously, the NCCN strongly recommends avoiding strong CYP3A4 inhibitors to minimize toxicities [39]. While we were unable to collect data regarding the cART regimens for PLWH in our sample, we believe the lower incidence of CIPN is a direct result of our multidisciplinary team, including a pharmacist, as well as our tandem clinic with an infectious disease physician, highlighting the importance of collaboration with HIV specialists.

There are several limitations to our study that must be noted. The single-center, retrospective design limited the amount of data collected, including vincristine dose reductions. Vincristine dose exposure may have been significantly different between the groups, which may have affected lymphoma and CIPN outcomes. Additional clinical information would have been helpful, such as concomitant medications, including antiretroviral therapy, CD4 count, and HIV viral load. Drug-drug interactions are a possible risk factor for CIPN in PLWH. Changes in ART may have been required to minimize drug-drug interactions and CIPN. Most modern ART does not cause neuropathy. Additional time points to assess CIPN, including resolution and any dose reductions, would have been helpful. Although the PLWH was very small, this is the first study examining treatment toxicity by HIV status.

Conclusion

In conclusion, our retrospective cohort study is the first to date assessing CIPN in patients receiving EPOCH ± R, stratified by HIV status. Although the incidence of CIPN was lower in PLWH, the incidence of CIPN was clinically significant, affecting a substantial number of patients in our sample. Poor documentation of CIPN is a major problem that may negatively impact patient outcomes. Future research should establish patient-reported outcome measures and identify potential risk factors and biological markers in vincristine-associated peripheral neuropathy. Pharmacologic and nonpharmacologic interventions warrant investigation for the treatment and prevention of CIPN from vincristine. Future studies should examine the association between depression/anxiety and CIPN during treatment.  

Authors’ contributions

The study was conceived and designed by Gretchen McNally, Tracy Wiczer, Mark Lustberg, Robert Baiocchi and Maryam Lustberg. Data collection and analysis were performed by Gretchen McNally, Connor Aossey, Tracy Wiczer, Loraine Sinnott, and Maryam Lustberg. The first draft of the manuscript was written by Gretchen McNally and all authors commented and edited prior versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

Data provided by The Ohio State University Data Analytics Group.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.