Safety of temozolomide use in adult patients with renal dysfunction

Abstract

Purpose

Temozolomide (TMZ), a cytotoxic DNA alkylating agent, is the main chemotherapy used for the treatment of high grade astrocytomas. The active alkylator, methylhydrazine, is not recovered in urine and thus renal function is not expected to affect clearance. Prescribing information for TMZ states pharmacokinetics have not been studied in adults with poor renal function, eGFR < 36 mL/min/1.73 m². We reviewed our clinical experience with TMZ in patients with impaired renal function to evaluate safety of administering full dose TMZ.

Methods

The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with eGFR < 60 mL/min/1.73 m² who received TMZ for treatment of high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphopenia hepatotoxicity, and number of TMZ cycles administered. Medical records of patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019 were accessed to identify cases for this study.

Results

Thirty-two patients were eligible for this study. Of the seven patients with eGFR < 36 mL/min/1.73m², 38/39 cycles (97%) were completed without grade 3–4 thrombocytopenia. No patients experienced grade 3–4 neutropenia, and grade 3–4 lymphopenia occurred in 5 cycles (15%). One patient discontinued TMZ 7 days prior to completion of radiation due to thrombocytopenia.

Conclusion

Hematologic toxicity in patients with severe renal dysfunction, eGFR < 36 mL/min/1.73m², is similar to that of patients with normal renal function. Severe renal impairment does not preclude use of temozolomide, but cautious monitoring of blood counts is warranted.

Introduction

Temozolomide (TMZ) is a cytotoxic DNA alkylating agent of the imidazotetrazine class that sought FDA approval in 1999 for the treatment of glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) at first relapse, in addition to first line treatment for patients with metastatic melanoma [1]. Currently, TMZ is FDA approved for the treatment of adult patients with newly diagnosed GBM in combination with radiotherapy for 6 weeks followed by maintenance or adjuvant treatment with TMZ for 6 cycles. Additionally, it is utilized in patients with refractory AA who progress on a nitrosurea and procarbazine [2]. Since its initial approval, the National Comprehensive Cancer Network (NCCN) has established recommendations and expanded utilization of TMZ in the treatment of numerous malignancies including other central nervous system malignancies, lymphomas, neuroendocrine and adrenal tumors, and soft tissue sarcomas [3]

TMZ is a prodrug that is hydrolyzed to its active form 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC) and temozolamide acid metabolite [4]. Upon further hydrolysis, MTIC is converted to 5-amino-imidazole-4-carboxamide (AIC), an intermediate compound in the biosynthesis of purines and nucleic acids as well as methylhydrazine, the active alkylating species. Approximately 38% of the total radioactive dose of TMZ is recovered over a 7-day period, 37.7% in the urine and 0.8% in the feces. That which is recovered in the urine is unchanged TMZ (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) 17% [4]. Population pharmacokinetics from the phase II data that contributed to the FDA new drug application demonstrated no effect of renal function defined as, CrCl 36 to 230 mL/min/m², on the clearance of TMZ [2]. TMZ administration in patients with severe renal impairment defined as eGFR < 36 mL/min/m² was not studied and therefore prescribing information recommends to use TMZ with caution in this population. To our knowledge, this will be the first description of TMZ use in adult patients with eGFR < 36 mL/min/m². Institutions have set individual precedent for utilization of TMZ in this population as there are often no alternative treatment options that prolong overall survival in patients with high grade glioma (HGG). As the active alkylating species, methylhydrazine, is not recovered in the urine, we hypothesized that eGFR < 36 mL/min/m² would not impact clearance of TMZ. This retrospective study was to determine our institutional experience on safety of administration of TMZ in patients with eGFR < 36 mL/min/m².

Materials and methods

This retrospective, single-institution, observational study was approved by the Johns Hopkins Medicine Institutional Review Board. The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with renal impairment who received TMZ for the treatment of their HGG or PCNSL. Secondary endpoints were to characterize the incidence and severity of neutropenia, lymphopenia, hepatotoxicity, and number of cycles administered in patients with renal impairment defined as eGFR < 60 mL/min/1.73m² who received TMZ for the treatment of their HGG or primary CNS lymphoma (PCNSL). Patients were identified via targeted reports produced from Epic Systems electronic medical record utilizing ICD-10 codes. Patients were stratified into the following categories by renal function: eGFR 45–59 mL/min/1.73m², eGFR 30–44 mL/min/1.73m², eGFR 15–29 mL/min/1.73m², and eGFR < 15 mL/min/1.73m² in accordance with the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines for chronic kidney disease evaluation and management [5]. Additionally, due to specifications for renal impairment made in the TMZ package insert, eGFR 36 mL/min/1.73m² was also a specified category [2]. Glomerular filtration rate (eGFR) was calculated utilizing the CKD-EPI creatinine equation in accordance with the KDIGO 2012 guidelines for chronic kidney disease evaluation and management [5].

Included patients were at least 18 years of age with HGG or PCNSL who started treatment and received at least one dose of TMZ with eGFR < 60 mL/min/1.73m² through The Johns Hopkins Hospital or Sibley Memorial Hospital between October 1, 2016 and September 30, 2019. Patients were excluded if they were actively enrolled in a clinical trial for systemic treatment of their HGG or PCSNSL while receiving concurrent TMZ, if baseline platelet (PLT) count was < 100,000 cells/mm³ and/or absolute neutrophil count (ANC) < 1000 cells/mm³, if they received metronomic TMZ, or were diagnosed with an acute venous thromboembolism (VTE) defined as diagnosis within 4 weeks of starting TMZ [8]. Patients with HGG received a regimen of radiation therapy, generally 60 Gy, and concomitant daily TMZ at a dose of 75 mg/m² for six weeks followed by a planned six cycles of adjuvant TMZ at a dose of 150–200 mg/m² daily on days 1–5 of each 28 day cycle [6]. Patients with PCNSL received TMZ 150 mg/m² per day for 5 days every 28 days plus rituximab 375 mg/m²/dose with or without high dose methotrexate (HDMTX). The HDMTX dose for patients was adjusted based on their creatinine clearance [9].

Medical charts were reviewed to obtain data at the start of therapy within the abovementioned treatment period. For each cycle TMZ dose received and cycle start date were recorded along with baseline and nadir for the following: platelet count (PLT), absolute neutrophil count (ANC), and lymphocyte count. Additionally, baseline and maximum aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, creatinine, and transfusions received were recorded. Furthermore, any visits to the emergency department, urgent care, and hospitalizations were recorded.

Grading of hematologic toxicity was based upon the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [10]. Grade 3 defined as severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living or grade 4 defined as life-threatening consequences; urgent intervention indicated were noted. Key severe grade 3 or 4 hematologic parameters were noted as follows: thrombocytopenia (grade 3, < 50,000–25,000/mm³; grade 4, < 25,000/mm³), lymphopenia (grade 3, < 500–200/mm³; grade 4, < 200/mm³), neutropenia (grade 3, < 1000–500/mm³; grade 4, < 500/mm³). Descriptive statistics were utilized to describe endpoints.

Results

A total of 32 patients with eGFR < 60 mL/min/1.73m² at least at one point during therapy met inclusion criteria; with a resultant 149 completed TMZ cycles. Clinical characteristics for included patients are described in Tables 1 and 2. Seven patients, four with GBM and three with PCNSL, were in the lowest renal function group (eGFR < 36 mL/min/1.73m²) at least at one point during therapy as displayed in Table 3. A patient with an eGFR of 28 mL/min/1.73m² during chemoradiation for their GBM treatment experienced severe thrombocytopenia and required discontinuation of TMZ and platelet transfusions. This patient also experienced severe lymphopenia. Adjuvant TMZ was held. Other drug therapies concomitantly received during time of therapy for this patient were reviewed. Sulfamethoxazole-trimethoprim 800–160 mg three times weekly was administered for prophylaxis against Pneumocystis jirovvecii pneumonia (PJP), however no concomitant drug therapy administered has been associated with > 10% incidence of thrombocytopenia in the literature. No patients with HGG experienced severe thrombocytopenia during adjuvant therapy. No patients with PCNSL experienced severe thrombocytopenia as demonstrated in Fig. 1. Additionally, no patients with HGG or PCNSL experienced severe neutropenia, Fig. 2, and severe lymphopenia occurred in 2 patients as demonstrated in Fig. 3. On a cycle level, 38/39 total cycles (97%) were completed without severe thrombocytopenia in patients who had eGFR < 36 mL/min/1.73m² at least at 1 point during therapy. A total of 21/22 cycles (95%) that were in the setting of an eGFR < 36 mL/min/1.73m² at that time were completed without development of severe thrombocytopenia.

Table 1.

Baseline characteristics of patients with renal dysfunction treated with temozolomide

	All patients (n = 32)
Sex	19 (59%)
Male	13 (41%)
Female
Age (years)	1 (3%)
30–40	2 (6%)
41–50	4 (13%)
51–60	10 (31%)
61–70	12 (38%)
71–80	3 (9%)
81–90
Race	27 (84%)
White	4 (13%)
Black	1 (3%)
Asian
Tissue diagnosis	20 (63%)
Glioblastoma	1 (3%)
Gliosarcoma	2 (6%)
Anaplastic astrocytoma	9 (28%)
Primary CNS lymphoma

Table 2.

Incidence of adverse effects per cycle in patients with eGFR < 36 mL/min/1.73 m² during that specific cycle

eGFR mL/min/1.73m2	Number of cycles	Grade 3/4 thrombocytopenia	Grade 3/4 neutropenia	Grade 3/4 lymphopenia	Grade 3/4 transaminitis	Grade 3/4 T.Bili increased
< 36	22	1	0	5	0	0

Table 3.

Minimum eGFR (mL/min/1.73m²) per cycle for patients with eGFR < 36 mL/min/1.73m² at least at one point during therapy Key: ––– (unavailable), cycles with eGFR < 36 are italicized

	Cycle 1	Cycle 2	Cycle 3	Cycle 4	Cycle 5	Cycle 6	Cycle 7	Cycle 8	Cycle 9	Cycle 10	Cycle 11	Cycle 12
Patient 1	33	29	33	33	33
Patient 2	22	36	29	24	29	24	24
Patient 3	35	21	52	41
Patient 4	28	30	33	31	29
Patient 5	28
Patient 6	33	34	40	39	40	––––	37	44	44	48	41	41
Patient 7	27	49	55	58	62

Fig. 1.

Characterization of platelet count (K/cu mm) for patients with eGFR < 36 mL/min/1.73 m2 during therapy Key: (Grade 3 thrombocytopenia), (Concomitant XRT + TMZ)

Fig. 2.

Characterization of absolute neutrophil count (ANC) (K/cu mm) for patients with eGFR < 36 mL/min/1.73 m2 during therapy Key: (Grade 3 neutropenia), (Concomitant XRT + TMZ)

Fig. 3.

Characterization of absolute lymphocyte count (K/cu mm) for patients with eGFR < 36 mL/min/1.73 m2 during therapy Key: (Grade 3 lymphopenia), (Concomitant XRT + TMZ)

Discussion

This study supports the hypothesis of a lack of clinical impact of renal function on safety of temozolomide use. The active alkylating species, methylhydrazine, is not recovered in the urine and thus renal function was not expected to affect clearance of this agent. For patients with HGG, there is no alternative systemic therapy that prolongs overall survival. At this institution, we therefore elected to administer full dose TMZ. A previously reported phase III clinical trial in patients with newly diagnosed glioblastoma treated with concomitant daily TMZ and RT followed by adjuvant monthly TMZ for 6 cycles, reported an incidence of severe thrombocytopenia of 9/287 patients (3%) during concomitant therapy, and in 32/287 (11%) of patients during adjuvant temozolomide therapy [6]. Additionally, a retrospective review including patients with newly diagnosed HGGs reported severe thrombocytopenia in 10/52 patients (19%; 95% CI 10%-33%) [7]. Within our limited sample size of patients with HGG and eGFR < 36 mL/min/1.73m², severe thrombocytopenia was seen in one of four, 25% of patients [6]. This severe thrombocytopenia occurred during concomitant chemoradiation. The clinical impact of concomitant radiation therapy on myelosuppression cannot be underestimated. Another study revealed patients who received concomitant therapy with chemotherapy, carmustine and cisplatin, and cranial radiation therapy had an increased platelet transfusion requirement but no significant worsening of anemia, a significantly higher incidence of leukopenia, and a significantly lower median white blood cell nadir per cycle [7, 11]. Additionally, 96 patients were included in another study with median CD4 count of 664 cells/mm² before radiation and temozolomide. Two months after initiating therapy, 73% of patients had CD4 counts < 300 cells/mm³ with 40% of CD4 counts < 200 cells/mm³ [12]. Incidence of grade 3–4 (severe) thrombocytopenia in our retrospective study was in alignment with what was revealed in the aforementioned study which reported real world incidence [7]. This was in contrast with that which was reported as part of the randomized controlled trial [6]. This perhaps highlights the value of real world data and its application to our patient population, although our study was limited by small sample size. Patients with eGFR < 36 mL/min/1.73m² did develop severe lymphopenia, however this did not affect their clinical course. Patients receive prophylaxis for PJP per institutional protocol from at the start of therapy with TMZ and continue through their adjuvant TMZ course or until their CD4 count recovers. As noted above, there were five total patients that developed severe thrombocytopenia with eGFR < 60 mL/min/1.73m², one of those patients had eGFR < 36 mL/min/1.73m². Similarly, three patients with eGFR < 60 mL/min/1.73m² experienced severe neutropenia and 11 developed lymphopenia while no patients experienced severe neutropenia or lymphopenia with eGFR < 36 mL/min/1.73m². This further confirms the notion that renal impairment does not predict myelosuppression or potentiate toxicity. Limitations of the study include as mentioned previously a small sample size including patients with only CNS malignancies, the retrospective design, and inclusion of patients from a single health-system.

In conclusion, administration of TMZ to this patient population may have been previously cautioned, limited, or avoided due to lack of data and recommendations against use provided in the package insert. Experience at our institution indicates that TMZ can be administered to patients with eGFR < 36 mL/min/1.73m² with a similar side effect profile to patients without renal dysfunction. However, cautious monitoring of blood counts and chemistries is advised.