Feasibility of Delivering High-Dose Methotrexate in Adolescent and Adult All Patients: A Retrospective Study

Abstract

Introduction HD-MTX is a key drug in the treatment protocols for ALL. The regimen needs to be administered with appropriate supportive measures and serum methotrexate level monitoring. A limited testing strategy is relevant in resource constraint settings since it allows a shorter duration of hospitalization. We report our experience with this strategy and its impact on the patient safety outcomes. Methods This is a retrospective study of all patients ≥ 15 years of age with newly diagnosed ALL or Lymphoblastic lymphoma (LBL) who were administered HDMTX (part of BFM-90 ALL protocol) at our institute between March 2013 to November 2013.The medical records were reviewed for clinical characteristics, disease-related details, HDMTX dose and cycles administered, leucovorin rescue and toxicities. Results A total of 423 cycles of HD-MTX were administered to 106 patients during the study period. The median duration for completion of all 4 cycles of HDMTX was 53 (IQR 49–60) days. The grade 3 or higher toxicities were anemia in 9.6%, neutropenia 19.4%, febrile neutropenia 5.7%, thrombocytopenia 4.4% and mucositis in 0.7%. There was statistically significant correlation between the levels at 42 h (≤ 1 mmol/L vs > 1 mmol/L) and toxicity- anemia, FN and mucositis observed more in the late clearance group. With limited sampling strategy whereby if the 42- hour level MTX level are < 1 mmol/L, 57% of patients could be discharged early. Conclusion HD-MTX can be safely administered to adolescent and adult ALL patients. A limited methotrexate level monitoring is a safe strategy that can optimize the resources better.

Introduction

High-dose Methotrexate (HD-MTX) is a key drug in the treatment protocols for acute lymphoblastic leukemia (ALL)¹. It can lead to significant toxicities in up to 10% of cases, with the risk being higher in adolescent and adult patients [1]. The regimen needs to be administered with appropriate supportive measures and serum methotrexate level monitoring [2]. We need to hospitalize the patients to administer the drug, hydrate, alkalize and monitor drug levels [3]. MTX level measurements at three time points, i.e. at 24, 42, and 48 h after the start of MTX infusion is recommended to detect a delay in clearance [3, 4]. Additional levels at 36 and 54 h are also recommended if the measured concentration at 24 and 48 h is above the expected values [4]. Serial monitoring of MTX levels help in deciding the dose and schedule of leucovorin rescue and is expected to prevent toxicities [4, 5]. Retrospective studies in pediatric ALL have reported that limited testing may be sufficient but whether the same is applicable in adolescent and adult ALL patients who are at an increased risk of toxicities is unknown [6]. A limited testing strategy is also relevant in our setting since it allows a shorter duration of hospitalization and encourages centers with limited testing facilities to deliver high-dose methotrexate. We routinely deliver HD-MTX to our AYA-ALL ( Adolescents Young Adults)cohort as an inpatient and discharge them early if the MTX level is < 1 mmol/L at 42 hours [7]. We report our experience with this strategy and its impact on the patient safety outcomes.

Methods

This is a retrospective study of all patients ≥ 15 years of age with newly diagnosed ALL or LBL who were administered HDMTX at our institute between March 2013 to November 2013. ALL patients were risk-stratified based on the baseline WBC count(> 30(X10⁹)/L for B ALL and > 100(X10⁹)/L for T ALL), Cytogenetics (high-risk cytogenetics included t(9;22), t(4;11), t(1;19)), and ploidy(hypodiploidy) [8, 9]. Patients with any of these factors were risk-stratified as high risk and others as standard risk. All patients received modified BFM 90 ALL protocol irrespective of the risk. Response assessment was done post Phase I_a of induction with bone marrow morphology and flow cytometry. Bone marrow response was assessed using the M Bone marrow criteria for ALL; if M0 to M1 status (blast cells < 5%) was achieved, the patient was considered to be a responder (in Clinical Remission) as reported in Stock et al [10]. MRD assessment was performed at the end of phase-I_a induction on the first-pull BM aspirate sample using 8 to 10-color flow cytometry assays [11, 12] MRD level of < 0∙01% was considered as negative and ≥ 0∙01% was considered as positiv [13].

The medical records of all patients who received 'M' phase- HD MTX of modified BFM 90 protocol [7] were reviewed for clinical characteristics, disease-related details, HDMTX dose and cycles administered, leucovorin rescue and toxicities. Toxicity was recorded as per the National Cancer Institute common toxicity criteria (common terminology criteria for adverse effects [CTCAE] version 4.0). The toxicity occurring in all patients was recorded for each cycle of HDMTX for the analysis. Patients were treated with modification of HDMTX doses to 3 g/m² for four doses administered during the 'M' phase. Pre-infusion alkaline hydration was carried out at 3L/m²/day until 2 consecutive urine pH was more than 7. After ensuring urine pH ≥ 7, initial 10% of the calculated MTX dose was given over 30 min and the rest 90% over 23.5 h. Alkaline pH was ensured for the duration of each cycle. Strict input and output charting were maintained. The serum MTX level was measured using enzyme immunoassay in our center at 42 h from the start of MTX infusion. Leucovorin rescue was commenced at the same time. The dose administered was 30 mg/m² for the first dose and 15 mg/m² every 6 h subsequently. Patients with a 42-h MTX level less than 1 mmol/L were discharged and prescribed a total of 6 doses of 15 mg/m2 oral leucovorin. Patients with levels more than 1 mmol/L, were kept admitted and MTX levels were monitored every 6 hourly and subsequent doses of leucovorin were administered as given in Table 1. Hydration fluid used was 0.45% normal saline or 5%dextrose with 8.4% sodium bicarbonate(40 mmol/L) without any potassium supplements. Leucovorin rescue and MTX level monitoring were continued until methotrexate concentration decreased to below 0.30 mmol/L.

Table 1.

Leucovorin rescue as per MTX level

MTX level at 42 h	Leucovorin rescue
> 1–2 mmol/L	Leucovorin 30 mg/m2
> 2–3 mmol/L	Leucovorin 45 mg/m2
> 3–4 mmol/L	Leucovorin 60 mg/m2
> 4–5 mmol/L	Leucovorin 75 mg/m2
> 5 mmol/L	MTX serum concentration in mmol/L x body weight in kg

MTX level should be < 1 mmol/L at 42 h, < 0.4 mmol/L at 48 h. Continue Leucovorin rescue until MTX concentration decreases to below 0.30 mmol/L

Results

Patient and Tumor Characteristics

Total 122 patients with ALL or LBL were treated during the study period. Out of 122 patients, 106 patients received HDMTX and the rest 16 either progressed post induction (7 patients) or died of septicemia (9 patients) during induction chemotherapy. A total of 423 cycles of HD-MTX were administered. The baseline characteristics are described in Table 2.

Table 2.

Baseline characteristics of patient

Characteristics	Total number of patients, n = 106 (%)
Age	15–30 years-75
	31–40 years-15
	41–50 years-13
	> 50 years-3
Median (Range)	22 (15–53)
Gender
Male	76 (72%)
Female	30 (28%)
Diagnosis
B ALL	54 (51%)
T ALL	46 (43%)
Others	6(6%)
Hyperleukocytosis (> 100,000/mm3) at presentation
Yes	22 (21%)
No	84 (79%)
Baseline CSF involvement	17 (16%)
Remission status post induction
Morphological-remission	98 (92%)
Not in remission	8 (8%)
Bone Marrow MRD post Ph Ia
Negative (< 0.01%)	67 (63%)
Positive (> 0.01%)	39 (37%)

Treatment Details

All patients received modified BFM-90 ALL protocol including HDMTX doses of 3 gm/m² The serum MTX level at 42 h from the start of infusion was documented. This report was available within 6 h in all patients. At 42 h, MTX level ≤ 1 mmol/L was documented in 241 of 423(57.1%) cycles while it was > 1 mmol/L in 182 of 423 cycles (42.9%). The median duration for completion of all 4 cycles of HDMTX was 53 (IQR 49–60) days.

Toxicity Details

Out of 106 patients, anemia was seen in 96 patients (90%), neutropenia in 81 patients (76%), thrombocytopenia in 70 patients (66%) and mucositis in 16 patients (15%). The grade 3 or more toxicities were anemia in 28 patients (26%), neutropenia in 44 patients (42%), thrombocytopenia 10 patients (9%) and mucositis 2 patients (2%).

Out of the total 423 cycles administered, anemia was the most common toxicity observed in 226 cycles (53.4%) followed by neutropenia in 206 cycles (48.7%).Thrombocytopenia occurred in 147 cycles (34.8%), mucositis in 47 cycles (11.1%) and acute renal injury was noted in 3 cycles (0.7%).The various grade 3 or higher toxicities seen were anemia in 41 cycles (9.6%), neutropenia in 82 cycles (19.4%), febrile neutropenia(FN) in 24 cycles (5.7%), thrombocytopenia in 19 cycles (4.4%) and mucositis in 3 cycles (0.7%). No patient developed long term renal injury owing to HDMTX. Overall, the toxicities were manageable in our cohort with no death owing to its toxicity.

Early clearance vs late clearance group: The incidence of FN was 5 (2.1%) in the early clearance group while it was 19(10.4%) in the late clearance group. Only three episodes (1.6%) were associated with renal toxicity in the latter group. There was statistically significant correlation between the levels at 42 h sampling (≤ 1 mmol/L vs > 1 mmol/L) and toxicity- anemia, febrile neutropenia and mucositis being observed more in the late clearance group. The incidence of toxicity with early and delayed clearance is shown in Table 3. One patient required discontinuation of high dose methotrexate because of CNS toxicity(encephalopathy) after the 3rd cycle of high dose methotrexate in the late clearance group.

Table 3.

Toxicity profile

Toxicity	All CTCAE grades		p-value	Grade 3/4		p-value
	42 h MTX ≤ 1, n = 241 (56.9%)	42 h MTX > 1, n = 182 (43.1%)		42 h MTX ≤ 1, n = 241 (56.9%)	42 h MTX > 1, n = 182 (43.1%)
Anemia	96 (39.8%)	130(71.4%)	0.2 X 10–9	13(5.4%)	28(15.4%)	0.001
Neutropenia	121(50.2%)	85(46.7%)	0.54	39(16.2%)	43(23.6%)	0.073
Febrile neutropenia	5(2.1%)	19(10.4%)	0.0005	5(2.1%)	19(10.4%)	0.0005
Thrombocytopenia	80(33.2%)	67(36.8%)	0.50	9(3.7%)	10(5.5%)	0.53
Mucositis	19(7.9%)	28(15.4%)	0.16	0	3(1.6%)	0.157
Acute Kidney injury	0	3 (1.6%)	0.157	0	0	–

Discussion

We report the safety and feasibility of administering HD-MTX from a retrospective cohort of adolescent and adult ALL patients treated with High-dose methotrexate in our institute. A total of 106 patients were administered HD-MTX in the 6-month study period accounting for a total of 423 infusions. In this older population, HD-MTX is feasible with only 10% patients developing clinically significant grade 3 or 4 toxicities. The drug can be delivered with a limited sampling strategy, with only 1 serum MTX level being sufficient in 57% of cases. HD-MTX is a critical drug in adolescent and adult ALL patients [14]. The dose varies in different protocols, but a dose of at least 2 gm/m2 is recommended [14, 15]. We use a dose of 3 g/m² in our cohort based on our earlier observation of increased toxicities with the 5 g/m² dosing strategy. Our patient population consists of predominantly male patients, which is representative of the gender bias in our setting. This has been reported earlier as well and reflects the social factors in seeking medical care [7]. The other characteristics, especially the immunophenotype and baseline total counts including the proportion with hyperleukocytosis are similar to other studies [16–18]. We had a significant number (31/106) of patients (29%) aged more than 30 years in our study. In our cohort of relatively elder population, four cycles were possible in the majority of our patients with only 1 requiring dose modification/discontinuation. The toxicities were also manageable, with grade 3 or 4 clinically relevant toxicities like anemia, febrile neutropenia and thrombocytopenia occurring in only 5–10%.

The incidence of mucositis in our setting was 11.5%. As compared to other pediatric study¹⁹ were the incidence was 17%. We also observed that though higher MTX level (> 1 mmol/L) was associated with increased incidence of oral mucositis (15.4 vs 7.9%), it was not statistically significant (p = 0.16).

Myelosuppression was the most common side effect seen in our patients. Similar observation was seen in a study of pediatric ALL patients where the incidence of anemia, neutropenia and thrombocytopenia were 62 ,64 and 37% with Grade ¾ toxicities seen in 10%, 43% and 14% respectively [20]. The hematological toxicities in our study were comparable and HDMTX was better tolerated compared to pediatric patients. The incidence of febrile neutropenia was 5.7% in our cohort. Similar study Vaishnavi et al [20] conducted in pediatric patients showed the incidence of febrile neutropenia was 9%. The difference in incidence of FN can be explained as in study Vaishnavi et al [20] the high risk pediatric ALL patients received ≥ 4 g/m2 of MTX which may have contributed to high incidence of FN.

We follow a limited sampling strategy whereby if the 42- hour level are ≤ 1, the patients are discharged. This is based on the premise that the subsequent hydration and leucovorin doses can be taken at home. This allows us to shorten the admission and maintain the dose intensity for the patients with a limited number of beds. With this strategy 57% of patients could be discharged early. The toxicities in this cohort were less compared to those patients who had a higher drug level. Similar observation was seen in the study by Khera et al [19], it was seen that incidence of FN was 2% in patients with MTX level > 1 mmol/L at 36 h as compared to none in patients with < 1 mmol/L.

While it may be feasible to administer HDMTX without TDM, it seems prudent to do limited TDM if MTX levels tests are available. But repeated testing may not be feasible in a resource constraint setting like our center which is one of leading cancer centers in South-East Asia. In another study from India Kapoor et al [6] recommended doing at least one drug level following MTX administration and the suggested time point was 42 h.

The strength of our study is in the number of patients studied, uniformity in delivering the methotrexate and the completeness of the data. The limitations of this study are lack of long-term follow-up data. We cannot identify any difference in terms of efficacy, since the analysis was not meant to answer this question.

The optimal strategy of delivering HD-MTX still remains a topic of research. The recent COG studies have even questioned the value of delivering HD-MTX particularly in the T-ALL cohort, where a Capizzi like regimen was found to be superior [21]. There is a need to define the dose and method of administration in adult ALL.

Conclusion

HD-MTX can be safely administered to the adolescent and adult ALL patient population. A limited methotrexate level monitoring is a safe strategy that can optimize the resources better.

Author contributions

Conceptualization: Hasmukh Jain, Jayashree Thorat, V.N. Avinash Bonda, Manju Sengar; Methodology: Hasmukh Jain, Jayashree Thorat, V.N. Avinash Bonda, Manju Sengar; Software Goutam Panda, Ramnath Shenoy, Hasmukh Jain, Jayashree Thorat; Validation: Hasmukh Jain, Jayashree Thorat, V.N. Avinash Bonda, Manju Sengar; Formal analysis: Goutam Panda, Ramnath Shenoy, Hasmukh Jain, Jayashree Thorat; Writing – original draft: Ramnath Shenoy, Goutam Panda, Hasmukh Jain, Jayashree Thorat; Writing – review & editing: Ramnath Shenoy, Goutam Panda, Hasmukh Jain, Jayashree Thorat; Supervision: Hasmukh Jain, Jayashree Thorat, V.N. Avinash Bonda, Manju Sengar; Project Administration: Hasmukh Jain, Jayashree Thorat, Manju Sengar; Funding Acquisition: Nil.

Funding

None.

Declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

The study involves a retrospective analysis of data and in compliance with ethical standards.

Consent to participate

This is a retrospective study hence for this type of study formal consent is not required.

Consent for publication

This is a retrospective study hence for this type of study formal consent is not required.