Whereas the survival for pediatric ALL was 10–20% 50 years ago, today᾿s long-term overall survival rates are approximately 80–90% . Much of this improvement in survival can be attributed to developing the most effective chemotherapy therapies, better disease risk stratification, and improved supportive care . The present study’s most commonly encountered toxicities in HDMTX cycles were hematological (neutropenia and anemia), oral mucositis, increased serum creatinine, thrombocytopenia, and increased ALT. These results showed much resemblance to other studies, but with varying frequencies [17, 18]. In the present study, except for oral mucositis and length of hospitalization, toxicities of HDMTX did not differ significantly between the 2.5 g/m2 and the 5 g/m2 HDMTX cycles. This agrees with other studies [19, 20], confirming that irrespective of the MTX dose, the toxicity of HDMTX was still comparable. The present work was also consistent with other studies reporting significantly reduced rates of oral mucositis with 5 g/m2 HDMTX compared to lower HDMTX doses [21, 22]. This finding might be explained by the greater cumulative LV dosages, and the more vigorous pre-hydration procedures used in the 5 g/m2 HDMTX when compared to the lower HDMTX doses . On the other hand, hospitalization due to MTX toxicity was significantly longer in the 5 g/m2 HDMTX cycles than the 2.5 g/m2 HDMTX cycles. This may reflect that the toxicities related to higher HDMTX doses needed a longer time to resolve.
In agreement with the present study results, Reiss et al.  had reported that hypoalbuminemia before HDMTX infusion was associated with anemia in adults with leukemia or lymphoma. They also observed that patients with lower albumin levels (≤3.4g/dL) had significantly longer hospitalization.
In our study, anemia, thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia when compared to cycles with normal pre-infusion albumin. Furthermore, pre-infusion hypoalbuminemia was found to be associated with G3–4 anemia and G3–4 thrombocytopenia. There was no significant difference in pre-infusion hemoglobin levels or platelets between cycles with and without hypoalbuminemia. The higher toxicity rates with hypoalbuminemia could be explained by the fact that low albumin levels are associated with delayed clearance of MTX with a potential increase in the risk of toxicity .
On the other hand, no significant relationship could be detected between pre-infusion hypoalbuminemia with G3–4 neutropenia, hepatotoxicity, or nephrotoxicity. Wiczer et al.  investigated variables that may contribute to methotrexate-induced renal toxicity in adults receiving HDMTX for treatment of leukemia or lymphoma, and they observed that low serum albumin (<3 g/dL) was a significant risk factor for nephrotoxicity. This difference may be due to the higher cutoff value of albumin used in our study.
Recognized drug interactions may delay MTX clearance and increase toxicity. Drugs that delay MTX renal secretion through possible blockage of proximal transporters are mainly involved in interactions that have a major clinical impact (toxicity) and should be avoided. Penicillin, NSAIDs, salicylic acid, and proton pump inhibitors are examples of these medications . The presence of concomitant drugs during HDMTX infusion and clearance in the present study was only reported in 7/120 (5.8%) of all HDMTX cycles. So, we were not able to assess drug–drug interactions and the possible potentiation of HDMTX toxicity.
The MTX24 level is particularly relevant for monitoring after HDMTX as it reflects the steady-state concentration during infusion. Kataoka et al.  who investigated 74 adults receiving HDMTX recommended MTX24 monitoring in patients with low albumin levels (<3.7 g/dL) to detect high-peak MTX concentrations that occurred as a result of delayed clearance. According to the total XV protocol, target 24-h MTX steady-state plasma concentrations are 33 and 65 μmol/L for the low risk and the standard/high-risk arms, respectively . In the present study, 5/15 (33.3%) and 2/15 (13.3%) of patients who received HDMTX at 2.5 g/m2 and 5 g/m2 had higher MTX24 levels than the targeted for this MTX dose. Three out of the seven high MTX24 levels were associated with pre-infusion hypoalbuminemia. Reiss et al.  compared time to MTX clearance (defined as the first documented time the MTX level ≤0.05 μmol) between patients with normal albumin levels and patients with hypoalbuminemia and found that hypoalbuminemia was significantly associated with longer MTX clearance time (median 96 vs. 72 h, p=0.004).
Malnutrition (undernutrition, overweight, and obesity) in children with cancer is associated with overall worse outcomes from diagnosis to long-term survival . In the current study, 2/30 (6.7%), 4/30 (13.3%), and 2/30 (6.7%) of children were underweight, overweight, and obese, respectively. These percentages are higher than that reported in a multi-center study conducted by the Middle East Childhood Cancer Alliance , where 0.5% and 3.1% of children with ALL were underweight and obese at diagnosis, respectively. Nevertheless, the BMI Z-scores calculated in the present study were based on weights measured after steroid therapy in the induction phase.
Seki et al.  observed that weight gain is often observed in children with ALL who undergo chemotherapeutic treatment, including steroids. Although it may be thought a transient phenomenon, Withycombe et al.  found that the increase of BMI Z-scores during induction was an independent predictor of obesity at the end of therapy. A recent study identified obesity and large size as new risk factors for delayed MTX elimination in patients aged 10.2 to 19.2 years old treated with HDMTX . Interestingly, a study showed a negative association between obesity and albumin level among children . In the present study, there was no significant relationship between hypoalbuminemia and the nutritional status of patients indicated by BMI Z-scores. In addition, there were no significant differences in HDMTX-related toxicities between malnourished patients and those without malnutrition. These contradicting results may be due to the small number of malnourished ALL children enrolled in the present study.
The present study highlights the importance of optimizing serum albumin levels of children once recognized as future HDMTX candidates. A nutrition specialist should be involved early in the multi-disciplinary team treating children with ALL. Raising serum albumin can be gradually achieved by applying a proper nutritional plan to avoid potential HDMTX toxicities . Other strategies of rapidly correcting serum albumin levels using human serum albumin are not encouraged. The majority of infused human serum albumin is redistributed into the extravascular space within 48 h, and therefore, it would be costly, temporary, and of uncertain benefit .
On the other hand, the present study had some limitations. First, we had a relatively small sample size, having only 38 cycles with hypoalbuminemia. Second, plasma MTX levels could not be estimated in all cycles and at more time points post-HDMTX infusion due to the unavailability of the test at our center and its high cost.