Acute Lymphoblastic Leukemia Regimens Research Articles

Hypoalbuminemia in children with acute lymphoblastic leukemia: relation to asparaginase therapy and impact on high dose methotrexate elimination

Abstract Purpose High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor. Methods To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25–29 g/L, C 30–34 g/L and D ≥ 35 g/L). Results Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%). Conclusion Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.

Achievement of therapeutic levels using dose-reduced peg-asparaginase in adult patients with acute lymphoblastic leukemia.

6530 Background: Peg-asparaginase (PEG) doses range from 2000-2500 IU/m2 in pediatric-inspired regimens for acute lymphoblastic leukemia (ALL). Pediatric PEG dosing in adolescents and young adults (AYAs) has resulted in improved outcomes, but PEG-associated toxicities increase with age and often limit its use. Therapeutic dosing is determined by asparagine (ASP) depletion for 14 days after dose; L-asparaginase levels can act as a surrogate marker of ASP depletion. We previously showed dose reduced PEG (defined as <2000 IU/m2) results in high rates of therapeutic L-asparaginase 7 days post PEG (Derman et al, Leuk Lymphoma 2020). Here we describe prolonged duration of ASP depletion and comparable toxicities after dose reduced PEG in adults with ALL. Methods: Patients ≥18 years with ALL or lymphoblastic lymphoma (LBL) who received PEG from 1/1/2008 to 9/28/2023 were identified for retrospective chart review. Those with ≥1 PEG trough level (defined as 10-20 days after dose) were included. The primary endpoint was therapeutic PEG levels (≥0.1IU/mL L-asparaginase) at 7 and 14 days post administration, with secondary endpoint being induction grade 3+ toxicities (CTCAE v.5.0). Results: 49 patients met inclusion criteria, of which 48 received PEG during induction. Median age was 34.7 (range 18-66), 67% were male and 53% had B-cell ALL. 17 (35%) received an induction dose ≤ 500 IU/m2, 22 (46%) received 501 to ≤1000 IU/m2 and 9 (19%) received >1000 IU/m2. Induction median dose was 1000 IU/m2. Among those with PEG trough levels, 79% were therapeutic after induction; of note, 4 patients were transitioned from PEG to Erwinia asparaginase due to silent inactivation. During induction, 23 (48%) patients had ≥1 grade 3+toxicity, including 5 (10%) with hepatotoxicity, 1 (2%) with pancreatitis, and 2 (4%) with a thrombotic event. There was no statistical relationship between dose level and toxicities (p=.8). Conclusions: This study demonstrates durability of therapeutic L-asparaginase levels and ASP depletion that persists 14 days despite dose reduction. There were decreased rates of hepatotoxicity and comparable rates of pancreatitis and thrombotic events compared to rates reported in CALBG 10403 (C10403) (Stock et al, Blood 2019), which utilized standard pediatric dosing. In addition, our cohort’s median age was significantly older than those treated on C10403. This suggests PEG dose reduction may offer similar therapeutic ASP depletion with comparable or reduced toxicities. Dose reduction should be studied prospectively in AYAs with ALL. [Table: see text]

Prognostic analysis of childhood T-lymphoblastic lymphoma treated with leukemia regimen

To investigate the prognosis of childhood T-lymphoblastic lymphoma (T-LBL) treated with acute lymphoblastic leukemia (ALL) regimen and related influencing factors. A retrospective analysis was performed for the prognostic characteristics of 29 children with T-LBL who were treated with ALL regimen (ALL-2009 or CCCG-ALL-2015 regimen) from May 2010 to May 2022. The 29 children with T-LBL had a 5-year overall survival (OS) rate of 84%±7% and an event-free survival (EFS) rate of 81%±8%. The children with B systemic symptoms (unexplained fever >38°C for more than 3 days; night sweats; weight loss >10% within 6 months) at initial diagnosis had a lower 5-year EFS rate compared to the children without B symptoms (P<0.05). The children with platelet count >400×109/L and involvement of both mediastinum and lymph nodes at initial diagnosis had lower 5-year OS rates (P<0.05). There were no significant differences in 5-year OS and EFS rates between the children treated with CCCG-ALL-2015 regimen and those treated with ALL-2009 regimen (P>0.05). Compared with the ALL-2009 regimen, the CCCG-ALL-2015 regimen reduced the frequency of high-dose methotrexate chemotherapy and the incidence rate of severe infections (P<0.05). The ALL regimen is safe and effective in children with T-LBL. Children with B systemic symptoms, platelet count >400×109/L, and involvement of both mediastinum and lymph nodes at initial diagnosis tend to have a poor prognosis. Reduction in the frequency of high-dose methotrexate chemotherapy can reduce the incidence rate of severe infections, but it does not affect prognosis.

Royal jelly induces ROS-mediated apoptosis in acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells: Shedding light on novel therapeutic approaches for ALL.

Until recently, a conventional chemotherapy regimen for Acute lymphoblastic leukemia (ALL) is considered an efficient therapeutic method in children. However, suboptimal long-term survival rates in adults, disease relapse, and drug-induced toxicities require novel therapeutic agents for ALL treatments. Today, natural products with pharmacological benefits play a significant role in treating different cancers. Among the most valued natural products, honey bees' royal jelly (RJ) is one of the most appreciated which has revealed anti-tumor activity against different human cancers. This study aimed to evaluate anti-leukemic properties and the molecular mechanisms of RJ cytotoxicity on ALL-derived Nalm-6 cells. The metabolic activity was measured by MTT assay. Apoptosis, cell distribution in the cell cycle, and intracellular reactive oxygen species (ROS) level were investigated using flow cytometry analysis. Moreover, quantitative real-time PCR (qRT-PCR) was performed to scrutinize the expression of various regulatory genes. RJ significantly decreased the viability of Nalm-6 cells but had no cytotoxic effect on normal cells. In addition, RJ induced ROS-mediated apoptosis by up-regulating pro-apoptotic genes while decreasing anti-apoptotic gene expression. The results outlined that ROS-dependent up-regulation of FOXO4 and Sirt1 inhibits the cells' transition to the S phase of the cell cycle through p21 up-regulation. The qRT-PCR analysis of autophagy-related gene expression also demonstrated that RJ induced BECN1 mediated autophagy in Naml-6 cells. Taken together, this study showed that RJ can be utilized as a potent natural substance to induce ALL cells' programmed cell death. However, further studies are required to examine this compound's pharmaceutical application.

The use of L-asparaginase for the treatment of solid tumors: data from experimental studies and clinical trials

Drug therapy is one of the main strategies of cancer treatment. L-asparaginase, the enzyme that hydrolyzes asparagine, has been included in the treatment regimens for acute lymphoblastic leukemia and other hematological malignancies since more than 50 years ago, but its use for the treatment of solid tumors is still extremely limited. This review analyzes experimental data on the sensitivity of cell lines and xenografts of solid tumors to L-asparaginase, examines the results of clinical trials. Among the mechanisms of the cytotoxic effect of L-asparaginase on tumor cells, such processes as depletion of aspartic and glutamic acids, influence on the internal and external pathways of apoptosis, inhibition of cellular processes through a decrease in the activity of the mTOR protein, and weakening of the expression of the telomerase gene are discussed. Separately, molecular markers are considered, which can be used to suggest the effectiveness of future therapy with L-asparaginase in solid tumors. These markers include expression levels of asparagine synthetase and glutamine synthetase genes, degree of methylation of the ASNS gene promoter region, PTEN protein activity and autophagy, bone marrow environment of tumor cells, as well as expression of genes associated with asparaginase resistance (such as the μ1 opioid receptor gene and the huntingtin-associated protein 1 gene).

Methotrexate Induced Central Nervous System Manifestations in Children Receiving Treatment for Acute Lymphoid Malignancies

Methotrexate (MTX) is an essential part of most chemotherapy regimens for acute lymphoblastic leukemia (ALL). It is administered intrathecally (IT), intravenously, and orally during ALL therapy. We performed a retrospective chart review to assess the central nervous system (CNS) manifestations induced by MTX in all children who received ALL therapy at our institution between July 2013 and June 2023. A list of patients with the ICD-9/10 codes for ALL or ALLy was obtained from the Electronic Medical Records for the study time period. Data collected included demographics, cytogenetics, laboratory test results, MTX pharmacological data if available, and details of the treatment of CNS manifestations attributable to MTX. Lastly, we had a single neuroradiologist re-review all the brain Magnetic Resonance Imaging (MRI) obtained in patients with MTX induced CNS manifestations. Sixty-five children were treated for ALL during the study decade. The average age at diagnosis was 4.7 ± 4 years. Our cohort consisted of 38 males and 27 females. Twelve of 65 patients (19%) developed MTX-induced CNS manifestations. The average age at the onset of symptoms was 5.3 ± 2 years. Ten patients had received a dose of IT MTX within 2 weeks of experiencing symptoms. Symptoms included raised intracranial pressure (ICP) (64%), headache (36%), confusion (36%), altered mental status (29%), and altered level of consciousness (29%). Treatment of MTX-induced CNS manifestations consisted of therapeutic drainage of cerebrospinal fluid (CSF) with their scheduled IT chemotherapy administration (65%), acetazolamide (57%), theophylline + leucovorin + dextromethorphan (64%), and addition of hydrocortisone with IT medications (36%). In 3 (25%) patients the subsequent doses of MTX were delayed. The symptoms of CNS manifestations resolved in 100% of cases and MTX was able to be readministered in all the patients. Only one patient had recurrence of CNS manifestations twice after rechallenging with MTX; however, with specific symptomatic treatment, was able to tolerate the remainder of the IT therapy inclusive of MTX. Brain MRIs were obtained in all patients. Initial imaging studies yielded normal results in 6 (50%) patients. Abnormal findings included subcortical white matter changes, vividly observed on T2/FLAIR MRI. These changes were represented by regions of acute hyperintensity seen in diffuse bilateral cerebral hemispheres (33%), parietal regions (33%), frontoparietal regions (17%), occipital regions (17%) and the left parietooccipital region (17%). A follow up MRI was performed 3 to 8 months after the initial MRI and was repeated up to 6 times over a course of 6 years in a patient. The earliest MRI improvement was evident after 3 months of initial imaging. About 20% of patients developed MTX induced CNS manifestations in our cohort. IT MTX was the most common culprit. Raised ICP, on opening pressure measured during IT procedures happened to be the most common finding. This has not widely been reported previously under MTX induced CNS complications in published data. One of the suspected etiologies is the inflammation of arachnoid villi impairing CSF drainage. These patients responded well to acetazolamide and therapeutic drainage of CSF. Finally subcortical while matter changes on T2/FLAIR MRI was a common CNS manifestation.

Acute Leukemias of Ambiguous Lineage Have Durable Response to Hypomethylating Agents Plus Venetoclax in Older Patients

Background: The standard of care for frontline therapy of acute leukemias of ambiguous lineage (ALAL) remains controversial due to their rarity; however, outcomes are generally poor. Intensive chemotherapy (IC) regimens are standard, with evidence suggesting that acute lymphoblastic leukemia regimens are more effective than those used for acute myeloid leukemia (AML). Strategies for treating older or frail patients are limited. Although treatment with a hypomethylating agent plus venetoclax (HMA/Ven) is standard therapy for IC-ineligible AML patients, the role of HMA/Ven in ALAL remains poorly characterized. We performed a retrospective chart review of patients at our institution with Philadelphia-negative ALAL, comparing the outcomes of those treated with HMA/Ven and those who received IC. Method: Patients ≥ 18 years treated at Weill Cornell Medical Center with newly diagnosed, pathologically confirmed acute undifferentiated leukemia (AUL), T/myeloid, or Philadelphia chromosome-negative B- and B/T-myeloid leukemia were included. Frontline HMA/Ven was defined as Ven plus azacytydine, decitabine, or oral decitabine/cedazuridine (one patient had initial HMA monotherapy followed by HMA/Ven). Intensive chemotherapy included patients who received variations of standard ALL or AML IC regimens (hyper- or mini-hyper-CV[A]D, cytarabine plus daunorubicin or idarubicin, or cladribine plus idarubicin and cytarabine) with or without Ven. Tyrosine kinase inhibitors including midostaurin or gilteritinib were added for patients with fms-like tyrosine kinase 3 ( FLT3) mutations. Baseline and disease characteristics were collected as well as disease response, subsequent lines of therapy, whether the patient proceeded to allogeneic hematopoietic cell transplantation (HCT), rate of morphologic complete remission (CR), and overall survival (OS). Results: Of 16 patients, 7 received frontline HMA/Ven. B/myeloid was the most common disease type (n=8), followed by T/myeloid (n=4), AUL (n=3), and 1 patient with B/T/myeloid disease. The median age was 74 years (interquartile range [IQR] 62-80). Patients who received HMA/Ven were older than those who received IC, with median ages of 79 (IQR: 77-82) and 62 (IQR: 56-70; p = 0.01), respectively. Baseline white blood cell, hemoglobin, platelet counts, and lactate dehydrogenase, as well as blast percentages in both peripheral blood and bone marrow were similar between the groups. Although not validated in ALAL, markers of adverse myeloid disease as per the ELN 2022 schema were prevalent in both groups, including mutations in RUNX1, ASXL1, SRSF2, and TP53 (Figure A). One HMA/Ven patient and 3 IC patients underwent HCT. Of evaluable patients, 83% and 88% of HMA/Ven and IC patients achieved CRs, respectively. At 2 years, both groups had 50% overall survival (95% CI 22.5-100 in both). Among HMA/Ven recipients, overall survival ranged from 10-56 months, not including two patients with ongoing follow-up at 3 and 46 months (Figure B). Discussion: The treatment of ALAL remains a challenge, particularly in older patients who may be unfit for intensive treatment strategies. In our study, patients who received HMA/Ven had similarly durable disease control to younger patients who received IC in the frontline setting. Prolonged responses were seen in both AUL and MPAL. Multicenter registry and prospective analyses are needed; however, given the rarity of these diagnoses, our findings suggest that HMA/Ven should be considered as a frontline therapy for unfit patients with ALAL.

Safety and Financial Analysis of Outpatient Hypercvad Arm a Administration for Acute Lymphoblastic Leukemia

The hyperCVAD chemotherapy regimen for acute lymphoblastic leukemia (ALL) traditionally requires patients to be admitted inpatient for administration due to the need for coordinating infusion times and managing toxicities. This may cause significant financial burden to the healthcare system and an emotional burden to patients and caregivers. Our institution established an Inpatient/Outpatient (IPOP) program in 2014 which specializes in outpatient administration of various high-risk chemotherapies, including hyperCVAD arm A. This study aims to evaluate the safety and financial impact of administering hyperCVAD arm A in the outpatient setting. A retrospective chart review was conducted on patients ≥18 years of age who received hyperCVAD arm A between January 2019 to July 2020 for treatment of B- or T-cell ALL at an National Cancer Institute-Designated Cancer Center in Florida. The primary endpoint of the study was the overall incidence of hospital admissions during outpatient chemotherapy administration during days 1 through 4 of hyperCVAD arms 2A, 3A, and 4A. Secondary endpoints included number of hospitalizations between cycles, number of hospital days saved by outpatient administration, infectious complications, adherence to institutional hematology/infectious diseases guidelines, and drug-related adverse events. Financial analysis was conducted based on reimbursement data and impact of hospital bed backfill to determine the overall financial impact outpatient hyperCVAD arm A administration. Direct margin was calculated by subtracting direct expense from reimbursement. Out of 83 patients who received hyperCVAD arm A during the examined time period, 42 (50%) met inclusion criteria. Majority of patients were excluded due to receiving hyperCVAD arm A for non-ALL indications (n=31) or receiving hyperCVAD for delayed intensification (n=3). A total of 103 cycles of hyperCVAD arm A were administered, with 56 cycles given in the outpatient setting to 26 patients. Based on an approximated 5 days of hospital admission required for administration of hyperCVAD arm A, administering the regimen via the IPOP service resulted in an estimated 280 days of avoided hospitalization for 26 patients. No patients were removed from the IPOP program due to adverse effects. One (4%) patient required hospitalization during days 1 through 4 of outpatient chemotherapy administration due to a non-ST-Elevation Myocardial Infarction. This patient was subsequently switched to blinatumomab treatment administered via the IPOP service. Eight (31%) patients were hospitalized after completing day 4 of each cycle for reasons not directly related to hyperCVAD arm A (table 2). Our reimbursement data found each outpatient cycle was associated with a 60% increase in margin compared to inpatient administration. Additionally, we expect a positive financial gain from backfilling of inpatient beds that would otherwise be occupied for approximately 5 days of hospitalization from hyperCVAD arm A administration. Considering the combined effect from these two factors, the administration of hyperCVAD arm A under the IPOP service resulted in a significant positive financial impact for our institution. Our findings provide evidence to support the administration of hyperCVAD arm A under the IPOP service is safe and feasible. Although there may be upfront costs associated with implementing an ambulatory program for administration of traditionally inpatient chemotherapy regimens, the outpatient approach demonstrated favorable financial implications and alleviated bed shortages.

Survival Outcomes, Efficacy and Tolerability of a Pediatric-Inspired Regimen (MASPORE) for Philadelphia-Negative Acute Lymphoblastic Leukemia in Young Adults at a Tertiary Hospital in Singapore

Introduction: Recent evidence has emerged to support the use of pediatric-inspired regimen as a standard of care in Adolescents and Young Adults (AYA) patients diagnosed with Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL). The backbone of the pediatric regimen is high cumulative doses of steroids, asparaginase, vincristine and more intensive CNS prophylaxis. Most literature, however, has been in the western population, with few data reported in Asia. MASPORE protocol is a locally designed pediatric-inspired regimen for treatment of ALL in AYA. The protocol uses a 3- or 4-drugs induction regimen (L-asparaginase, Vincristine, Dexamethasone +/- Daunorubicin) based on standard or high-risk disease. PCR-based measurable residual disease (MRD) marker was utilized for disease monitoring and dynamic risk stratification, which led to subsequent intensification of regimen as needed. Methods: In this IRB approved retrospective analysis, patients aged 18-39 years old with Ph- ALL who received MASPORE regimen from January 2009 to December 2021 at the National University Hospital Singapore were identified via our institution database. Treatment outcomes, including measurable residual disease (MRD) monitoring, and toxicity profile were analyzed. Survival outcomes were estimated using Kaplan-Meier method. High risk disease at diagnosis was defined as high white blood cell (&amp;gt;30x10 9/L for B-ALL, &amp;gt;100x10 9/L for T-ALL), hypodiploidy, t(4;11) and other MLL gene rearrangement. Results: 32 patients were identified during the study period; 3 patients were excluded due to incomplete data. The median age was 23 years old (range 18-33 years) with majority being male (86.2%). 16 patients (55.2%) had B-ALL and 13 (44.8%) had T-ALL. High risk disease was present in 7 (43.8%) B-ALL patients and 8 (61.5%) in T-ALL patients. 2 patients in B-ALL group had CNS involvement at diagnosis. The majority (96.5%) achieved complete remission after the induction phase. 1 patient died within first 1 month of treatment due to pancreatitis. 5 patients in high risk group received allogenic stem cell transplantation (alloSCT), whereas 2 patients with standard risk required alloSCT due to relapse and persistent MRD positivity. MRD result was available for 26 patients. In the entire cohort, MRD negativity was achieved in 22 patients (75.9%). Subtype was not associated with achievement of MRD negativity (80% in B-ALL vs 90.9% in T-ALL). High risk patients however had a lower odds of achieving MRD negativity after induction (OR 0.114 95% CI 0.017-0.742, p=0.021). The median follow-up for survivors was 41 months (range 27 to 89 months). Relapse and mortality rate was low at 13.8% each. 5-year OS for patients with B-ALL and T-ALL were 92.3% and 75.2%, respectively (Figure 1a). 5-year OS for patients with standard and high-risk disease were 84.4% and 84.0%, respectively (Figure 1b). Delayed achievement of MRD negativity (i.e. after induction) was not associated with inferior survival outcomes, albeit our sample size was small. In terms of adverse events, Asparaginase-related toxicities included 11 patients (37.9%) with thrombotic events (4 cerebral venous thrombosis and 7 deep vein thrombosis), and 5 patients (17.2%) with grade 2 or more pancreatitis. 7 patients (24.1%) had at least 1 episode of grade 3 or 4 transaminitis. 7 patients (24.1%) had grade 3 or 4 sepsis during the course of treatment. 2 patients developed osteonecrosis of the hip requiring operation and cessation of steroids. Conclusion: Our locally designed MASPORE protocol tailored in accordance to risk stratification demonstrated promising survival outcomes. Similar outcomes observed in standard and high-risk disease suggests the benefit of such an approach. Toxicities were mainly related to L-asparaginase use. Individualized dosing based on drug level monitoring will help to further optimize the treatment intensity with reduced toxicities.

Lack of benefit from premedication for pegylated asparaginase during pediatric acute lymphoblastic leukemia/lymphoma therapy: A side-by-side comparison.

Pegylated l-asparaginase (PEG) is integral to treatment regimens for acute lymphoblastic leukemia (ALL) and lymphoma. Hypersensitivity reactions (HSRs) to PEG are common and can preclude continued administration. Data supporting recommendations for universal premedication (UPM) prior to PEG infusion to reduce incidence of HSRs are limited; UPM has become common practice. Two free-standing children's hospitals independently implemented UPM prior to PEG infusions in 2016 and 2019, respectively. In a side-by-side retrospective analysis, incidence and severity of HSRs were analyzed pre- and postimplementation of UPM in youth ≥1 years old treated with frontline PEG-containing ALL regimens (2015-2018, 2016-2020). All HSRs were centrally reviewed within each institution to confirm and grade the HSR (Common Terminology Criteria for Adverse Events, v5). Planned analyses of subsets at potentially greater risk for HSRs included intensive PEG regimens (≥5 doses), adolescent and young adults (AYA), Hispanic/Latinx ethnicity, and obesity. In 410 patients (by institution, n=282 and n=128), the overall incidence of Grade≥3 HSRs was 20% (56 out of 282) and 18% (23 out of 128), respectively. No difference in incidence of Grade≥3 HSRs in patients with versus without UPM was found at either institution (23vs. 19%, p=.487 and 19vs. 17%, p=.845). UPM also did not reduce the severity of HSRs, nor influence HSR risk within any patient subset. UPM prior to PEG infusion did not alter incidence or severity of HSRs at either institution. HSR remains a common complication of PEG therapy, impacting the patient experience. Alternative strategies to reduce HSRs are urgently required.

Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis.

Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective. To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP. From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared. The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication. ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

How I approach B-lymphoblastic lymphoma in children.

There are limited data pertaining to the prognostic features and optimal therapeutic approach for the 20%-25% of children with lymphoblastic lymphoma (LLy) who have the B-lymphoblastic subtype. Outcomes are favorable following treatment modeled after acute lymphoblastic leukemia (ALL) regimens, but prognosis is dismal after relapse, and there are no established features for predicting therapy response. Ongoing US and international trials will include the largest cohort of uniformly treated patients with B-LLy to date, providing an opportunity to define clinical and molecular predictors of relapse and to establish a standard of care for treatment to improve outcomes for this rare pediatric cancer.

Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. BPDCN is most often characterized by its presentation with distinct cutaneous lesions. Bone marrow involvement, lymphadenopathy, splenomegaly, and/or cytopenias are also seen to varying degrees. BPDCN presents with diffuse, monomorphous blasts with irregular nuclei, fine chromatin, and scant, agranular cytoplasm. Expression of CD4, CD56, and CD123 is the hallmark of BPDCN. The presence of ≥4 of CD4, CD56, CD123, TCL1, TCF4, and CD303 is necessary for the diagnosis of BPDCN. Prior to December 2018, management of BPDCN revolved around intensive chemotherapy using acute myeloid leukemia or acute lymphoblastic leukemia regimens. However, responses were transient with poor overall survival (OS). Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for BPDCN. Even so, only a minority of patients are candidates for alloSCT given the preponderance of disease in older individuals. For the few fit patients who are candidates for alloSCT, the aim is to achieve complete remission prior to alloSCT. Tagraxofusp (SL-401), a recombinant fusion protein containing interleukin-3 fused to truncated diphtheria toxin, was the first approved CD123-targeted therapy for BPDCN based on a phase I/II clinical trial showing a 90% overall response rate. It was approved by the FDA on December 21, 2018. Capillary leak syndrome is an important adverse effect of tagraxofusp that requires close monitoring. Several clinical trials are underway to study other regimens for the treatment of BPDCN, including IMGN632 (pivekimab sunirine), venetoclax (alone and in combination with hypomethylating agents), CAR-T cells, and bispecific monoclonal antibodies.

Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

High-dose methotrexate (HD-MTX; 5000mg/m2 ) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity, which may disproportionately affect Latino children. This study evaluated risk factors for neurotoxicity after HD-MTX in an ethnically diverse population of patients with ALL. The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Children's Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32; 95% CI, 0.98-11.21; p=.05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80; 95% CI, 1.39-24.17; p=.02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Proactive therapeutic drug monitoring of vincristine in pediatric and adult cancer patients: current supporting evidence and future efforts.

Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN.Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure-clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole.

Outpatient Administration of High-Dose Methotrexate for Leukemia and Lymphoma in Adults without Drug Monitoring: Risk Factors for Acute Kidney Injury

Introduction: Methotrexate is an antifolate that has been an essential part of regimens for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, inducing critical organ damage and death if not early detected and treated. Therefore, these regimens are usually administered in the hospital, with intravenous (IV) hydration, drug level, urine pH monitoring, and MTX-guided leucovorin rescue. Although some factors for drug-induced acute kidney injury (AKI) have been pointed and recommendations are published, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes. Methods This is a retrospective nested case-control study conducted at an academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Most patients with ALL received a 6-hour infusion, while those with NHL received a 2-hour infusion in a day clinic, along with intravenous hydration, urine alkalinization, and leucovorin rescue. Patients were followed outpatient by a multidisciplinary team. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Hematologic and liver toxicity were graduated according to CTCAE v5.0. Conditional logistic regression was used to find baseline risk factors. Results A total of 404 patients received at least one HDMTX infusion, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis, followed by other NHL subtypes (25.5%). Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Characteristics of cases are summarized in Table 1. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p=0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p=0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p=0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p=0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p=0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], see figure 1). Among those patients with AKI, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p=0.03). Concerning remaining toxicities, grade 3 or more thrombocytopenia, neutropenia, and hyperbilirubinemia were found in 36%, 64%, and 36%, respectively. 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Conclusions Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Feasibility and Improvement in Survival with a Risk-Adapted Treatment Regimen for Childhood Acute Lymphoblastic Leukemia in a Limited Resource Setting

Introduction: High-intensity therapeutic regimens results in ALL have not been reproduced in limited resource settings, due to the lack of appropriate support therapy, diagnostic methods, limited access to drugs, and high treatment related mortality. For low and middle-income countries, treatment of these patients represents a challenge. In Mexico acute leukemia represents 49% of all pediatric cancers, with a 5-year overall survival between 50 and 60%, a relapse rate of 26%, induction related mortality of 3-10%, and a mortality in remission of 14%. We report the results of an adjusted treatment regimen based on an adapted risk stratification for a limited-resource setting. Objective: To implement a risk stratified treatment protocol for a limited resource setting, with the aim of reducing induction related mortality, and improving EFS and OS. Materials and Methods: From January 2017 to March 2020, all patients diagnosed with ALL between 0 and 15 years of age in a single center in northeast México were captured in a prospectively maintained database. Depending on risk stratification, patients received an adjusted treatment protocol with variations on intensity and duration for the different phases. The main differences were the amount of anthracycline doses during induction (2 for low, 3 for intermediate/high patients), the requirement of at least 20 doses of L-asparaginase for intermediate/high risk patients, and the use of Capizzi-style methotrexate for intermediate risk and high-dose methotrexate only for high-risk patients (Table1). Demographic data was reported using distribution analysis, and the Kaplan-Meier method was used to analyze and predict OS and EFS. Results: There were 59 male and 41 female patients; the median age at diagnosis was 5.5 years. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 94% and 6% patients, respectively, with a follow-up of 41 (0.33-65) months. Regarding risk stratification, 42%, 34%, and 24% children were classified as high, intermediate, and low-risk, respectively. After one week of corticosteroids 80% of patients had a good response, and 84% of patients achieved a negative measurable residual disease (MRD) after induction chemotherapy. Estimated EFS and OS at 5 years were 70% and 77.5% respectively. Of the 93 patients evaluable for response, MRD positivity (16%), induction related mortality (6%), and relapse (16%) rates were lower in this cohort when contrasted with previous protocols. EFS for low, intermediate, and high-risk groups was 73%, 85%, and 56% and OS 88%, 90% and 61% (Figure 1) Conclusions: The implementation of a risk-adjusted chemotherapy regimen adapted for our limited-resource center, improved treatment continuity and was associated with better OS, and EFS. Early relapse rates were also reduced, without increasing induction mortality associated with toxicity. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and standardize therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Comparison of Outcomes in Hispanic and Non-Hispanic Patients with Ph-Negative Acute Lymphoblastic Leukemia Using the Modified Pediatric-Based University of Southern California Acute Lymphoblastic Leukemia (USC ALL) Regimen in the Era of Novel Agents

INTRODUCTION: Hispanic patients with acute lymphoblastic leukemia (ALL) are historically known to have poor outcomes compared to non-Hispanic patients which may be associated with healthcare disparities, although further elucidation is needed. Since we take care of a large population of Hispanic patients, we now report further updated outcomes in Hispanic compared to Non-Hispanic ALL patients using the modified USC ALL regimen in the era of novel agents like blinatumomab and inotuzumab. METHODS: This retrospective chart review included adults 18 years old with newly diagnosed Ph-negative ALL (2016-2020). Primary objectives were 3-year over-all survival (OS), event-free survival (EFS) and disease-free survival (DFS) stratified by MRD flow status and blinatumomab use. Secondary objectives were complete remission/complete remission with incomplete recovery (CR/CRi), MRD by flow, descriptive statistics of patients stratified into Hispanic and non-Hispanic cohorts evaluated using Fisher's exact test. OS, DFS, EFS reported through Kaplan Meier curves and Log-rank tests. Two-sided p-value ≤0.05 was significant. RESULTS: 121 Ph-negative ALL patients were reviewed. 87 Hispanic patients (HP) and 34 non-Hispanic patients (NHP). Median ages in HP and NHP were 39 and 35 years; median BMI 29 and 26.9 kg/ m2 (p=0.42-0.51), respectively. About equal males and females in HP while NHP had 70.6% males compared to 29.4% females (p=0.08). Both HP and NHP were mainly Ph-negative ALL, 50.6% vs 47.1%, 25.4% vs 20.6% were Ph-like, respectively (p=0.884). Most of our population had unfavorable risk by NCCN, 86.8% in HP and 90.5% in NHP (p=0.99). 71.1% HP and 62.5% NHP received PEG during induction 1 (p=0.37), and 69.6% of HP and 63% of NHP received PEG during induction 2 (p=0.52). After induction 1: 91.1% of HP and 80% in NHP achieved CR/Cri (p=0.18). 55.7% of HP and 40.9% of NHP achieved MRD negativity by flow (p=0.23). After induction 2: 92.7% of HP and 79% of NHP achieved CR/CRi, with 7.3% in HP being refractory compared to 21.1% of NHP (p=0.19). 73.3% of HP and 64.7% of NHP achieved MRD negativity by flow (p=0.54). 26.4% of HP and 35.3% of NHP had relapse (p=0.33), 4.6% of HP and 20.6% of NHP had refractory disease (p=0.01), while 4.6% of HP compared to 20.6% of NHP died (p=0.27). Blinatumomab was given in 35.6% of HP and 32.3% of NHP (p=0.73). Meanwhile only 6.9% of HP and 2.9% of NHP received inotuzumab (p=0.67). 39.1% of HP underwent allogenic hematopoietic stem cell transplant (allo-HSCT) versus 26.5% in NHP (p=0.19). 26.4% HP and NHP who received blinatumomab did not undergo allo-HSCT. 3.4% of HP and 11.8% of NHP underwent CAR-T (p=0.096). 3y OS was 82.4% in HP vs 75.8% in NHP (p=0.18). 3y EFS was 58.6% in HP vs 43.7% in NHP (p=0.008). 3y DFS was 62.4% in HP vs 57.1% in NHP (p=0.08). In HP when stratified by MRD flow negativity post induction, there was no statistically significant difference in 3y OS (79.1% vs 90%) (p=0.4), 3y DFS 65.9% vs 60.4% (p=0.8) and 3y EFS 65.9% vs 52.9% (p=0.66). In NHP when stratified by MRD flow negativity post induction, there was also no statistically significant difference in 3y OS (100% vs 88.9%) (p=0.56), 3y DFS (75% vs 67.5%) (p=0.84) and 3y EFS (75% vs 67.5%) (p=0.8). Of note, when survival is stratified by blinatumomab use, in HP: 3y OS 71.6% vs 88.3% (p=0.14), 3y EFS was 27.8% vs 76.6% (p=0.001), 3y DFS was 37.2% vs 76.6% (p=0.001) (Fig 1-2). In NHP: 3y OS 72.7% vs 77.7% (p=0.56), 3y EFS was 36.4% vs 44.4% (p=0.2), 3y DFS was 42.4% vs 64% (p=0.02). No clear difference in grade 3/4 PEG toxicities were found in HP compared to NHP except grade 4 hypertriglyceridemia which was noted more in HP 31.3% compared to 9.7% in NHP (p=0.019). CONCLUSIONS: Our updated data shows a trend to better outcomes in HP compared to NHP in terms of OS and DFS, and a statistically significantly better EFS in the Hispanic population. Having MRD negativity by flow showed no statistically significant difference in both groups. Of note, 3y EFS and 3y DFS were significantly lower in HP who received blinatumomab since these patients were MRD flow positive and lacked deeper remissions, but 3y OS (71.6%) remained high regardless, even though 26.4% who received blinatumomab were not able to go for allo-HSCT. In NHP, the trend is like that of HP but less pronounced. This suggests the beneficial effect of blinatumomab especially in Hispanic patients. Further follow-up is necessary to provide a more robust and mature survival data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diagnostic challenge in mixed phenotype acute leukemia with T/megakaryocyte or T/myeloid lineages accompanied by t(3;3)

BackgroundThe diagnosis of mixed phenotype acute leukemia (MPAL) with T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is always a challenge. Therefore, multiple experimental methods are usually required to avoid misdiagnosis. In this report, we presented a rare case of MPAL with T/myeloid lineages accompanied by t(3;3) and discussed the experience of differential diagnosis and our appreciation of the MPAL with T/megakaryocyte and T/myeloid lineages accompanied by t(3;3).Case presentation:A 31-year-old woman was admitted to our hospital due to recurrent fever for 20 days. Two distinct blast populations were detected by flow cytometry analysis: one population fulfills the immunophenotypic criteria for T-lymphoblastic leukemia, while the other population is highly suggestive of megakaryoblasts. These immunophenotypic features support the diagnosis of MPAL (T/megakaryocyte), which is rarely reported​. Interestingly, a complex karyotype was detected afterward by cytogenetics with t(3;3)(q21;q26.2), indicating a diagnosis of AML with t(3;3), a subset of which is also characterized by megakaryocytic markers such as CD41 and CD61. It seems that the second blast population detected by flow cytometry could not be classified into either diagnosis based on the morphology, immunophenotyping, and even cytogenetic findings, posing a real diagnostic problem because of the lack of clear-cut cytogenetic morphological defined criteria to distinguish between acute megakaryocytic leukemia and AML with t(3;3). Combining all of the examination data, this case was ultimately diagnosed as MPAL (T + My)-NOS with t(3;3) through differential diagnosis. Before the cytogenetic results were available, the patient received an acute lymphoblastic leukemia (ALL) regimen for MPAL treatment, but the effect was unsatisfactory. After the diagnosis was clear, she received an AML-like regimen with azacitidine for 7 days and venetoclax for 14 days, and achieved complete morphological remission.ConclusionMPAL with either T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is rare, and it is difficult to make a clear diagnosis. Thus, comprehensive examinations, including bone marrow cell morphology, flow cytometry analysis, cytogenetics, and molecular analysis are recommended to avoid misdiagnosis. AML-like regimen including azacitidine and venetoclax may be effective for treating MPAL (T + My)-NOS with t(3;3).

RISK FACTORS FOR ACUTE KIDNEY INJURY IN OUTPATIENT ADMINISTRATION OF HIGH-DOSE METHOTREXATE IN ADULTS WITHOUT DRUG MONITORING

Methotrexate is an antifolate that has been an essential part of chemotherapy regimens for acute lymphoblastic leukemia (ALL) and specific subtypes of non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, possibly inducing critical organ damage and death if not early treated. Although some factors for drug-induced acute kidney injury (AKI) have been pointed out, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes in a real-life setting. This is a retrospective nested case-control study conducted at a large academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Conditional logistic regression was used to find baseline risk factors. A total of 404 patients received at least one HDMTX, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis. Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p = 0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p = 0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p = 0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p = 0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p = 0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], p = 0.06). Among these cases, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p = 0.03). 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.