A challenging case of an adolescent and young adult patient with high-risk acute lymphoblastic leukemia: the need for a multidisciplinary approach: a case report

Adolescents and young adults (AYA) diagnosed with acute lymphoblastic leukemia (ALL) have faced poorer survival rates compared with the history of this illness treatment in children [1]. However, several European and US studies have reported improved outcomes for AYA patients treated with pediatric-based protocols [2‐4]. however, AYA patients receiving pediatric regimens and doses, unlike children, have disproportionately increased toxicities affecting almost every organ and system [5], most likely due to pubertal changes, inadequate nutritional status, and altered drug metabolism [6]. The most common nonhematological toxicities in AYA patients during induction include hyperglycemia, febrile neutropenia, and transaminitis [3].

The aim of this paper is to present the case of an adolescent with high-risk ALL who experienced various adverse episodes throughout the intensive chemotherapy, including multiple frequent toxicities mentioned above. However, the focus of our interest is on rather rare entities, such as steroid-induced psychosis that seldom develops in children and adolescents, and choroid plexus hemosiderosis, infrequently identified as a first sign of iron overload.

A 15-year-old Caucasian male presented with painless cervical lymphadenopathy and excessive sweating. The patient’s family and psychosocial history was unremarkable. Moreover, no relevant past interventions were recorded in the adolescent’s medical history. Normocytic anemia (Hemoglobin 86 g/L Mean corpuscular volume 93.6fL), thrombocytopenia (Plt 49 × 10⁹/L), and blasts (36%) dominated in the peripheral blood. Bone marrow analysis by flow cytometry revealed the diagnosis of precursor B-ALL (60% of aberrant “common” B-cells by European Group for Immunological Classification of Leukemias (EGIL) classification; TdT+, CD19+, CD10+, CD79a+, citIgM−). A favorable hyperdiploid clone (55, XY,  X, +4, +6, +10, +14, +17, +18, +21, +21/46, XY) was detected by classical cytogenetic technique (G-banding). PBX1 gene duplication and tetrasomy of chromosome 21 were verified by fluorescence in situ hybridization (FISH). Clonal IgH and T-cell receptor (TCR) gene rearrangements were confirmed by molecular analysis (real-time polymerase chain reaction). No unfavorable cytogenetic or molecular disease features (for example, bcr/abl, KTM2A) were discovered. Additionally, next-generation sequencing (NGS) investigation of the tumor DNA revealed NRAS and CBL mutations but without potential therapeutic implications. No leukocytes or blasts were discovered in cerebrospinal fluid, and initial brain magnetic resonance (MR) was normal, thus central nervous system (CNS) was free of disease (CNS1 status). Diagnostic assessment was carried out according to the protocol’s standards, and no special (for example, financial) work-up or therapeutic challenges were encountered.

Chemotherapy according to the ALL-Intercontinental Berlin–Frankfurt–Münster (IC BFM) 2009 protocol was initiated, consisting of induction (prednisone, vincristine, daunorubicin, PEG-asparaginase, intrathecal methotrexate), early intensification (cyclophosphamide, cytarabine, 6-mercaptopurine, intrathecal methotrexate), consolidation (combination of dexamethasone, vincristine, vindensine HD-cytarabine, HD-methotrexate, cyclophosphamide, ifosfamide, PEG-asparaginase, etoposide, intrathecal therapy), and re-induction therapy (dexamethasone, vincristine, doxorubicin, PEG-asparaginase, cyclophosphamide, cytarabine, 6-thioguanine), followed by maintenance (6-mercaptopurine, methotrexate). While good prednisone response (peripheral absolute blast count < 1000/µL) was achieved by day 8 (peripheral absolute blast count 237/µL), flow cytometry minimal residual disease (FC-MRD) on day 15 and 33 was 28.9% and 0.03%, respectively. Solely due to high FC-MRD percentage of blasts (> 10%) on day 15, the patient was classified into high-risk (HR) disease group. Persistent minimal residual disease (MRD) (0.0012%) was detected by day 78, no MRD (0%) status was achieved prior to second high-risk block (consolidation), and the patient remained disease-free through further intensive chemotherapy course. Following the decision of the national transplantation team, the patient was not eligible for allogeneic hematopoietic transplantation.

Throughout the 10-month intensive chemotherapy, the patient experienced multiple toxicities of various degrees. Treatment-related adverse events of moderate to higher grade, according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, are listed in Table 1. The most troublesome complications warranting multidisciplinary approach are described in more detail below.

B-precursor HR-ALL AYA patients are known to have inferior outcomes and increased treatment-related toxicities compared with children [8]. Superior outcomes in AYA patients are, however, achieved by implementing more intensive, pediatric-type protocols, with survival rates reaching 70% [9]. Lower event-free and survival rates in AYA patients are, among other factors, due to unfavorable tumor biology. The frequency of Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL) and other HR abnormalities increases with age, in contrast to favorable cytogenetics in younger patients [9]. Although our patient displayed no disadvantageous genetic features, persistent MRD, known to be of extreme prognostic relevance, raised great concern. While MRD clearance, although slow, was still achieved in consolidation and allogeneic transplant avoided, a multitude of newly arising toxicities remained a challenge.

One in ten pediatric patients experiences hyperglycemia as a common side effect of ALL treatment [6]. Grade 3–4 hyperglycemia, a major concern in our patient throughout the treatment, was observed in almost 30% of AYA population treated with Children's Oncology Group (COG) pediatric-inspired chemotherapy regimens [10]. Higher proportion of steroid and asparaginase-related hyperglycemia in AYA patients might be the result of postpubertal hormonal changes, and given the former contradictory results, the correlation with infection predilection remains to be determined [6].

Although the frequency of febrile neutropenia (FN) in AYA patients is reported lower compared with younger individuals, our patient developed fever during hematologic aplasia in every stage of intensive chemotherapy. However, an association to hyperglycemia was not apparent [8]. Nevertheless, malnutrition has been repeatedly described as a predisposing factor for FN [11‐13].

Although less than 10% of AYA patients are malnourished at time of diagnosis, almost half of them experience more than 5% weight loss during cancer treatment [14]. Not only was our patient severely underweight (Body mass index, BMI 15.9 kg/m²) when first faced with hematologic malignancy, but significant weight loss (14%) was also observed during induction. High-risk disease and hyperglycemia, both present in our patient, among other features, are recognized as risk factors for negative weight trend during induction [15]. However, an early dietitian referral and specialist gastroenterologist involvement, along with timely enteral nutrition and supplement introduction, resulted in desirable weight gain at the end of intensive chemotherapy regimen (+4 kg).

Hepatotoxicity, sometimes severe, is a common side effect of contemporary pediatric ALL regimens, in one-fourth of cases occurring during induction, with obesity and age (> 15 years) being regarded as risk factors [16]. Transitory rise in transaminases in our patient followed every administration and was related to PEG-asparaginase exposure but never required any specific interventions nor treatment postponement (max ALT 342 U/L, AST 265 U/L, GGT 482 U/L). Other PEG-asparaginase attributable toxicities, such as hypersensitivity reactions, pancreatitis, and thromboembolic events, were not described in our patient [17]. However, therapeutic drug monitoring (TDM) was performed and dose modification conducted, possibly decreasing the occurrence of asparaginase-related adverse events.

Increased risk of high-dose methotrexate (MTX) renal toxicity was found to be correlated with delayed MTX elimination [18, 19]. Since serum creatinine levels and concentration of MTX after 48 hours had excellent value in predicting AKI, with area under the curve (AUC) of 89.2% and 96.8%, respectively, it is necessary to follow-up these values and initiate intravenous hydration, urine alkalization, and if necessary, renal replacement therapy on time.

Patients with HR-ALL are at higher risk for iron overload, accompanied by endocrine and liver dysfunction, compared with other risk groups, yet no regular iron status monitoring is routinely performed in many pediatric oncology centers [20, 21], a practice that our center should consider implementing. Accumulation of iron in the liver correlates with the amount of transfused iron, occurring rather early, after as much as ten transfusions, while for the iron to be loaded in the heart and endocrine organs, high transferrin saturations are needed [22]. Moreover, choroid plexus iron depositions, at any stage of treatment, have rarely been described in literature [23]. In our patient, the peak ferritin level correlated with neurological and psychological deterioration and characteristic brain MRI findings of iron overload (Fig. 2). Iron deposits of moderate intensity were verified by liver MRI, while heart tissue remained intact. Hereditary hemochromatosis gene (HFE) mutations, which aggravate iron overload in ALL patients, were not detected in our case [24]. Hepatic dysfunction, dysglycemia, and endocrine disorders, such as primary thyroid gland hypofunction, are organ abnormalities commonly related to hemosiderosis in literature [25]. Occasional hepatotoxicity, central hypothyroidism, and hypocortisolism in our patient were not considered to be related to hemosiderosis, as explained above, but preexisting nephropathy played an important role in iron chelation selection. Orally active once-daily deferasirox is a frequently preferred iron chelator, especially in the outpatient setting [25, 26], usually being well tolerated [27], as in our case. Nevertheless, regarding clinical presentation, neurological symptomatology could not be interpreted based on choroid plexus hemochromatosis, as it is mostly asymptomatic [23], so further elucidation was sought.

Steroid-induced psychosis, a variety of neuropsychiatric symptoms related to glucocorticoid use, is frequently described in adult populations rather than children, with fewer than 20 cases reported worldwide [28]. All routes of corticosteroid administration (oral, intravenous, inhalation) at any time point of treatment may provoke psychotic symptoms, but clear risk factors (for example, type and dose of glucocorticoid) have not yet been established [29]. Hippocampal injury caused by glucocorticoids, resulting in behavioral and emotional dysfunction, in pediatric patients with cancer might be aggravated by synergistic toxicity of other chemotherapeutic agents [30]. The hallucinations that arose in our patient with negative personal and family history of psychiatric disorders and that caused him significant stress and impairment were associated with recent steroid exposure, while infection, severe electrolyte, and serum glucose disorders were ruled out. Combination of an antipsychotic drug (for example, haloperidol) with steroid dose reduction or discontinuation is generally an effective treatment strategy [31]. Risperidone, a preferred antipsychotic in literature [28, 32], was also our child psychiatrist’s medication of choice, leading to complete symptom resolution. An optimal medicamental prophylactic approach (for example, carbamazepine, chlorpromazine, etc.) still needs to be determined [31].

In conclusion, treating an AYA patient with high-risk leukemia and multiple therapy-related morbidities remains a challenge, even in the era of abundant and effective supportive treatment. A timely and appropriate multidisciplinary approach is mandatory to ensure no significant delays, and modification in scheduled therapy is required, late effects diminished, and quality of life preserved, to achieve optimal treatment outcomes.