Acute Lymphoblastic Leukemia: Pharmacologic Management

Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric leukemia and makes up one-quarter of cancer cases among adolescents and children younger than 15 years.^1,2 An estimated 6540 people will be diagnosed with the hematologic malignancy in 2023.³ Of these new cases, approximately 53.5% are expected to affect children and adolescents younger than 20 years.³ 

Although the incidence rates of ALL rates have increased in recent decades, outcomes have improved; the 5-year survival rate has risen from 31% a half century ago to more than 70% in recent years.^3,4 Approximately 90% of children live at least 5 years following receipt of a diagnosis of ALL, but prognoses remain dismal for those older than 50 years.⁴

ALL develops via uncontrolled clonal proliferation of lymphoid progenitor cells in the lymphoid compartment. The cell of origin is pre-B cells in 80% to 85% of cases, T cells in 10% to 15% of cases, and mature B cells in less than 5% of cases.⁵

Acute Lymphoblastic Leukemia Treatment 

Risk Stratification

Treatment recommendations for ALL are primarily dependent on stratification into risk groups based on various clinical and laboratory factors. This enables clinicians to offer appropriate treatment of aggressive leukemia while sparing patients with good prognostic factors from more toxic therapies.^2,5

The National Cancer Institute (NCI) stratifies children, adolescents, and young adults with ALL into risk groups based on 2 factors: patients with less than 50,000 white blood cells per µL and who are between the ages of 1 and 10 years are considered to be standard risk, while patients with at least 50,000 white blood cells per µL and/or those aged 10 years and older are considered high risk.²

In 2007, the Children’s Oncology Group (COG) developed a risk stratification system for pediatric ALL patients. This system takes into account⁶: 

• NCI risk group at diagnosis
• Cytogenetic findings, including extreme hypodiploidy (fewer than 44 chromosomes), trisomy (an additional chromosome), and the presence of fusion genes such as BCR/ABL or TEL/AML1
• Response to therapy, based on minimal residual disease (MRD) on day 29 of induction treatment
• Presence of extramedullary disease, including testicular or central nervous system (CNS) involvement

Another risk stratification strategy, developed by the Berlin-Frankfurt-Münster group, identified slightly different risk groups²: 

• Patients who have negative MRD upon completion of induction therapy (week 5 of therapy) and consolidation therapy (week 12) are in the standard-risk group
• Patients who have high MRD (more than 5 x 10^-4 ALL cells) upon the end of induction therapy and negative MRD at the end of consolidation therapy are in the intermediate-risk group
• Patients who have high MRD at the end of consolidation therapy and all patients with T-cell ALL (T-ALL) who exhibit a poor response to prednisone are in the high-risk group

For adults with ALL, age and white blood cell count are prognostic factors that can help inform treatment decisions.⁷ Treatment plans for adult populations also tend to be based on a patient’s response to treatment and presence of MRD after the initial induction therapy phase. 

Management of B-Cell Acute Lymphoblastic Leukemia in Children

Induction Therapy

Remission induction chemotherapy for B-cell ALL (B-ALL)  generally lasts for 4 weeks. This treatment phase aims to achieve a complete response, which can typically be reached in 98% of patients. However, infants and pediatric patients with high leukocyte counts at diagnosis may be slightly less likely to experience a complete remission.²

Standard B-ALL pharmacologic treatment in children typically includes some combination of the following²:

• A corticosteroid such as prednisone or dexamethasone
• Vincristine
• Asparaginase, including pegaspargase, calaspargase pegol, or asparaginase Erwinia chrysanthemi 
• An anthracycline such as daunorubicin or doxorubicin
• Cyclophosphamide
• Intrathecal chemotherapy

Treatment regimens from the Berlin-Frankfurt-Münster group typically include a corticosteroid, an anthracycline, vincristine, and asparaginase. Protocols from the Cancer and Leukemia Group B (CALGB) use a similar regimen with the addition of cyclophosphamide. For patients at NCI standard risk, COG trials use a corticosteroid, vincristine, and pegaspargase. Patients at NCI high risk receive a corticosteroid, vincristine, pegaspargase, and an anthracycline.²

Prophylactic intrathecal chemotherapy is an important part of pediatric ALL treatment regimens. Without this treatment, at least 50% of patients with ALL will experience spread of blasts to their CNS.⁸

The Philadelphia chromosome (Ph), which leads to the formation of the BCR-ABL1 transgene, is much less common in children with ALL than in adults with ALL. Approximately 3% of children with ALL have Ph-positive disease. The current treatment regimen for patients with this cytogenetic feature includes the use of tyrosine kinase inhibitors (TKIs) in addition to chemotherapy. Dasatinib is more capable of infiltrating the CNS compared with imatinib, and children, adolescents, and young adults with Ph-positive ALL tend to experience improved outcomes when treated with dasatinib.⁴

Consolidation Therapy

At the end of induction therapy, patients should be assessed for complete remission. Historically, patients were considered to have achieved complete remission if their bone marrow had fewer than 5% lymphoblasts. More recently, the Ponte-di-Legno Consortium established that complete remission should entail achieving MRD of less than 1% and/or M1 cytomorphology in addition to having no evidence of extramedullary disease, including the absence of blasts in the CNS and testes. Measurement of MRD should be performed using techniques like next-generation sequencing (NGS), allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), reverse transcriptase PCR (RT-PCR), or flow cytometry.^2,9

Once complete remission has been achieved, patients receive intensified (high-dose) therapy. The goal of this treatment phase, known as the consolidation phase, is to eradicate any remaining leukemia cells and help ensure that blasts do not become drug resistant.^2,8 Consolidation therapy, which is typically administered in cycles over the span of 3 to 6 months, often consists of^2,8,10:

• Cyclophosphamide
• Low-dose cytarabine
• Mercaptopurine
• Intrathecal therapy

Anthracyclines and alkylating agents are not typically recommended during the consolidation phase, as they may lead to long-term adverse effects. However, they are more commonly recommended for pediatric patients with high-risk B-ALL. Children with very-high-risk ALL may also receive additional therapies, including high-dose cytarabine, etoposide, or ifosfamide.¹⁰

The addition of blinatumomab to the consolidation phase may improve pediatric ALL survival rates.¹¹

Maintenance Therapy 

In pediatric patients, maintenance therapy typically lasts between 2 and 3 years. This treatment phase, which consists of lower chemotherapy doses, helps prevent relapse of leukemia.⁸

Maintenance therapy in pediatric patients often includes low-dose methotrexate (given once per week) and mercaptopurine (administered daily). In many cases, it also includes continuing intrathecal therapy.²

Some groups have adopted variations of this regimen. For example, some schemas add additional doses of vincristine and pegaspargase for higher-risk patients. Some regimens also include gradually increasing doses of methotrexate. Lower-risk patients, on the other hand, may have some doses eliminated or truncated.²

Intrathecal Therapy 

Intrathecal chemotherapy aims to prevent the spread of leukemic cells to the CNS or to kill blasts that have already become established in the CNS.²

In children with ALL, intrathecal therapy consists of methotrexate with or without hydrocortisone and cytarabine. Systemic chemotherapies that also contribute to CNS prophylaxis include dexamethasone, asparaginase, and high-dose or escalating-dose methotrexate.²

When CNS involvement is present at diagnosis of ALL, intrathecal chemotherapy is generally combined with cranial radiation therapy.²

The intensity of intrathecal treatments should be based on a patient’s risk level. Patients are at higher risk and may require more intensive prophylactic therapy if they have ≥5 white blood cells per µL within the cerebrospinal fluid (CSF) at the time of diagnosis. Additionally, patients with fewer than 5 white blood cells per µL in the CNS and those who have received a traumatic lumbar puncture that resulted in blasts in the CSF are at increased risk for relapse within the CNS.²

Treatment of Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia

Treatment for relapsed ALL begins with reinduction therapy, which aims to bring about another complete remission. The reinduction phase may be similar to the induction phase administered during the initial diagnosis or it may consist of high doses of both cytarabine and methotrexate.⁴ Blinatumomab may also be an option. This medication, a bispecific T-cell engager that recognizes both CD3 (found on T cells) and CD19 (found on B cells), has been approved by the US Food and Drug Administration (FDA) for both children and adults with B-ALL in the first or second complete remission.¹²

Following reinduction therapy, blinatumomab or allogeneic hematopoietic stem cell transplantation (HSCT) is recommended for patients who experience early relapse and for those who experience late relapse with high MRD at the end of reinduction therapy. It is not yet clear whether HSCT or chemotherapy provides better outcomes for other late relapses.² 

Chimeric antigen receptor (CAR) T-cell therapy may also be an option for pediatric patients with relapsed or refractory B-ALL. During this treatment, a patient’s T cells are harvested and genetically engineered to target B cells, typically through the CD19 antigen.² 

Treatment for CNS relapses is typically accomplished with intensive systemic chemotherapy, intrathecal chemotherapy, and radiation therapy. Other options that may improve prognosis include HSCT and CAR T-cell therapy. Testicular relapses generally include chemotherapy paired with local radiation treatments.²

Management of T-Cell Acute Lymphoblastic Leukemia in Children

Most treatment regimens use intensive multiagent chemotherapy containing an anthracycline for all pediatric patients with T-ALL, regardless of risk level.¹³ For example, COG recommends the following regimen²: 

• A corticosteroid
• Vincristine
• Pegaspargase
• An anthracycline

Pediatric patients with T-ALL are less likely to achieve a complete remission by the end of induction therapy and often benefit from an early consolidation phase.^2,13

It is more difficult to bring about another complete remission in the setting of relapsed pediatric T-ALL compared with B-ALL. Relapsed or refractory T-ALL is often treated with nelarabine, with or without cyclophosphamide and etoposide. If a second complete remission is achieved, HSCT is typically recommended.²

Management of Mature B-Cell Acute Lymphoblastic Leukemia in Children

Rituximab is an approved treatment for newly diagnosed pediatric ALL arising from mature B-cell populations. This anti-CD20 monoclonal antibody can be administered along with chemotherapy in pediatric patients older than 6 months.¹⁴ 

Induction therapy is often extremely effective in children with mature B-cell ALL. When relapses develop, they typically occur within a year of treatment. Therefore, maintenance therapy is typically not recommended.¹⁵ 

Management of Acute Lymphoblastic Leukemia in Adults

Adolescents and young adults with ALL tend to have a better prognosis when they receive pediatric treatment regimens compared with regimens designed for adults.² Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that adolescents and young adults receive regimens inspired by pediatric treatment schema.¹⁵ 

Induction Therapy 

NCCN guidelines recommend that adults with Ph-negative disease receive multiagent chemotherapy or participate in a clinical trial as part of induction therapy. Alternatively, patients who are at least 65 years old or who have severe comorbidities may opt for palliative care with a corticosteroid.¹⁵

A common chemotherapeutic regimen for adults with ALL is hyper-CVAD, consisting of¹⁵: 

• Cyclophosphamide
• Vincristine 
• Doxorubicin
• Dexamethasone
• Methotrexate
• Cytarabine

Adults with Ph-positive ALL typically receive a TKI such as imatinib or dasatinib in addition to chemotherapy or a corticosteroid. Some regimens also incorporate the monoclonal antibodies rituximab or ofatumumab for adults with CD20-positive ALL.¹⁵

Consolidation Therapy

Patients should be assessed for complete remission and MRD upon completion of the induction phase of treatment. Those who do not achieve complete remission should be treated with regimens designed for refractory disease.¹⁵

For most patients with MRD-negative adult ALL, consolidation therapy consists of multiagent chemotherapy or blinatumomab. Blinatumomab is the preferred treatment for patients with MRD. HSCT should be considered when appropriate.¹⁵

The NCCN recommends consolidation therapy with a TKI, with or without chemotherapy or blinatumomab, for patients who have Ph-positive ALL. Some patients may also be a candidate for HSCT during the consolidation phase.¹⁵

Maintenance Therapy

Maintenance therapy is typically given for 2 to 3 years in adult patients. 

Regimens often consist of vincristine and prednisone pulses each month. If the patient can tolerate it, weekly doses of methotrexate and daily doses of mercaptopurine may be added, or HSCT may be considered. Maintenance blinatumomab is also an option for patients with Ph-negative ALL. Patients with Ph-positive disease should continue to take a TKI during maintenance therapy.¹⁵

Treatment of Relapsed or Refractory Adult Acute Lymphoblastic Leukemia

The following options should be considered for adult patients with relapsed or refractory ALL¹⁵:

• Inotuzumab ozogamicin
• Blinatumomab
• Brexucabtagene autoleucel
• Tisagenlecleucel
• Chemotherapy
• Clinical trial

Patients with Ph-positive disease should take a TKI along with chemotherapy, a corticosteroid, blinatumomab, or inotuzumab ozogamicin. Tisagenlecleucel or brexucabtagene autoleucel may also be considered following failure of treatment with a TKI.¹⁵ 

Management of T-Cell Acute Lymphoblastic Leukemia in Adults

Adult T-ALL is typically treated with multiagent chemotherapy, with or without asparaginase.¹⁶

Adults with T-ALL are more likely to have CNS involvement at the time of diagnosis. Therefore, intrathecal chemotherapy and high-dose methotrexate are often recommended in this population.¹⁶

Nelarabine is a treatment option for those with relapsed or refractory T-ALL, although some studies also show that it may improve outcomes in the frontline setting.¹⁵

When and How To Use Approved Pharmacotherapies 

Treatments for ALL vary widely in their forms and dosages. The following tables summarize basic dosage and administration information for various therapies approved for the treatment of ALL. 

Table 1. Management Guidelines for Chemotherapy for Acute Lymphoblastic Leukemia

Drug	Administration	Dosage
Clofarabine	IV infusion over 2 h	52 mg/m2 for 5 d consecutively per 28-d cycle; repeat cycles every 2-6 wk
Cyclophosphamide	IV infusion	40-50 mg/kg in divided doses over 2-5 d for patients with no hematologic deficiency, OR 10-15 mg/kg every 7-10 d, OR 3-5 mg/kg twice per wk
Cytarabine	IV infusion, intrathecal administration, or SC injection	Not indicated
Daunorubicin	IV infusion	25 mg/m2 for most pediatric patients, 1 mg/kg for children under the age of 2, both administered day 1 of each wk; 45 mg/m2/d for adult patients, administered on days 1, 2, and 3 of cycle
Doxorubicin	IV injection	60-75 mg/m2 when used as a single agent or 40-75 mg/m2 when used in combination with other agents, both administered every 21-28 d
Mercaptopurine	Oral tablet	1.5-2.5 mg/kg/d once daily
Methotrexate	Oral tablet	20 mg/m2 once weekly
Nelarabine	IV infusion over 1 h in pediatric patients and over 2 h in adults	650 mg/m2 in pediatric patients consecutively for 5 d and repeated every 21 d; 1500 mg/m2 in adults on days 1,3, and 5, and repeated every 21 d
Pegaspargase	IM injection or IV infusion over 1-2 h	2500 IU/m2 for patients ≤21 y and 2000 IU/m2 for patients >21y, both no more frequently than every 14 d
Vincristine	IV injection	1.5-2 mg/m2 for most pediatric patients, 0.05 mg/kg for children weighing ≤10 kg, 1.4 mg/m2 for adult patients, all at weekly intervals

IM = intramuscular; IV = intravenous; SC = subcutaneous.

From FDA-approved prescribing information.^17-26

Table 2. Management Guidelines for Monoclonal Antibody Treatment and Immunotherapy for Acute Lymphoblastic Leukemia

Drug	Administration	Dosage
Blinatumomab	Continuous IV infusion with infusion pump	9 µg/d for days 1-7 and 28 µg/d for d 8-28 for initial induction therapy for patients weighing ≥45 kg, 5 µg/m2/d for days 1-7 and 15 µg/m2/d for days 8-28 for patients weighing <45 kg; up to 2 cycles* for induction, 3 cycles for consolidation, and up to 4 additional cycles of continued therapy
Brexucabtagene autoleucel	Suspension for IV infusion	1 x 106 CAR-positive T cells/kg in a single administration
Dasatinib	Oral tablet	Dosage per day based on body weight for pediatric patients;  140 mg once daily for adult patients
Imatinib	Oral tablet	600 mg once daily
Inotuzumab ozogamicin	IV injection	Dosing regimens vary based on day within the cycle and whether the patient has achieved CR†
Ponatinib	Oral tablet	45 mg once daily
Rituximab	IV infusion	375 mg/m2 for 2 doses during each of the 2 induction courses and 1 dose during each of the 2 consolidation courses
Tisagenlecleucel	Suspension for IV infusion	0.2-5 x 106 CAR-positive T cells/kg for patients weighing ≤50 kg, 0.1-2.5 x 108 CAR-positive T cells/kg for patients weighing >50 kg, both in a single administration

*A cycle consists of 28 days of continuous treatment followed by 14 treatment-free days.  ^†See prescribing information for details. CAR = chimeric antigen receptor; IV = intravenous.

From FDA-approved prescribing information.^27-35

Monitoring Adverse Events and Drug-Drug Interactions in Acute Lymphoblastic Leukemia

Regular monitoring of patients with ALL is needed to identify and address adverse events. Close monitoring is particularly important for pediatric patients with ALL, as side effects may continue to develop years after cancer therapy has been concluded. Additionally, adverse effects are a particular problem for infants; approximately 10% of this population experience treatment-related mortality.²

A special population of concern is children with Down syndrome and ALL. Children with Down syndrome make up about 2% to 3% of pediatric ALL diagnoses. This population develops complications such as infections and seizures at higher rates compared with the general pediatric ALL population. Children with Down syndrome may require careful monitoring and less-intensive chemotherapy regimens.²

Many adverse events can be prevented or alleviated. Supportive care during the treatment of ALL often consists of¹⁵:

• Antiemetics
• Pain management
• Enteral or parenteral nutritional support
• Prevention and treatment of infections
• Blood transfusions
• Administration of growth factors
• Leucovorin as a methotrexate rescue agent

The following tables describe common adverse events, drug-drug interactions, and considerations for use in special populations for pharmacotherapies commonly used in ALL. 

Table 3. Side Effect Profiles for Chemotherapy for Acute Lymphoblastic Leukemia

Drug	Most Common Adverse Events	Side Effects that May Necessitate Treatment Discontinuation or Modification	Drug-Drug Interactions	Use in Special Populations
Clofarabine	Nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus (skin itching), pyrexia (fever), fatigue, palmar-plantar erythrodysesthesia (hand-foot syndrome), anxiety, flushing, mucosal inflammation	Hypotension, infection, exfoliative or bullous rash, systemic inflammatory response syndrome, capillary leak syndrome, venous occlusive disease of the liver, hepatotoxicity, renal toxicity	None indicated	Not recommended in pregnant or lactating people
Cyclophosphamide	Neutropenia, fever, alopecia (patchy hair loss), nausea, vomiting, diarrhea	Severe hemorrhagic cystitis	Protease inhibitors, ACE inhibitors, natalizumab, paclitaxel, thiazide diuretics, zidovudine, anthracyclines, cytarabine, pentostatin, trastuzumab, G-CSF, GM-CSF, amphotericin B, indomethacin, azathioprine, busulfan, etanercept, metronidazole, tamoxifen, coumarins, cyclosporine, depolarizing muscle relaxants	Contraindicated in those with urinary outflow obstruction and in pregnant or lactating individuals
Cytarabine	Anorexia, nausea, vomiting, diarrhea, oral and anal inflammation or ulceration, hepatic dysfunction, fever, rash, thrombophlebitis, bleeding	None indicated	Beta-acetyldigoxin, gentamicin	Not recommended in pregnant people
Daunorubicin	Alopecia, nausea, vomiting, mucositis, diarrhea, abdominal pain	None indicated	None indicated	May be more likely to cause cardiotoxicity in pediatric and elderly populations; patients with renal or hepatic impairment should receive a decreased dose; not recommended in pregnant patients
Doxorubicin	Alopecia, nausea, vomiting	Cardiomyopathy, suspected extravasation	Trastuzumab; inhibitors and inducers of CYP3A4, CYP2D6, or P-gp	Not recommended in patients with severe hepatic impairment
Mercaptopurine	Myelosuppression (including anemia, leukopenia, and thrombocytopenia), anorexia, nausea, vomiting, diarrhea, malaise, rash	Macrophage activation syndrome	Allopurinol, warfarin	Not recommended in pregnant and lactating individuals and in patients who may want to become pregnant in the future
Methotrexate	Ulcerative stomatitis (oral mucositis), leukopenia, nausea, abdominal distress	Serious infections, neurotoxicity, anaphylaxis, lymphoproliferative disease, myelosuppression, hepatotoxicity, severe renal toxicity, pulmonary toxicity, severe gastrointestinal toxicity	Oral antibiotics, penicillin, highly protein-bound drugs, probenecid, antifolate drugs, aspirin and other NSAIDs, hepatotoxic products, proton pump inhibitors, weak acids, nephrotoxic products, nitrous oxide, folic acid	Contraindicated for pregnant or lactating patients as well as those hoping to become pregnant in the future
Nelarabine	Cytopenias (including anemia, leukopenia, neutropenia, and thrombocytopenia), headache, nausea, vomiting, diarrhea, constipation, fatigue, dizziness, cough, shortness of breath, fever	Signs of high-grade neurotoxicity		Not recommended in pregnant or lactating people
Pegaspargase	Hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, elevated bilirubin, pancreatitis, abnormal clotting, thrombotic events, hypersensitivity	Infusion reaction,  thrombosis, bilirubin at least 3 times ULN, high-grade pancreatitis, hemorrhage	Glucocorticoids	Not recommended in pregnant or lactating people or in those with severe hepatic impairment
Vincristine	Leukopenia, neuritic pain, constipation, alopecia, sensory loss, paresthesia, slapping gait, loss of deep tendon reflexes, muscle wasting	Extravasation	Phenytoin, inhibitors and inducers of CYP3A	Not recommended for pregnant or lactating patients

ACE = angiotensin-converting enzyme; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; NSAIDs = nonsteroidal anti-inflammatory drugs; P-gp = P-glycoprotein; ULN =  upper limit of normal.

From FDA-approved prescribing information.^17-26

Table 4. Side Effect Profiles for Monoclonal Antibody Treatment and Immunotherapy for Acute Lymphoblastic Leukemia

Drug	Most Common Adverse Events	Side Effects that May Necessitate Treatment Discontinuation or Modification	Drug-Drug Interactions	Use in Special Populations
Blinatumomab	Infection, pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia	CRS, TLS, signs of neurologic toxicity, pancreatitis	None indicated	Not recommended in pregnant or lactating patients
Brexucabtagene autoleucel	Fever, CRS, hypotension, encephalopathy, tachycardia, nausea, vomiting, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection, constipation, anorexia	Not available	Not indicated	Not recommended in pregnant or lactating patients
Dasatinib	Myelosuppression, edema, nausea, vomiting, abdominal pain, diarrhea, constipation, headache, skin rash, hemorrhage, shortness of breath, cough, fatigue, musculoskeletal pain, mucositis, febrile neutropenia, arrhythmia, hypertension, hypotension, anorexia, infection	Myelosuppression, pulmonary arterial hypertension, severe dermatologic reaction	Antacids, H2 antagonists, proton pump inhibitors, inducers and inhibitors of CYP3A4	Not recommended in pregnant or lactating patients
Imatinib	Edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, abdominal pain	Cytopenias, signs of liver toxicity	Warfarin, inducers and inhibitors of CYP3A4	Not recommended in pregnant or lactating patients
Inotuzumab ozogamicin	Thrombocytopenia, neutropenia, leukopenia, infection, anemia, fatigue, fever, hemorrhage, nausea, headache, abdominal pain	Signs of liver toxicity, hepatic veno-occlusive disease, persistent neutropenia or thrombocytopenia	Drugs that prolong the QT interval	Not recommended in pregnant or lactating patients
Ponatinib	Rash, dry skin, joint pain, nausea, abdominal pain, constipation, headache, fatigue, hypertension, edema, fever, pancreatitis, hemorrhage, anemia, hepatic dysfunction, arterial occlusive events	Arterial occlusive events, venous thrombotic events, heart failure, hepatotoxicity, hypertension, pancreatitis, neuropathy, hemorrhage, edema, cardiac arrhythmia, myelosuppression, RPLS	Strong inducers or inhibitors of CYP3A	Not recommended in pregnant or lactating patients
Rituximab	Febrile neutropenia, stomatitis, enteritis	Severe infusion reactions, severe cardiac arrhythmias, signs of renal toxicity, severe mucocutaneous reactions, severe infection, HBV reactivation, PML	Cisplatin	Not recommended in pregnant or lactating patients
Tisagenlecleucel	CRS, infection, hypogammaglobulinemia, fever, anorexia, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, nausea, vomiting, encephalopathy, diarrhea, hypotension, cough, hypoxia, tachycardia, edema, fatigue, acute kidney injury	Not available	Not indicated	Not recommended in pregnant or lactating patients

CRS = cytokine release syndrome; HBV = hepatitis B virus; PML = progressive multifocal leukoencephalopathy; RPLS = reversible posterior leukoencephalopathy syndrome; TLS = tumor lysis syndrome. 

From FDA-approved prescribing information.^27-35

Diagnosis and Management of Cytokine Release Syndrome

Patients utilizing blinatumomab or CAR T-cell therapy should be monitored for cytokine release syndrome (CRS), a potentially life-threatening condition in which an aggressive inflammatory response induces a cytokine storm. Symptoms of CRS, which may be of varying severity, including³⁶: 

• Flu-like symptoms
• Headache
• Fatigue
• Joint or muscle pain
• Nausea or vomiting
• Fever
• Rash
• Edema
• Hypotension
• Tachycardia
• Arrhythmia
• Hypoxia
• Pulmonary edema
• Seizures
• Circulatory shock
• Vascular leakage
• Multiorgan system failure

Laboratory findings of CRS include cytopenia, high C-reactive protein (CRP) levels, elevated creatinine and liver enzyme levels, increased partial thromboplastin time (TPP), and decreased international normalized ratio (INR). Milder cases of CRS may be managed with antipyretic agents, antihistamines, and fluids. High-grade CRS should be managed with monoclonal antibodies that target IL-6 or its receptor; tocilizumab is the current gold standard.³⁶

Diagnosis and Management of Tumor Lysis Syndrome

Patients with ALL should also be monitored for tumor lysis syndrome (TLS). This condition can occur when large numbers of leukemia cells are destroyed within a short time period, causing the peripheral blood to fill with various intracellular components. Symptoms of TLS may include³⁷: 

• Nausea or vomiting 
• Anorexia
• Fatigue
• Numbness
• Muscle pain
• Arrhythmias
• Dark urine
• Decreased urine
• Seizures

Metabolic abnormalities on laboratory assessment may assist in the identification of TLS as it can cause elevated levels of uric acid, phosphorus, and potassium as well as decreased levels of calcium. This condition is managed with intravenous hydration, diuretics, or rasburicase to help protect kidney function.³⁸

References

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Author Bio

Maureen McNulty studied molecular genetics and English at Ohio State University. She has spent more than a decade researching the genetic causes of — and possible treatments for — multiple types of cancer. Maureen is now a medical writer who is passionate about helping people use science to enrich their lives.