Susan Colace, MD, MSCI

Acute lymphocytic leukemia (ALL) is a heterogeneous malignancy that may develop from B or T lymphocytes (B-ALL, T-ALL) and affects patients of all ages.¹ In the United States, an estimated 6,540 new cases are diagnosed each year—including 3,100 in individuals aged < 20 years—and approximately 1,390 deaths annually.^2,3 It is the most encountered cancer in patients aged < 20 years, and generally carries a good prognosis; almost all younger patients achieve remission with current therapies. Five-year overall survival (OS) is 90% in patients aged < 15 years, 75% in patients aged 15-19 years, and 61% in adolescent/young adult patients (which generally includes patients up to age 39).^2,4,5 In contrast, only about 30% of adults with ALL achieve remission with current therapies.

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Acute lymphocytic leukemia (ALL) is a heterogeneous malignancy that may develop from B or T lymphocytes (B-ALL, T-ALL) and affects patients of all ages.¹ In the United States, an estimated 6,540 new cases are diagnosed each year—including 3,100 in individuals aged < 20 years—and approximately 1,390 deaths annually.^2,3 It is the most encountered cancer in patients aged < 20 years, and generally carries a good prognosis; almost all younger patients achieve remission with current therapies. Five-year overall survival (OS) is 90% in patients aged < 15 years, 75% in patients aged 15-19 years, and 61% in adolescent/young adult patients (which generally includes patients up to age 39).^2,4,5 In contrast, only about 30% of adults with ALL achieve remission with current therapies.

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Acute lymphocytic leukemia (ALL) is a heterogeneous malignancy that may develop from B or T lymphocytes (B-ALL, T-ALL) and affects patients of all ages.¹ In the United States, an estimated 6,540 new cases are diagnosed each year—including 3,100 in individuals aged < 20 years—and approximately 1,390 deaths annually.^2,3 It is the most encountered cancer in patients aged < 20 years, and generally carries a good prognosis; almost all younger patients achieve remission with current therapies. Five-year overall survival (OS) is 90% in patients aged < 15 years, 75% in patients aged 15-19 years, and 61% in adolescent/young adult patients (which generally includes patients up to age 39).^2,4,5 In contrast, only about 30% of adults with ALL achieve remission with current therapies.

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers