Acute Lymphoblastic Leukemia (ALL)

The 4 general phases of chemotherapy for acute lymphoblastic leukemia include

The goal of induction treatment is complete remission, defined as < 5% blast cells in the bone marrow, an absolute neutrophil count > 1000/mcL (> 1 × 10⁹/L), a platelet count > 100,000/mcL (> 100 × 10⁹/L), and no need for blood transfusion. In patients with complete remission, a low measurable residual disease (also known as minimal residual disease or MRD) is the most important prognostic factor (1 Treatment references Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more ). Measurable or minimal residual disease is microscopic disease that is not detected by standard assays but can be measured by more sensitive assays. A low measurable residual disease (MRD negativity) is defined variably (based on the assay used) as < 0.01 to 0.1% leukemic cells in bone marrow.

Components of induction therapy include

Some regimens use a corticosteroid to reduce disease burden prior to intensive induction. In younger adults, a regimen that includes asparaginase and/or cyclophosphamide for induction, similar to treatment protocols used in children, may increase rates of response and achievement of undetectable minimal residual disease. If complete remission is not achieved after induction, some regimens recommend a second induction course to try to get more patients to complete remission before consolidation.

For patients with Philadelphia chromosome–positive (Ph+) ALL, a tyrosine kinase inhibitor (eg, imatinib, dasatinib) can be added to the drug regimen. For patients with CD20 positive B-lymphoblastic leukemia, rituximab can be added.

The goal of consolidation is to prevent leukemic regrowth. Consolidation therapy usually lasts a few months and combines regimen-specific courses of non–cross-resistant drugs that have different mechanisms of action. For adults with Ph+ ALL, allogeneic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is recommended as consolidation therapy.

Interim maintenance and late/delayed intensification therapy are used after consolidation therapy. These phases of therapy incorporate a variety of chemotherapeutic agents with different doses and schedules that are less intense than induction and consolidation.

Most regimens include maintenance therapy with monthly vincristine, weekly methotrexate, daily mercaptopurine, and 5 days/month corticosteroid. Therapy duration is usually 2½ to 3 years.

CNS prophylaxis starts during induction and continues throughout all phases of treatment. Because lymphoblasts often infiltrate the spinal fluid and meninges, all regimens include CNS prophylaxis and treatment with intrathecal methotrexate, cytarabine, and hydrocortisone in combination or as monotherapy. High doses of systemic methotrexate and/or cytarabine penetrate the CNS, providing extra CNS prophylaxis if regimens include these drugs. Cranial nerve or whole-brain irradiation was previously often done for patients at high risk of CNS disease (eg, high WBC count, high serum lactate dehydrogenase, B-cell phenotype), but its use has been decreasing in recent years.

About one third of patients with acute lymphoblastic leukemia are older adults (> 65). Older ALL patients are more likely to have precursor B-cell ALL and have higher risk and more complex cytogenetics, including Philadelphia chromosome positive (Ph+) or t(v;11q23) MLL (KMT2A) rearranged disease.

Some, but not all, older patients can tolerate standard induction therapy. Subsequent treatment regimens (CNS prophylaxis, postremission consolidation or intensification, and maintenance) depend on the individual patient's comorbidities and performance status. For example, older patients with several comorbidities and poor performance status may undergo gentler induction therapy without consolidation or maintenance. In older patients with Ph+ ALL, tyrosine kinase inhibitors (eg, imatinib, dasatinib) plus corticosteroids given with either low-intensity or no chemotherapy have resulted in 95 to 100% complete remission rate, with a 45 to 50% 2-year relapse free survival and about 70% 2-year overall survival. For older patients with ALL who are in their first complete remission, nonmyeloablative or reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is an option.

Targeted immunotherapy drugs that are available for treatment of relapsed or refractory ALL are increasingly used for treatment of older patients with ALL in clinical trials or clinical practice.

Older patients with ALL probably tolerate asparaginase more poorly than younger patients do.

Leukemic cells may reappear in the bone marrow, CNS, testes, or other sites. Bone marrow relapse is particularly ominous. Although a new round of chemotherapy may induce a second remission in the majority of children and about one third of adults, subsequent remissions tend to be brief. Chemotherapy causes only a few patients with early bone marrow relapse to achieve long disease-free second remissions or cure.

New immunotherapy approaches show impressive results in relapsed/refractory ALL. Antibodies, such as blinatumomab, that bring T cells into close proximity to leukemic blasts demonstrate activity in relapsed ALL. Chimeric antigen receptor T (CAR-T) cells, engineered and generated from the patient's T cells, induce remission in patients with relapsed ALL with remarkable efficacy, albeit with significant toxicity (2 Treatment references Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more ).

Available immunotherapies for relapsed or refractory ALL include

Blinatumomab, a biospecific CD19-directed CD3 T-cell engager, prolongs overall survival for children and adults with relapsed or refractory B-cell precursor ALL, whether Ph+ or Ph-. Life-threatening toxicities may include cytokine release syndrome Cytokine release syndrome Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more and neurologic toxicities (eg, seizures, encephalopathy with altered consciousness, and disordered speech, coordination, and/or balance). Interruption or stopping blinatumomab with or without use of high-dose dexamethasone may be necessary. The most common neurologic symptoms after blinatumomab use are headache and tremor (3 Treatment references Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more ).

Inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate with calicheamicin, is also available for adults with relapsed or refractory B-cell precursor ALL. One study found significantly higher remission rates after 1 to 2 cycles of therapy with inotuzumab ozogamicin than with standard chemotherapy (4 Treatment references Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more ). Inotuzumab may cause hepatotoxicity, including fatal and life-threatening veno-occlusive disease and is associated with higher post-transplant non-relapse mortality.

Tisagenlecleucel, a CD19-directed genetically modified autologous T-cell immunotherapy, is available for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in a 2nd or later relapse. Life-threatening toxicities may include cytokine release syndrome Cytokine release syndrome Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more and neurologic toxicities (5 Treatment references Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more ).

Brexucabtagene autoleucel, a CD19-directed genetically modified autologous T cell immunotherapy, is FDA-approved and can be used to treat adult patients with relapsed or refractory B-cell precursor ALL. Complications, including cytokine release syndrome Cytokine release syndrome Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more and neurologic toxicities, may be life threatening.

Other agents that have been available, but for which clinically meaningful outcomes have not been convincingly demonstrated (ie, the approvals were based upon response rate but there were no trials verifying an improvement in disease-related symptoms or increased survival). Examples include

Stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more following reinduction chemotherapy or immunotherapy offers the greatest hope of long-term remission or cure if an HLA-matched sibling is available. Cells from other relatives or from matched, unrelated donors are sometimes used. Transplantation is rarely used for patients > 65 years because it is much less likely to be successful and because adverse effects are much more likely to be fatal.

CNS relapse treatment includes intrathecal methotrexate (with or without cytarabine or corticosteroids) twice weekly until all signs disappear. The role of continued intrathecal drug use or CNS irradiation is unclear.

Testicular relapse may be evidenced clinically by painless firm swelling of a testis or may be identified on biopsy. If unilateral testicular involvement is clinically evident, the apparently uninvolved testis should undergo biopsy. Treatment is radiation therapy of the involved testis and administration of systemic reinduction therapy.

Supportive care is similar in the acute leukemias and may include

Transfusions of red blood cells and sometimes platelets are administered as needed to patients with bleeding or anemia. Prophylactic platelet transfusion is done when platelets fall to < 10,000/mcL (< 10 × 10⁹/L). Anemia (hemoglobin < 7 or 8 g/dL [< 70 to 80 g/L]) is treated with transfusions of packed red blood cells. Granulocyte transfusions are not routinely used.

Antimicrobials are often needed for prophylaxis and treatment because patients are immunosuppressed; in such patients, infections can progress quickly with little clinical prodrome. After appropriate studies and cultures have been done, febrile patients with neutrophil counts < 500/mcL (< 0.5 × 10⁹/L) should begin treatment with a broad-spectrum bactericidal antibiotic that is effective against gram-positive and gram-negative organisms (eg, ceftazidime, piperacillin and tazobactam, meropenem). Fungal infections, especially pneumonias, may develop and are difficult to diagnose, so chest CT to detect fungal pneumonia should be done early (ie, within 72 hours of presentation with neutropenic fever, depending on the degree of suspicion). Empiric antifungal therapy should be given if antibacterial therapy is not effective within 72 hours. There is a significant drug-drug interaction between vincristine, which is commonly used in all ALL treatment regimens, and azole antifungals. In patients with refractory pneumonitis, Pneumocystis jirovecii infection Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately.

Posaconazole, a 2nd-generation triazole antifungal drug, is indicated for primary prophylaxis in patients age > 13 years who are at high risk of developing invasive Aspergillus and Candida infections because of immunosuppression (eg, hematopoietic stem cell transplant recipients with graft-versus-host disease). In patients with drug-induced immunosuppression (eg, prolonged use of corticosteroids for ALL treatment), trimethoprim/sulfamethoxazole (TMP/SMX), dapsone, atovaquone, or pentamidine is indicated to prevent P. jirovecii pneumonia. Acyclovir or valacyclovir prophylaxis is generally recommended for all patients.

Hydration, urine alkalinization with IV sodium bicarbonate, and allopurinol or rasburicase can prevent and treat the hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (ie, tumor lysis syndrome Tumor Lysis and Cytokine Release Syndromes Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ) caused by the rapid lysis of leukemic cells during initial therapy in ALL. Hyperuricemia is minimized by reducing the conversion of xanthine to uric acid by giving allopurinol (a xanthine oxidase inhibitor) or rasburicase (a recombinant urate-oxidase enzyme) before starting chemotherapy. Patients with G6PD deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in people with African ancestry that can result in hemolysis after acute illnesses or intake of oxidant... read more may develop severe hemolysis from rasburicase, which is contraindicated in these patients.

Psychologic support may help patients and their families with the shock of illness and the rigors of treatment for a potentially life-threatening condition.