Acute lymphoblastic leukemia (ALL) is a malignancy of precursor B or T lymphocytes (lymphoblasts) characterized by uncontrolled proliferation of malignant lymphocytic cells with replacement of normal bone marrow elements and bone marrow failure. Lymphoblastic lymphoma (LBL) is diagnosed when the disease presents in extramedullary sites (most commonly as mediastinal mass in T-cell disease) and <20% of the bone marrow is involved.

• Acute lymphocytic leukemia
• Acute lymphoblastic leukemia
• ALL

• ALL is primarily a disease of children, adolescents, and young adults.
• Overall incidence is 1.8/100,000 persons per year; 65% are <34 yr. It is most commonly diagnosed among people aged <20.
• Incidence varies according to race and ethnic group, being more common in Hispanics and Whites than Blacks.
• Male:female ratio is 55:45.

Expected overall 5 yr relative survival is 71% but substantially better in children and approaches 95%.

• Findings consistent with bone marrow failure and peripheral cytopenias-pallor, bruising, petechiae
• Lymphadenopathy or hepatosplenomegaly
• Fever (disease related or infectious), bone pain, weakness, weight loss, mental status changes, and neurologic findings associated with central nervous system (CNS) involvement (if present)
• T-cell LBL is usually associated with a mediastinal mass
• Table E1 summarizes the clinical presentation of acute ALL and LBL

• Most cases are sporadic without established risk factors.
• Ionizing radiation exposure appears to be a risk factor.
• Down syndrome (trisomy 21) is associated with an approximately 3% risk of developing leukemia by age 30, predominantly ALL. ALL may be seen with other hereditary premalignancy syndromes (e.g., ataxia-telangiectasia).

Disorders associated with lymphocytosis (lymphocytes >5000/mcl):

• Adults: Chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia
• Adolescents/young adults: Infectious mononucleosis syndromes due to Epstein-Barr virus or cytomegalovirus, among others, may present with lymphocyte abnormalities with appearance suggestive of leukemic blasts
• Disorders associated with circulating blasts or blast-like cells such as acute myeloid leukemia, prolymphocytic leukemia, blastoid mantle cell lymphoma, and Burkitt lymphoma (mature B-cell leukemia/lymphoma)
• LBL
• Aplastic anemia; ALL may present without circulating leukemia cells and with only manifestations of bone marrow failure

• Initial evaluation of a patient with ALL is summarized in Table E2.
• Identification of circulating abnormal cell population by flow cytometry. CD19, cytoplasmic CD22, and/or cCD79a identifies most B lineage cells. Immature leukemic blasts should have absence of surface immunoglobulin (sIg) and will usually express CD 10, CD34, and stain positive for terminal deoxynucleotidyltransferase (TdT). A strong expression of CD20, expression of sIg, and negativity of TdT should prompt a workup for a mature B cell neoplasms such as Burkitt lymphoma because this distinction is critical. Cytoplasmic CD3 and CD7 establish immature T-cell lineage in most cases. Aberrant myeloid markers (CD13, CD33) can be seen. Early T-cell precursor (ETP-ALL) has a unique immunologic signature, as well as different prognosis and treatment approaches.
• Cytochemical stains are sometimes easier to perform and may be available sooner but are less specific. ALL blasts should be negative for myeloperoxidase and esterase stains.
• Bone marrow examination (Fig. E1).
• Genetic studies define important treatment categories, of which the most important is Philadelphia chromosome positive (Ph+) vs. Philadelphia chromosome negative (Ph-) disease, because these are treated differently. Although rare in children (incidence 2% to 5%) Ph+ ALL represents the most common genetic subgroup in ALL in adults with an overall incidence of 20% to 25%. The incidence increases with age and accounts for more than 50% of cases of ALL in patients who are older than 60 yr of age.¹ Ph status can be determined rapidly by polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) and should be available within 24 to 48 h of diagnosis. The World Health Organization classification (5^th edition) recognizes genetic variants of ALL as distinct syndromes (Table E3), and the clinical significance of common abnormalities is outlined in Table E4.
• Genetic profiling for "Ph-like" ALL (genetic profile similar to Ph+ disease, but no BCR/ABL abnormality) or IKZF1 (IKAROS) mutations may provide additional prognostic information but may not be uniformly available. Ph-like ALL may respond to tyrosine kinase inhibitor therapy and may behave more like Ph+ ALL; however, Ph-like ALL cases contain a number of genetic alterations that activate kinase and cytokine receptor signaling. Alterations can be grouped into two major subclasses that include ABL-class fusions involving ABL1, ABL2, SDF1R, and PDGFRB that phenocopy BCR-ABL1, and alteration of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling.
• Other alterations in the Ph-like genomic landscape activate other kinases, including BLNK, DGKH, FGFR1, OL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway.
• Lumbar puncture is usually done at diagnosis, if practical, to assess for CNS involvement and to initiate CNS prophylactic therapy.

• CBC reveals normochromic, normocytic anemia, thrombocytopenia.
• Peripheral smear will usually reveal lymphoblasts, but in some cases only the marrow is involved.
• Initial blood work should also include assessment for basic organ function (creatinine, bilirubin), blood glucose (glucocorticoids are part of therapy), and spontaneous tumor lysis syndrome (K⁺, Ca⁺⁺, PO4⁺⁺, uric acid).
• Coagulation studies (full disseminated intravascular coagulation [DIC] screen) before lumbar puncture.
• Studies appropriate to identifying and risk-stratifying leukemia as outlined previously.

• Chest x-ray examination to evaluate fever and for the presence of mediastinal mass.
• Computed tomography (CT) for symptomatic complaints. Be cautious about contrast dye exposure in patients with evidence of spontaneous tumor lysis syndrome to avoid further renal injury.

• Survival of children with ALL has improved from 10% to above 90% in the last 40 yr and is a major success story of modern medical science and research. Adults have fared less well, but cure rates have also improved to about 60% to 70% in standard-risk patients in recent trials. Adults in particular have benefited from tyrosine kinase inhibitor therapy for Ph+ ALL, because this disease is more common in adults and may represent 50% or more of disease in patients over 50.
• Hyperleukocytic leukemia (white blood cell count >100,000/mcl) is uncommon in ALL and lymphocyte counts of 100,000 may be well tolerated. Prednisone and vincristine usually offer rapid cytoreduction, and leukapheresis is rarely (but sometimes) required.
• Tumor lysis syndrome is common in ALL and was seen in 23% of patients in one large series. It is sometimes spontaneous-that is, present before therapy is given-and is a potential cause of early death. Tumor lysis syndrome is caused by release of intracellular potassium, phosphate, and nucleic acids. The nucleic acids adenosine and guanosine are eventually metabolized to uric acid. Elevated potassium may cause cardiac dysrhythmia and death. Elevated uric acid may cause renal failure through renal urate crystal deposition and possibly other mechanisms. Elevated phosphates cause renal calcium phosphate deposition and kidney injury while also lowering serum calcium, which can cause cardiac dysrhythmia and spasms. Therapy is directed mainly at maintaining renal function through vigorous hydration (3 L normal saline per day if practical, alkalinization not recommended); "forced diuresis" if necessary to maintain urine output at 2 ml/kg/h; and dialysis if necessary to control K⁺, phosphates, or fluid balance. Allopurinol, up to 800 mg/day for adults, 300 to 450 mg/m²/day for children, is given routinely. Rasburicase is a recombinant urate oxidase that rapidly lowers uric acid levels. The dose is 0.2 mg/kg, and one dose is usually enough. Rasburicase should be avoided in patients with G6PD deficiency. Phosphate binders are of uncertain value but are usually given. Asymptomatic hypocalcemia is not treated to avoid increasing calcium phosphate deposition. Definitions of laboratory and clinical tumor lysis and defined risk categories are outlined in Table E5.
• Numerous protocols have been used for Ph-ALL, and the specific protocol is likely to be determined by institution/physician familiarity and access to clinical trials, among other factors.
• In the 1990s and early 2000s, it was noted that adolescents and young adult (AYA) patients had better outcomes on pediatric trials than on adult trials. Consequently, this group (currently defined as ages 15 to 39) is now often (especially younger AYAs) treated on pediatric protocols by pediatric services or on adult "pediatric inspired" protocols.
• Therapy for Ph-negative ALL generally has four components:
  1. Induction therapy, typically with corticosteroids, cyclophosphamide (some regimens), vincristine, an anthracycline (doxorubicin or daunorubicin usually), and asparaginase. The CD20 directed antibody rituximab has shown benefit in patients with >20% CD20 expression on their blast cells.
  2. Consolidation therapy is high-dose chemotherapy aimed at preventing relapse after remission and commonly consists of cytarabine and methotrexate in combination with other agents.
  3. Maintenance therapy is low-intensity outpatient therapy that is continued for 2 to 3 yr after completion of consolidation. Prednisone, monthly vincristine, methotrexate, and oral 6-mercaptopurine (POMP regimen) are commonly used.
  4. CNS prophylaxis is universal and is usually done with intrathecal therapy (methotrexate alone or in combination with cytarabine and hydrocortisone) administered by lumbar puncture or an Ommaya reservoir. Due to increased toxicity, cranial radiotherapy is reserved for patients with high-risk features, such as active CNS disease at diagnosis.
• Allogeneic bone marrow transplant in first remission of ALL is controversial because of improving results with current nontransplant therapies. It is usually recommended for patients in whom the likelihood of cure is considered less than 50% to 60% with chemotherapy alone, depending on age and donor availability. Autologous bone marrow transplant is rarely used in Ph-ALL. In 2008, the final results of the MRC/UKALL XII/ECOG E2993 study were published. This study evaluated the relative safety and efficacy of chemotherapy, and autologous and allogeneic transplant after first complete remission (CR) in Ph– patients. This was a randomized trial of 1826 patients with newly diagnosed ALL. Patients who had a matched related donor were offered an allogeneic transplant. Patients without a donor were further randomized to an autologous transplant or chemotherapy and maintenance. The key conclusions of this study were:
  1. Allogeneic transplant in first CR is associated with lower relapse rates vs. autologous transplant or chemotherapy/maintenance therapy alone in Ph– patients.
  2. Allogeneic transplant in first CR improved overall survival in standard risk patients. There was a lower risk of relapse in both standard and high-risk patients. There was high treatment-related mortality in high-risk older patients. The increased mortality offsets the benefit of lower relapse risk for the patient group.
• The findings did not support autologous transplant as replacement therapy in any ALL group.
• More recently, treatment decisions, including the decision to proceed with allogeneic hematopoietic cell transplantation in ALL, are based on the presence or absence of measurable residual disease (MRD). MRD can be measured using multicolor flow cytometry or modalities that use next-generation sequencing (NGS) (e.g., ClonoSeQ).
• Risk factors for treatment failure in recent protocols are outlined in Table E6. Prognostic factors in ALL are summarized in Tables E7 and E8. MRD has emerged as the strongest prognostic factor independent of traditional pretherapeutic risk factors.
• Therapy of Ph+ ALL consists of a tyrosine kinase inhibitor-imatinib, dasatinib, nilotinib, ponatinib have been used-with chemotherapy.
  1. 2-yr survival rates are reported at 50% to 65%, with various regimens.
  2. Low-intensity induction chemotherapy with dasatinib and prednisone or imatinib, vincristine, and prednisone have resulted in remission rates of 100% and 98% and may allow for less toxicity and hospitalization at diagnosis.
  3. Allogeneic bone marrow transplant is commonly used as consolidative therapy if available but has become more controversial. Maintenance therapy with tyrosine kinase inhibitor is usually given after BMT or non-BMT therapy.
• Therapy of relapsed disease:
  1. Allogeneic bone marrow transplant is offered for relapsed disease, but relapse after BMT is common, and long-term cure rates have been low at about 20%.
  2. In 2017, the FDA approved three new therapies for relapsed ALL: Chimeric antigen receptor T-cell (CAR-T) therapy, a form of targeted immunotherapy, yielded a remission rate of 90% in pediatric and young adult (<26 yr) patients with relapsed B-cell ALL. Chimeric antigen T-cells are created by harvesting the patient’s T cells, then transfecting them with lentivirus vector that inserts DNA expressing an anti-CD19 domain (the target antigen on B cells) coupled to a T-cell receptor. The T cells expressing the chimeric anti-CD19/T-cell receptor specifically target CD19-expressing B cells. The CAR-T cell population is then expanded ex vivo and reinfused to the patient. About 70% of remissions were durable at 6 mo. The main side effect is cytokine release syndrome (CRS) associated with "vascular leak," hypotension, respiratory and renal insufficiency, and coagulopathy. CRS is treated with tocilizumab and anti-IL6 receptor blocking antibody. CAR-T cells for ALL have been given the generic designation tisagenlecleucel (trade name Kymriah). It currently costs $475,000 and is available at centers certified for its use.
  3. In October 2021, the FDA granted approval for another CD-19 directed CART brexucabtagene autoleucel (trade name Tecartus) for treatment of adult patients (≥18 yr) with relapsed or refractory B-cell ALL. This was based on a single arm multicenter trial (ZUMA-3) where out of 54 patients who were evaluated for efficacy, 28 achieved CR within 3 mo. The duration of complete response was estimated to exceed 12 mo for more than half of the patients. CRS occurred in 92% of patients and neurotoxicity in 87%.
  4. Blinatumomab is a bispecific antibody that binds CD19 and CD3, redirecting T cells to leukemia cells. It was FDA-approved for relapsed ALL, including Ph+ ALL, in adults and children. Blinatumomab is administered as a continuous infusion for 4 wk (9 μg/day wk 1, 28 μg/day thereafter), with maintenance therapy for 4 wk every 12 wk. In a large phase III trial, the remission rate was 44% (vs. 25% with chemotherapy), a small number durable. In a smaller phase II trial for Ph+ ALL, the remission rate was 36%. A small number of blinatumomab responses have been durable. Blinatumomab can also be associated with cytokine release syndrome.
• Inotuzumab ozogamicin (IO) is an antibody drug conjugate in which chemotherapeutic agent calicheamicin is bound to an anti-CD22 antibody. In a large phase III trial, the remission rate was 81% vs. 33% for standard chemotherapy, with a median duration of 4.6 mo. Approximately 40% of IO patients were successfully bridged to transplant vs. 10% with chemotherapy. A small number of responses were durable.
• Survivorship:
  1. Survivors of childhood and adult ALL are increasingly being seen in primary care practices; as of 2006 there were estimated >50,000 survivors, likely increasing by about 2000+/yr.
  2. Long-term complications of ALL therapy include secondary malignancy from chemotherapy (usually in first 5 to 10 yr) or from radiation: If given, no plateau in risk, congestive heart failure from anthracycline therapy (often manifesting 20 to 30 yr after treatment), osteopenia and avascular necrosis from glucocorticoid therapy, obesity, and neurocognitive defects. Key recommendations include the following:
  3. Echocardiography every 3 to 5 yr for asymptomatic congestive heart failure, more often if anthracycline exposure was >250 to 300 mg/m², because asymptomatic congestive heart failure may warrant therapy. This may show up decades after therapy.
  4. Screening for malignancy and endocrinopathies in pertinent radiation fields.
  5. Attention to the increased risk of obesity and metabolic derangement in survivors.
  6. Recent reviews (see "References") summarizing current recommendations and guidelines are accessible online (http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf).

• Acute Lymphocytic Leukemia (ALL) (Patient Information)
• Tumor Lysis Syndrome (Related Key Topic)