Acute Lymphoblastic Leukemia

• Peter Rintels, M.D.

 Basic Information

Definition

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 is diagnosed when the disease presents in extramedullary sites (most commonly as mediastinal mass in T cell disease) and less than 25% of the bone marrow is involved.

Synonyms

1. Acute lymphocytic leukemia

2. Acute lymphoblastic leukemia

3. ALL

ICD-10CM CODES
C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse

Epidemiology & Demographics

1. •

   ALL is primarily a disease of children (peak incidence occurring at 3-5 years of age).

2. •

   Overall incidence is 4.5 cases per 100,000 persons per year; 60% are under age 20. It is the most common malignancy of childhood. (SEER database accessed 11/26/15)

3. •

   Incidence varies according to race and ethnic group: 14.8 cases per million for blacks, 35.6 cases per million for whites, and 40.9 cases per million for Hispanics.

4. •

   Male:female ratio is 55% to 45%.

Physical Findings & Clinical Presentation

1. •

   Findings consistent with bone marrow failure and peripheral cytopenias–pallor, bruising, petechiae.

2. •

   Lymphadenopathy or hepatosplenomegaly.

3. •

   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).

4. •

   T cell lymphoblastic lymphoma is usually associated with a mediastinal mass.

5. •

   Table 1 summarizes the clinical presentation of acute lymphoblastic leukemia.

   TABLE1 Clinical Presentation of Acute Lymphoblastic LeukemiaAdapted from Hoffman R: Hematology, basic principles and practice, ed 6, Philadelphia, 2013, Saunders.

   Symptoms and Signs	Etiology	Management
   Fever	Disease or infection	Fever workup with blood, urine cultures, and chest x-ray. Broad-spectrum antimicrobial coverage with attention to localizing symptoms (i.e., cough, abdominal pain).
   Fatigue, pallor	Anemia (bone marrow failure, bleeding)	RBC transfusion. Transfuse with caution if hyperleukocytosis is present.
   Petechiae, bruising, bleeding	Thrombocytopenia, DIC (bone marrow failure, tumor lysis)	Transfuse with platelets, coagulation protein support if indicated (uncommon).
   Pain	Leukemia infiltrating bones or joints or expanding BM cavity	Establish diagnosis and start chemotherapy.
   Respiratory distress, superior vena cava syndrome	Mediastinal mass	Avoid sedation in the presence of tracheal compression; establish diagnosis as soon as possible and start chemotherapy.
   ALL, Acute lymphoblastic leukemia; BM, bone marrow; RBC, red blood cell.

Etiology

1. •

   Most cases are sporadic without established risk factors.

2. •

   Ionizing radiation exposure appears to be a risk factor.

3. •

   Down’s 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)

    

Diagnosis

Differential Diagnosis

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

1. •

   Adults: Chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia.

2. •

   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.

3. •

   Disorders associated with circulating blasts or blastlike cells such as acute myeloid leukemia, prolymphocytic leukemia, blastoid mantle cell lymphoma, and Burkitt’s lymphoma (mature B cell leukemia/lymphoma).

4. •

   Lymphoblastic lymphoma.

5. •

   Aplastic anemia; ALL may present without circulating leukemia cells and with only manifestations of bone marrow failure.

Workup

1. •

   Identification of circulating abnormal cell population by flow cytometry. CD19 identifies most precursor B cells. Immature leukemic blasts should have absence of surface immunoglobulin and will usually express CD34 and stain positive for terminal deoxynucleotidyltransferase (TdT). Cytoplasmic CD3 and CD7 establish immature T cell lineage in most cases. Aberrant myeloid markers (CD13, CD33) can be seen.

2. •

   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.

3. •

   Bone marrow examination (Fig. E1).

   

4. •

   Genetic studies define important treatment categories, of which the most important is Philadelphia chromosome positive (Ph+) vs. Philadelphia chromosome negative (Ph–) disease, as these are treated differently. 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 hours of diagnosis. The WHO classification recognizes genetic variants of ALL as distinct syndromes (Table 2), and the clinical significance of common abnormalities is outlined in Table 3.

   TABLE2 WHO Classification of Precursor Lymphoid NeoplasmsFrom Arber DA et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood 127:2391-2405, 2016.

   B-lymphoblastic leukemia/lymphoma, not otherwise specified. B-lymphoblastic leukemia/lymphoma with recurrent cytogenetic abnormalities B-lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v∗;11q23) MLL rearranged. B-lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q32;q32); IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); EZA-PBX1 (TCF3-PBX-1) T-lymphoblastic leukemia/lymphoma. Provisional entities: B-lymphoblastic leukemia/lymphoma BCR/ABL1 like B lymphoblastic leukemia/lymphoma with iAMP21 Early T cell precursor lymphoblastic leukemia/lymphoma

   v∗, Variable gene partners.

   TABLE3 More Common Recurrent Cytogenetic Abnormalities in B-Lymphoblastic Leukemia/Lymphoma

   Abnormality	Clinical Relevance
   t(9;22)(q34;q11.2); BCR-ABL1	Incidence approximately 3% in children, 25% in adults, rising with age; requires therapy with tyrosine kinase inhibitors.
   t(v∗;11q23) MLL rearranged.	Most common variant is t(4;11); often presents with very high WBC; confers worse prognosis; rare in adults; common in infant leukemia.
   t(12;21)(p13;q22); TEL-AML1	Common in children (20%-30%); rare in adults; confers improved prognosis.
   Hyperdiploidy	Seen in about 25% of children, less in adults; confers favorable prognosis.
   Hypodiploidy	Uncommon; confers worse prognosis.
   t(5;14)(q32;q32); IL3-IGH	Rare; commonly associated with eosinophilia; T cell disease, ? neutral prognostically
   t(1;19)(q23;p13.3);	Incidence approximately 5%; intermediate/favorable in children, intermediate/poor in adults.
   v∗, Variable gene partners. Many of these disorders also have distinct immunophenotypes by flow cytometry. Additional molecular abnormalities of recently defined relevance include mutations of IKZF1, which encodes a lymphoid transcription factor IKAROS, is associated with high relapse rates and gene expression profile similar to BCR-ABL1 translocated disease. Gene expression profiling has identified a subgroup of “Philadelphia chromosome-like” ALL with a gene expression similar to BCR-ABL1 translocation associated disease, which confers worse prognosis, but which may identify new opportunities for targeted therapies.

5. •

   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.

6. •

   Lumbar puncture is usually done at diagnosis, if practical, to assess for CNS involvement and to initiate CNS prophylactic therapy.

Laboratory Tests

1. •

   Complete blood count reveals normochromic, normocytic anemia, thrombocytopenia.

2. •

   Peripheral smear will usually reveal lymphoblasts, but in some cases only the marrow is involved.

3. •

   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).

4. •

   Coagulation studies (full disseminated intravascular coagulation [DIC] screen) prior to lumbar puncture.

5. •

   Studies appropriate to identifying and risk-stratifying leukemia as outlined previously.

Imaging Studies

1. •

   Chest x-ray to evaluate fever and for the presence of mediastinal mass.

2. •

   CT for symptomatic complaints. Be cautious about contrast dye exposure in patients with evidence of spontaneous tumor lysis syndrome to avoid further renal injury.

Treatment

Acute General Rx

1. •

   Survival of children with ALL has improved from 10% to 90% in the last 40 years 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, since this disease is more common in adults and may represent 50% or more of disease in patients over 50.

2. •

   Hyperleukocytic leukemia (WBC >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.

3. •

   Tumor lysis syndrome is common in ALL and was seen in 23% of patients in one large series. It is sometimes spontaneous—i.e., 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 liters 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 4.

   TABLE4 Tumor Lysis SyndromeAdapted from Howard SC et al: The tumor lysis syndrome, N Engl J Med 364:1844-1854, 2011 and Coiffier B et al: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence based review, J Clin Oncol 26:2767-2778, 2008.

   Laboratory Tumor Lysis Syndromea Uric acid: ≥8 mg/dl or 476 μmol/L Potassium: ≥6.0 mmol/L Phosphorus: ≥4.5 mg/dl or 1.5 mmol/L (adults), ≥6.5 mg/dl or 2.1 mmol (children) • Calcium: Correctedb Ca++ <7.0 mg/dl or 1.75 mmol/L or ionized Ca++ <1.12 mg/dl or 0.3 mmol/L, or 25% increase from baseline uric acid, potassium, phosphorus; 25% decrease for calcium. Clinical Tumor Lysis Syndrome Acute kidney injury • Rise in serum creatinine ≥0.3 mg/dl (26.5 μmol/L). • Any creatinine >1.5 age-appropriate upper limit normal if no baseline available. • Oliguria defined as urine output <0.5 ml/kg/hr for 6 hours. Cardiac arrhythmia Seizure Symptomatic hypocalcemia (e.g., neuromuscular irritability such as tetany)

4. •

   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.

5. •

   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 15-39) is now often (especially younger AYAs) treated on pediatric protocols by pediatric services or on adult “pediatric inspired” protocols.

6. •

   Therapy for Ph- negative ALL generally has four components:

   1. 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 greater than 20% CD20 expression on their blast cells.

   2. 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. 3.

      Maintenance therapy is low-intensity outpatient therapy that is continued for 2 to 3 years after completion of consolidation. Prednisone, monthly vincristine, methotrexate, and oral 6-mercaptopurine (POMP regimen) are commonly used.

   4. 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.

7. •

   Allogeneic bone marrow transplant in first remission of ALL is controversial because of improving results with current non-transplant 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.

8. •

   Risk factors for treatment failure in recent protocols are outlined in Table 5.

   TABLE5 Risk Factors for Treatment Failure in Recent ALL TrialsRoberts KG et al: Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia, N Engl J Med 371(11):1005-1015, 2014.

   t(v∗;11q23) MLL rearranged.

   Hypodiploidy

   Minimal residual disease after remission or consolidation∗

   Philadelphia chromosome like genomic signature (in Ph- ALL)†

   Early precursor T (ETP) ALL (absent CD1a, CD8, weak CD5, myeloid or stem cell antigen expression).

9. •

   Therapy of Ph+ ALL consists of a tyrosine kinase inhibitor—imatinib, dasatinib, nilotinib, ponatinib have been used—with chemotherapy.

   1. ▪

      2-year 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.

10. •

    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 (under age 26 years) 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-CD 19/T-cell receptor specifically target CD1-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 months. The main side effect is cytokine release syndrome (CRS) associated with “vascular leak,” hypotension, respiratory and renal insufficiency, and coagulapathy. 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. ▪

       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 weeks (9 μg/day week 1, 28 μg/day thereafter), with maintenance therapy for 4 weeks every 12 weeks. 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.

11. •

    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 months. Approximately 40% of IO patients were successfully bridged to transplant vs. 10% with chemotherapy. A small number of responses were durable.

12. •

    Survivorship

    1. ▪

       Survivors of childhood and adult ALL are increasingly been seen in primary care practices; as of 2006 there were estimated > 50,000 survivors, likely increasing by about 2000+ per year.

    2. ▪

       Long-term complications of ALL therapy include secondary malignancy from chemotherapy (usually in first 5-10 years) or from radiation (if given, no plateau in risk, congestive heart failure from anthracycline therapy (often manifesting 20-30 years after treatment), osteopenia and avascular necrosis from glucocorticoid therapy, obesity, and neurocognitive defects. Key recommendations include the following:

       1. 1.

          Echocardiography every 3 to 5 years for asymptomatic congestive heart failure, more often if anthracycline exposure was >250 to 300 mg/m², since asymptomatic congestive heart failure may warrant therapy. This may show up decades after therapy.

       2. 2.

          Screening for malignancy and endocrinopathies in pertinent radiation fields.

       3. 3.

          Attention to the increased risk of obesity and metabolic derangement in survivors.

       4. 4.

          Recent reviews (see references) summarizing current recommendations and guidelines are accessible online (http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf, http://www.sign.ac.uk/pdf/sign132.pdf).

Suggested Readings

• E. Curran, W. Stock: How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 125:3702–3710 2015 25805810

• L. Diller: Adult primary care after childhood acute lymphoblastic leukemia. N Engl J Med. 365:1417–1424 2011 21995389

• R. Foa, et al.: Dasatinib as first line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 118:6521–6528 2011 21931113

• S.C. Howard, et al.: The tumor lysis syndrome. N Engl J Med. 364:1844–1854 2011 21561350

• S.P. Hunger, C.G. Mullighan: Acute lymphoblastic leukemia in children. N Engl J Med. 373:1541–1552 2015 26465987

• H. Kantarjian, et al.: Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 376:836–847 2017 28249141

• H.M. Kantarjian, et al.: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 375:740–753 2016 27292104

• S.I. Maude, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 371:1507–1517 2014 25317870

• S. Maury, et al.: Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 375:1044–1053 2016 27626518

• S. Paul, et al.: Adult acute lymphoblastic leukemia. Mayo Clin Proc. 91 (11):1645–1666 2016 27814839

• K.G. Roberts, et al.: Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 371:1005–1015 2014 25207766

Related Content

1. Acute Lymphocytic Leukemia (ALL) (Patient Information)

2. Tumor Lysis Syndrome (Related Key Topic)