para>Many chemotherapy drugs are teratogenic. ‚
EPIDEMIOLOGY
- Predominant age in adults: Median age, 35 to 40 years; incidence increases with age.
- Predominant sex: male > female (slightly)
Incidence
In the United States: 3,000 adult cases per year ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- Unknown
- Epstein-Barr virus is implicated in Burkitt leukemia/lymphoma.
Genetics
- Increased incidence in children with Down syndrome or in rare familial diseases such as ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, Klinefelter syndrome, and neurofibromatosis (1)
- With P53 mutation in Li-Fraumeni syndrome
- Can rarely occur in adult identical twins
RISK FACTORS
- Age >60 years
- Incidence seems to increase after exposure to chemical agents such as benzene or to radiation, but acute myeloid leukemia (AML) is more common.
- May follow aplastic anemia
DIAGNOSIS
HISTORY
- Anemia: fatigue, shortness of breath, light-headedness, angina, headache
- Thrombocytopenia: easy bruising
- Neutropenia: fever, infection
- Lymphocytosis: bone pain
- CNS: confusion
PHYSICAL EXAM
- Thrombocytopenia: petechiae, ecchymoses, epistaxis, retinal hemorrhages
- Anemia: pallor
- Neutropenia: fever, infection
- Lymphocytosis: lymphadenopathy, splenomegaly; less often, hepatomegaly
- CNS: cranial nerve palsies, confusion
DIFFERENTIAL DIAGNOSIS
- Malignant disorders: other leukemias, especially AML; chronic myeloid leukemia in lymphoid blast phase; prolymphocytic leukemia; malignant lymphomas; multiple myeloma; bone marrow metastases from solid tumors (breast, prostate, lung, renal); myelodysplastic syndromes
- Nonmalignant disorders: aplastic anemia, myelofibrosis, autoimmune diseases (Felty syndrome, lupus), infectious mononucleosis, pertussis, autoimmune thrombocytopenic purpura, leukemoid reaction to infection
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
CBC with differential, liver function tests, uric acid, anemia: normochromic, normocytic ‚
- Thrombocytopenia
- Peripheral blood lymphoblasts (B-cells or T-cells)
- Elevated lactate dehydrogenase
- Elevated uric acid
Follow-Up Tests & Special Considerations
Special tests ‚
- Immunophenotyping of marrow/blood lymphoblasts: B lineage (CD19, CD20, CD22, CD24); T lineage (CD2, cCD3, CD5, CD7); common ALL antigen (CD10); human leukocyte antigen (HLA)-DR; terminal deoxynucleotidyl transferase (TdT); aberrant myeloid antigens (CD13, CD33); stem cell antigen (CD34)
- Cytochemical stains: Myeloperoxidase, negative; Sudan black B, usually negative; TdT, positive; periodic acid " “Schiff ‚ ± is variable, depending on subtype.
- Cytogenetics: Specific recurring chromosomal abnormalities have independent diagnostic and prognostic significance (hyperdiploidy >50 chromosomes or t[14q11q13] are favorable; the Philadelphia chromosome, t[9;22], t[4;11], ¢ ˆ ’7 and +8 are unfavorable). A translocation t(8;14) or t(2;8) or t(8;22) identifies Burkitt-type mature B-cell leukemia that requires specific therapy.
- Reverse transcription polymerase chain reaction for rapid diagnosis of BCR/ABL+ ALL
- Genomic analysis by next-generation sequencing: detection of mutations associated with Ph-like ALL
- HLA typing of patient and siblings for hematopoietic cell transplantation
- Chest CT scan and/or chest radiograph to evaluate for mediastinal mass or hilar adenopathy and for pulmonary infiltrates suggestive of infection
- US exam to assess splenomegaly or renal enlargement suggestive of leukemic infiltration
Diagnostic Procedures/Other
- Bone marrow examination with aspiration, biopsy, immunophenotyping, cytochemistry, cytogenetics, and molecular diagnostics
- Lymph node biopsy is rarely necessary but can be diagnostic.
- Lumbar puncture is typically done both for diagnosis of CNS involvement and for intrathecal chemotherapy. It should be done at diagnosis and immediately if neurologic symptoms or signs are present. Repeat lumbar puncture after bone marrow remission is achieved to evaluate occult CNS involvement and continue prophylactic CNS treatment.
Test Interpretation
Diffuse replacement of marrow and lymph node architecture by sheets of malignant lymphoblasts ‚
TREATMENT
GENERAL MEASURES
- Appropriate health care
- Inpatient care during remission induction chemotherapy
- Postremission therapy is usually outpatient.
- Protective isolation from infection
- Adequate calcium and vitamin D supplementation may reduce bone injury from corticosteroids and avascular necrosis of large joints.
MEDICATION
First Line
Optimal therapy is not yet known (2)[B]. ALL should be treated at a comprehensive oncology center. All treatment regimens are still investigational but clearly effective for some fraction of patients. Younger adults (<40 years old) benefit from pediatric-inspired regimens (3,4)[B]. The modified Cancer and Leukemia Group B protocol 9111 is an example of therapy for older adults (5)[B]: ‚
- Remission induction
- Cyclophosphamide: 1,200 mg/m2 IV on day 1 (800 mg/m2 if ≥60 years old)
- Daunorubicin: 45 mg/m2 IV on days 1, 2, and 3 (30 mg/m2 if ≥60 years old)
- Vincristine: 2 mg IV on days 1, 8, 15, and 22
- Pegylated asparaginase 2,000 U/m2 (max 3,750 U) given on day 5. 1,000 U/m2 may be better tolerated.
- Dexamethasone 10 mg/m2 on days 1 to 7 and 15 to 21
- Filgrastim, G-CSF: 5 Ž ¼g/kg/day SC starting on day 4 has been shown to shorten the duration of neutropenia and improve the complete remission rate, especially in older patients.
- Imatinib mesylate: 600 to 800 mg/day (or dasatinib 70 mg BID) are effective alone and in combination with chemotherapy for Philadelphia chromosome-positive ALL (6)[B].
- Consolidation (repeat twice in 8 weeks)
- Cyclophosphamide: 1,000 mg/m2 IV day 1
- Intrathecal (IT) methotrexate: 15 mg with hydrocortisone 50 mg on day 1
- Mercaptopurine (6-mercaptopurine): 60 mg/m2/day on days 1 to 14
- Cytarabine: 75 mg/m2/day SC on days 1 to 4 and 8 to 11
- Vincristine: 2 mg IV on days 15 and 22
- Pegylated asparaginase 2,000 U/m2 (maximum 3,750 U) on day 15
- CNS prophylaxis and interim maintenance: 24 Gy cranial irradiation
- IT-methotrexate: 15 mg with hydrocortisone 50 mg on days 1, 8, 15, 22, and 29
- Mercaptopurine : 60 mg/m2/day on days 1 to 70, taken in the evening
- Oral methotrexate: 20 mg/m2 on days 36, 43, 50, 57, and 64
- Late intensification
- Doxorubicin: 30 mg/m2 IV on days 1, 8, and 15
- Vincristine: 2 mg IV on days 1, 8, and 15
- Dexamethasone: 10 mg/m2 on days 1 to 14
- Cyclophosphamide: 1,000 mg/m2 IV on day 29
- Thioguanine (6-thioguanine): 60 mg/m2 on days 29 to 42
- Cytarabine: 75 mg/m2 SC on days 29 to 32 and 36 to 39
- Prolonged maintenance
- Vincristine: 2 mg/m2 IV for 16 months
- Prednisone: 60 mg/m2 for 5 days with the vincristine or dexamethasone 10 mg/m2 on days 1 to 5
- Mercaptopurine : 60 mg/m2/day for 16 months, taken in the evening
- Oral methotrexate: 20 mg/m2/week for 16 months
- Special: Philadelphia chromosome " “positive ALL (6,7)[B]
- Imatinib mesylate (400 to 800 mg/day) is effective alone and in combination with chemotherapy.
- Dasatinib (70 mg BID) is effective in combination with dexamethasone or with chemotherapy (7)[B].
- Contraindications: Doses and schedule may need to be altered for older patients and for concurrent infection and organ toxicity (8)[C].
- Precautions
- Tumor lysis syndrome (elevated uric acid, potassium, and phosphate with decreased calcium, leading to renal failure, disseminated intravascular coagulation, and cardiac arrhythmias) may be prevented by administering allopurinol 300 mg/day. Begin 2 days before chemotherapy begins. Reduce doses if used with mercaptopurine or azathioprine. Give increased fluids; IV urate oxidase (rasburicase) can be used to treat hyperuricemia rapidly.
- Oral sulfamethoxazole-trimethoprim or aerosolized pentamidine is given for Pneumocystis jiroveci prophylaxis.
- Profound immunosuppression: Take appropriate precautions when patient is neutropenic.
- High-dose cyclophosphamide causes severe nausea and vomiting. Use appropriate antiemetic regimen to prevent.
- Neurotoxicity, ileus with vincristine
- Asparaginase may cause severe allergic reactions as well as impaired pancreatic and liver function. Monitor serum glucose concentrations frequently and carefully. Pancreatitis or thrombosis may occur. Peg-asparaginase is preferred now and can be used IV, SC, or IM in place of native Escherichia coli asparaginase.
- Avascular (osteo) necrosis (AVN) of bone may occur in adolescents and young adults after alkylating agents and corticosteroids.
- Rituximab (anti-CD20 monoclonal antibody) appears to improve the outcome of patients with ALL if CD20 is expressed on >20% of their blast cells.
- Also note: Burkitt leukemia/lymphoma (mature B-cell ALL-L3)
- The outcome is clearly better if high-dose methotrexate and alkylating agents are used as part of initial therapy.
- Only 18 weeks of treatment are required.
- Rituximab (anti-CD20 monoclonal antibody) improves the outcome of patients with Burkitt leukemia when added to chemotherapy (9)[B].
Second Line
- Clofarabine has been approved for relapsed childhood ALL. Nelarabine has been approved as a single agent for relapsed T-cell ALL. Pegylated asparaginase (IV or IM) is now used in place of E. coli " “derived L-asparaginase. Liposomal vincristine has been approved for single-agent use for the treatment of relapsed ALL in adults.
- Immunoconjugates such as inotuzumab ozogamicin are under investigation.
- The bifunctional antiCD19/antiCD3 antibody blinatumomab is approved for relapsed/refractory ALL (10)[B].
- Allogeneic hematopoietic stem cell transplantation is recommended for any patient with relapsed ALL or during first remission if high-risk genetic features are present (11)[B],(12)[A].
ISSUES FOR REFERRAL
ALERT
ALL can become a fatal disorder quickly. As soon as the diagnosis is suspected, patients should be referred immediately to an appropriate oncology center.
‚
SURGERY/OTHER PROCEDURES
Surgical placement of a percutaneous, silastic, double-lumen central venous catheter or a percutaneous intravenous central catheter (PICC) ‚
COMPLEMENTARY & ALTERNATIVE MEDICINE
Unproven; may result in adverse drug interactions with chemotherapy ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Ambulatory as tolerated ‚
Patient Monitoring
- Daily during induction chemotherapy for metabolic and infectious complications
- Weekly during remission consolidation chemotherapy
- Monthly during maintenance therapy
- Every 3 months thereafter
DIET
- Nutritional support; if needed IV hyperalimentation
- Avoid alcohol.
- Calcium and vitamin D
PATIENT EDUCATION
- Risks of infection, transfusion, chemotherapy
- Stop smoking.
PROGNOSIS
- ¢ ˆ ¼80 " “95% of adults <60 years will achieve a complete remission, and 35 " “60% will remain free of disease at 5 years.
- Older patients (>60 years) do less well, but 80% may achieve a complete remission.
- Patients with unfavorable cytogenetic subtypes (especially t[9;22] and t[4:11]) should undergo allogeneic stem cell transplantation in first remission if an HLA-identical donor is available. Autologous stem cell transplantation should be considered for Ph+ ALL patients who become reverse transcriptase polymerase chain reaction negative for BCR/ABL and lack an allogeneic donor.
COMPLICATIONS
- Infections (Pneumocystis carinii pneumonia, bacterial pneumonia or sepsis, fungal pneumonia)
- Bleeding
- Coagulopathy (deep vein thrombosis) from asparaginase therapy
- Need for transfusions
- Sterility from treatment
- Arachnoiditis and CNS effects from intrathecal chemotherapy, high-dose methotrexate and irradiation
- Pancreatitis and liver dysfunction from chemotherapy
- Osteonecrosis of joints (avascular necrosis) related to corticosteroids
- Relapse of ALL in marrow or extramedullary sites (CNS, testis)
REFERENCES
11 Mullighan ‚ CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012;2012:389 " “396.22 Bassan ‚ R, Hoelzer ‚ D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29(5):532 " “543.33 Stock ‚ W, La ‚ M, Sanford ‚ B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children 's Cancer Group and Cancer and Leukemia Group B studies. Blood. 2008;112(5):1646 " “1654.44 Curran ‚ E, Stock ‚ W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015;125(24):3702 " “3710.55 Larson ‚ RA, Dodge ‚ RK, Linker ‚ CA, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood. 1998;92(5):1556 " “1564.66 Chalandon ‚ Y, Thomas ‚ X, Hayette ‚ S, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711 " “3719.77 Fo ƒ ‚ R, Vitale ‚ A, Vignetti ‚ M, et al. GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521 " “6528.88 G ƒ ¶kbuget ‚ N. How I treat older patients with ALL. Blood. 2013;122(8):1366 " “1375.99 Rizzieri ‚ DA, Johnson ‚ JL, Byrd ‚ JC, et al. Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002. Br J Haematol. 2014;165:102 " “111.1010 Topp ‚ MS, G ƒ ¶kbuget ‚ N, Stein ‚ AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57 " “66.1111 Mattison ‚ RJ, Larson ‚ RA. Role of allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia. Curr Opin Oncol. 2009;21(6):601 " “608.1212 Oliansky ‚ DM, Larson ‚ RA, Weisdorf ‚ D, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukemia: update of the 2006 evidence-based review. Biol Blood Marrow Transplant. 2012;18(1):16 " “17.
CODES
ICD10
- C91.00 Acute lymphoblastic leukemia not having achieved remission
- C91.01 Acute lymphoblastic leukemia, in remission
- C91.02 Acute lymphoblastic leukemia, in relapse
ICD9
- 204.00 Acute lymphoid leukemia, without mention of having achieved remission
- 204.01 Acute lymphoid leukemia, in remission
- 204.02 Acute lymphoid leukemia, in relapse
SNOMED
- 91857003 Acute lymphoid leukemia, disease (disorder)
- 91856007 Acute lymphoid leukemia in remission
- 425688002 philadelphia chromosome-positive acute lymphoblastic leukemia (disorder)
CLINICAL PEARLS
ALL can become fatal quickly; as soon as diagnosis is suspected, refer the patient to an oncology center. Optimal therapy is not yet known. ALL should be treated at a comprehensive oncology center. All treatment regimens are still investigational but clearly are effective for a large fraction of patients. ‚