Acute lymphoblastic leukemia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [3] Carlos A Lopez, M.D. [4]

Overview

Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS prophylaxis and maintenance treatments with chemotherapeutic drugs such as prednisone plus Vincristine plus cyclophosphamide plus doxorubicin or methotrexate plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a bone marrow transplant. Drugs approved for acute lymphoblastic leukemia include: Methotrexate, nelarabine, blinatumomab, cyclophosphamide, clofarabine, cytarabine, dasatinib, doxorubicin hydrochloride, mercaptopurine, pegaspargase, prednisone. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.

Medical Therapy

Chemotherapy

  • The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).

Treatment for acute leukemia can include:

Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:

Induction chemotherapy

Low risk therapy

  • Low risk therapy
    • 1.1 Pediatric
      • Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
      • Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
      • Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
      • Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive acute lymphoblastic leukemia
      • Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive acute lymphoblastic leukemia
      • Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
      • Alternative regimen(3):Daunorubicin in infants and children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. in children and adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
      • Alternative regimen(5):Doxorubicin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
      • Alternative regimen (6):Hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
    • 1.2 Adult
      • Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
      • Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
      • Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
      • Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive acute lymphoblastic leukemia
      • Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
      • Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
      • Preferred regimen (2): Hyper-CVAD: Hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
      • Alternative regimen (2):Methotrexate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
      • Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28
    • 1.3 Renal impairment
      • Pediatric
        • Preferred regimen(1): Vincristine
          • No adjustment required
        • Preferred regimen(2): Prednisone
          • No adjustment required
        • Preferred regimen(3): Asparaginase
          • No adjustment required
        • Preferred regimen(4): Imatinib
          • Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
          • Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
          • Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
        • Alternative regimen(1): Dexamethasone
          • No adjustments required
        • Alternative regimen(2):Daunorubicin
          • CrCl <30 mL/minute: Administer 50% of dose
          • Hemodialysis: Administer 50% of dose


      • Adult
        • Preferred regimen(1): Vincristine
          • No adjustment required
        • Preferred regimen(2): Prednisone
          • No adjustment required
        • Preferred regimen(3): Asparaginase
          • No adjustment required
        • Preferred regimen(4): Imatinib
          • Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
          • Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
          • Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
        • Alternative regimen(1): Dexamethasone
          • No adjustments required
    • 1.4 Hepatic impairment
      • Pediatric
        • Preferred regimen(1): Vincristine
        • Preferred regimen(2): Prednisone
          • There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
        • Preferred regimen(3): Asparaginase
          • Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
        • ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
        • ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
        • ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
        • Preferred regimen(4): Imatinib
          • If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
          • Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
        • Alternative regimen(1): Dexamethasone
          • No adjustment required
        • Alternative regimen(2):Daunorubicin
      • Adult
        • Preferred regimen(1): Vincristine
          • Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
          • Serum bilirubin >3 mg/dL: Do not use
        • Preferred regimen(2): Prednisone
          • No adjustment required
        • Preferred regimen(3): Asparaginase
        • Preferred regimen(4): Imatinib
          • Mild-to-moderate impairment: No dosage adjustment required
          • Severe impairment: Decrease dose by 25%
        • Alternative regimen(1): Dexamethasone
          • No adjustments required

High risk therapy

Consolidation therapy

  • It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
  • A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
  • Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP)
  • High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.[3]
    • 1.1 Pediatric
      • Preferred regimen(1): Methotrexate:
        • High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
        • Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
      • Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
      • Preferred regimen(3):Daunorubicin In infants and children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
      • Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
      • Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
      • Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
    • 1.2 Adult
      • Preferred regimen(1): Methotrexate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
      • Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
      • Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
      • Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
      • Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
      • Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV

CNS prophylaxis

  • The objective is to stop the cancer from spreading to the brain and nervous system
  • Standard prophylaxis may consist of:[4]
  • Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
    • 1.1 Pediatric
      • Preferred regimen(1): Methotrexate, dosage varies amongst age and they are the following: <1 year: 6 mg,1 to <2 years: 8 mg,2 to <3 years: 10 mg,3 to ≤8 years: 12 mg and >8 years: 15 mg. Given intrathecally
      • Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol
    • 1.2 Adult
      • Preferred regimen(1): Methotrexate, 15 mg day 1, 8, 15, 22, and 29. Given intrathecally
      • Preferred regimen(2): Cytarabine 300 mg/m2/ intrathecally, frequency dependent upon protocol

Radiotherapy in CNS prophylaxis

Maintenance therapy

  • Treatment with chemotherapeutic drugs (e.g., prednisone plus vincristine plus cyclophosphamide plus doxorubicin; methotrexate plus 6-MP) to prevent disease recurrence once remission has been achieved
  • Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase
  • In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy
  • During maintenance therapy, patients are at risk for infection. Fever in children who are receiving chemotherapy must be assesed and treated enthusiatically, especially for patients who are either neutropenic or have a central venous access device.The following drugs are given:

prophylaxis is continued to prevent Pneumocystis pneumonia

  • Treatment is administered on an outpatient basis, and typically is known to cause less toxicity
    • 1.1 Pediatric
      • Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV. Given every 4 weeks
      • Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
      • Preferred regimen(1): Methotrexate 20 mg/m2 once weekly, given PO
      • Preferred regimen(5): Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
      • Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
      • Preferred regimen(6): Mercaptopurine 75 mg/m2 once daily on days 1 to 84 of an 84-day cycle, given PO
    • 1.1 Adult
      • Preferred regimen(1): Vincristine 2 mg/m2/dose IV. Given every 4 weeks
      • Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
      • Preferred regimen(1): Methotrexate 10 mg/m2/day IV for 5 days every month for 2 years
      • Preferred regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
      • Preferred regimen (6): Cyclophosphamide 1 to 5 mg/kg/day PO
      • Preferred regimen(6): Mercaptopurine 50 mg 3 times/day for 2 years, given PO

Follow-up therapy

For acute lymphoblastic leukemia patients, follow-up usually consists of:

  • Regular visits to oncologist, who conducts physical examinations, imaging studies and various procedures
  • Regular visits to there primary care physicians who provide counseling, vaccinations, prophylactic antibiotics
  • Supportive care, such as intravenous nutrition and treatment with oral antibiotics, especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
  • Transfusions with red blood cells and platelets
  • Immunizations are given such as varicella and influenza. Live attenuated vaccines are not given, because of hypo-immune state the patients are in.

Relapse monitoring

  • Acute lymphoblastic luekemia relapse most commonly happens in the bone marrow and usually associated with persistent peripheral blood cytopenias
  • Healthcare providers should be very observant of insistently abnormal blood counts in the acute lymphoblastic luekemia survivor
  • Monitoring for the presence of measurable residual disease is also common place in patients who have had a stem cell transplant as part of their treatment regimen
  • Prompt referral for bone marrow examination is needed if there is suppression of more than one cell line or unexplained suppression of one cell line that goes on for longer than three to four weeks

Management of relapse

  • About 10 to 15 percent of children fail initial treatment of Acute lymphoblastic luekemia, but relapse rates are higher (25 to 30 percent) in certain high-risk groups
  • Patients with relapsed acute lymphoblastic leukemia require aggressive re-induction therapy and intensification, often using drugs not used in the original treatment regimen
  • Patients with high-risk acute lymphoblastic leukemia, such as those with high white blood cell counts or children older than 10 years of age, often do not respond well to treatment with additional chemotherapy only
  • Patients who have central nervous system or testicular relapse need radiation therapy at some point during the rescue therapy program
  • The following drugs are used:
    • Blinatumomab
    • Clofarabine
    • Nelarabine
    • Etoposide
    • Cyclophosphamide
    • Cytarabine

Miscellaneous therapies

Allogeneic hematopoietic cell transplantation

  • Selected patients with high-risk disease have an increased occurance of relapse during delayed intensification chemotherapy
  • This includes patients with severe hypodiploid acute lymphoblastic luekemia, those with the KMT2A rearrangement, and infants with acute lymphoblastic luekemia
  • With the exception of patients less than 1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic hematopoietic cell transplantation during first remission
  • There is evidence that hematopoietic cell transplantation offers a survival advantage to those greater than 10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell acute lymphoblastic leukemia, induction failure, and patients greater than 1 year of age with 11q23 rearrangements

Chimeric antigen receptor T (CAR-T) cell therapy

  • Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings
  • This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses
  • The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population
  • The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.[5]
  • A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene
  • The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."[5]
  • CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies."
  • In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker
  • The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia

Radiation Therapy

  • Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a bone marrow transplant (total body irradiation)
  • Radiation in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain
  • Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia
  • Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side effects
  • As a result, the use of whole brain radiation has been more limited.[6]

Drugs Approved for acute lymphoblastic leukemia

The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:[7]

Late Effects of Treatment for Adult acute lymphocytic leukemia

  • Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies
  • Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[7]

References

  1. Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R (February 2010). "Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999". Leukemia. 24 (2): 383–96. doi:10.1038/leu.2009.260. PMID 20033052.
  2. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM (June 2008). "Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study". Blood. 111 (12): 5477–85. doi:10.1182/blood-2008-01-132837. PMC 2424148. PMID 18388178.
  3. Cooper SL, Brown PA (February 2015). "Treatment of pediatric acute lymphoblastic leukemia". Pediatr. Clin. North Am. 62 (1): 61–73. doi:10.1016/j.pcl.2014.09.006. PMC 4366417. PMID 25435112.
  4. Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S (May 2010). "Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies". Cancer. 116 (10): 2290–300. doi:10.1002/cncr.25008. PMID 20209620.
  5. 5.0 5.1 Makita S, Yoshimura K, Tobinai K (2017). "Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma". Cancer Sci. 108 (6): 1109–1118. doi:10.1111/cas.13239. PMC 5480083. PMID 28301076.
  6. Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD (December 1993). "The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group". Int. J. Radiat. Oncol. Biol. Phys. 27 (5): 1001–9. PMID 8262820.
  7. 7.0 7.1 "National Cancer Institurte".

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