Acute lymphoblastic leukemia medical therapy: Difference between revisions

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***Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
***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
***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 Oral: 140 mg once daily also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
***Alternative regimen(1):Dasatinib Oral: 140 mg once daily 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(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): 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.
***Alternative regimen (3):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.
*Patients will undergo this regimen for the first month of treatment
*Patients will undergo this regimen for the first month of treatment


Revision as of 15:26, 8 February 2019

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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, Nelarabine, Pegaspargase, Prednisone and Mercaptopurine. 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
  • Consolidation therapy
  • CNS prophylaxis
  • Maintenance treatment
  • Follow-up therapy

Induction chemotherapy

  • To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
  • For adult acute lymphoblastic leukemia standard induction plans include:
  • Other drug plans may include:

Low risk therapy

  • Low risk therapy
    • 1.1Pediatric
      • 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 Oral: 140 mg once daily 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):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.
  • Patients will undergo this regimen for the first month of treatment
    • 1.2Adult
      • 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): 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

High risk therapy

Consolidation therapy

therapy (1-3 months in adults; 4-8 months in children) to eliminate 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]

CNS prophylaxis (preventive therapy) to stop the cancer from spreading to the brain and nervous system. Standard prophylaxis may consist of:[4]

  1. Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug methotrexate.
  2. High-dose systemic and IT methotrexate, without cranial irradiation
  3. IT chemotherapy.

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.

Maintenance treatments 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.

Follow-up therapy for acute lymphoblastic leukemia patients usually consists of:

  • Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), 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

A laboratory test known as polymerase chain reaction (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. PCR testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia cyclophosphamide-based regimens that are used for non-hodgkin's lymphoma.

Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.

People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.

Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by allogeneic bone marrow transplant (alloBMT).

Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.

Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.

As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System CNS, most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

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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