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Treatment of Acute Lymphoblastic Leukemia


Medical editor Lorentz Brinch MD
Hematologist
Oslo University Hospital

General

The principle for treating acute lymphoblastic leukemia is to give chemotherapy which reduces or optimally, eradicates the leukemic clone.

About half of the patients fall into an age group where chemotherapy is expected to be beneficial or eradicate the disease. The patient's age is an indicator for what is reasonable to expect. The condition for achieving long-term survival or curing the disease is to reach complete hematological remission (CHR), which is defined as < 5% blasts in normocellular bone marrow combined with a nearly normalized cell count in the blood.  

In practice, this is only achievable after infusion of chemotherapy with such a high dose intensity that the treatment is life-threatening. Chemotherapy will heavily affect normal hematopoiesis causing bone marrow aplasia with serious neutropenia, thrombocytopenia, and anemia, in periods from one to multiple weeks.

The most intensive treatment regimens are relevant for patients under about 60 years, while patients between 60-70 years can be treated with an intensive induction protocol to cure the disease only in certain cases. Patients older than 70 years will in most cases, achieve the best benefit from good palliative treatment. An exception is patients with acute hypergranular promyelocyte leukemia (M3).

Diagnostics and treatment to cure the disease should occur at a hematology section of a regional hospital or a well-equipped central hospital with a designated section for blood diseases. They should have sufficient resources of blood banking and competent on-call personnel. If necessary, there should be cooperation with a regional hospital.

Indication

  • Acute lymphoblastic leukemia 

Goals

  • Hematological, cytogenetic, and molecular control of the disease.
  • Cure the disease. 

Norsk selskap for hematologi. Handlingsprogram for diagnostikk og behandling av akutt lymfoblastisk leukemi/lymfoblastisk lymfom og burkitt lymfom leukemi hos voksne [Online]. Mars 2006 [hentet 15. april 2007]; tilgjengelig fra: URL:http://www.legeforeningen.no/asset/33493/1/33493_1.doc


Treatment Plan

Treatment is based on the Hammersmith 82 regimen, which in recent updates provides successful results for total survival. For rare variants of the disease, documentation of this regimen is uncertain, therefore other alternatives are available.

Patients with acute lymphoblastic leukemia are usually not candidates for an allogeneic stem cell transplantation in the first remission because results from chemotherapy are usually good. The most important exception is for patients with detected Philadelphia chromosome and/or BCR-ABL fusion transcription in the leukemia cells. For these patients, an imatinib regimen and allogeneic stem cell transplantation are recommended in the first remission. There are also other prognostic factors.

Surveillance of minimal residual disease (MRD) in bone marrow is recommended in patients < 60 years where an allogeneic stem cell transplantation may be appropriate, but where the indication is uncertain based on traditional risk factors.

Hammersmith 82

Treatment for acute lymphoblastic leukemia consists of an induction phase of 16 weeks followed by maintenance treatment for three years.

Induction treatment

  • Vincristine 2 mg intravenously day 1 for weeks 1–5
  • Doxorubicin 30 mg/m2 intravenously day 1 weeks 2, 3 and 4
  • Asparginase 10000 µg/m2 intravenously every other day in weeks 2 and 3
  • Metotrexate intrathecal 15 mg day 1 in weeks 3, 5, 7, 10, 12, 14 and 16
  • Cyclophosphamide 750 mg/ m2 intravenously day 1 in weeks 3 and 5
  • Prednisolone 40 mg/m2 orally daily in weeks 1–4, gradually reducing until discontinuation in week 5
  • DTC:
    • Daunorubicin 50 mg/m2 intravenously days 1, 3 and 5 in week 7
    • Cytosar 200 mg/ m2/ 24 hours, on days 1–5 in week 7
    • Thioguanin 150 mg/m2 orally on days 1–5 in week 7
  • Metotrexate 1500 mg/m2 intravenously with calcium folinate in weeks 10 and 12
  • Mercaptopurine 35 mg/m2 orally daily in weeks 10–16

An examination of bone marrow is performed in week 4-5 before starting DTC and with the MRD examination in week 16. Modification of dosage intensity is often necessary due to serious side effects.

Maintenance treatment (x 13)

  • Dexamethazone 6 mg/m2 orally daily in weeks 1–3
  • Vincristine 2 mg intravenously day 1 weeks 1–3
  • Doxorubicin 30 mg/m2 intravenously day 1 in week 2
  • Cyclophosphamide 600 mg/m2 intravenously day 1 in week 3
  • Methotrexate 15 mg/m2 orally daily for 3–5 days in week 4
  • Mercaptopurin 70 mg/m2 orally daily in weeks 5–8
  • Methotrexate 15 mg/m2 for 3–5 days in week 8
  • Mercaptopurine 80 mg/m2 orally daily in weeks 9–11
  • Methotrexate 15 mg/m2, 3–5 days in week 12 

In the first two maintenance cycles, monthly intrathecal methotrexate (15 mg) is administered for a total of 13 intrathecal injections.

Vincristine can often not be given in full because of polyneuropathy.

During maintenance treatment, moderate bone marrow suppression is striven for (neutrophiles and granulocytes are held between 0.5–1.5 x 109/l.

During the last three maintenance cycles, doxorubicin is replaced with cytarabine to avoid too high accumulation of anthracycline dosage.

If infections due to treatment occur as a result of bone marrow suppression, the treatment intensity should be reduced. 

Treatment of elderly patients (~60+)

Older patients with acute lymphoblastic leukemia usually suffer more from side effects than benefit from the most intense chemotherapies. The goal of treatment is palliative for most of these patients.

If assessing whether it is possible to complete intensive chemotherapy: normal ALL-protocol (Hammersmith) can be used as a framework with reduction of dosage and shortening. Stop vincristine if there is neuropathy. Asparaginase can be omitted in some. High-dose methotrexate is not tolerated well in elderly; maximum dosage is 500 mg/m2.

When remission is reached after induction, direct transition to simplified maintenance (6 mercaptopurine + methotrexate (if possible)) should be considered, without consolidation.

Patients over 60 often do not tolerate intense chemotherapy well, but may benefit from taking imatinib for a period, for Ph+ (BCR-ABL+) acute lymphoblastic leukemia.

The OPAL or VAD regimen is used by some as a palliative induction regimen for acute lymphoblastic leukemia in elderly patients with reduced function status.

Acute lymphoblastic leukemia in the central nervous system

For blasts in spinal fluid, intrathecal methotrexate is administered (15 mg twice per week) until the spinal fluid is free of blasts. Thereafter, weekly four times, for example.

The CNS prophylaxis is resumed according to protocol if the response has been successful.

Systemic treatment is continued according to protocol.

At least 8 intrathecal injections should be administered with not more than a 1 month interval after the spinal fluid is free of blasts.

If the brain is involved, CNS radiation of 24 Gy may be considered when remission is reached.

In a palliative situation, cytarabine with depot properties can be considered to reduce the number of injections.


Preparation

  • Provide information about the disease, treatment, and side effects.
  • Evaluate family donor situation.
  • Insert central vein catheter.

Implementation

Acute pre and pro B-lymphoblastic leukemia

Approximate age 18–60 years:

  • normal ALL-protocol (Hammersmith 82).

Acute T-lymphoblastic leukemia

Approximate age 18–60 years:

  • normal ALL-protocol (Hammersmith 82), alternatively hyper CVAD

The documentation of the effect of Hammersmith 82 is somewhat less here than in pre and pro B-ALL, and the alternatives are equally relevant.    

Bukitt’s lymphoma/leukemia

GMALL B-ALL/NHL 2002 with rituximab.

In the special case of Burkitt’s lymphoma/leukemia, there is often a very quick treatment response and therefore a high risk for developing Tumor Lysis syndrome.

Ph+ (BCR-ABL+) acute lymphoblastic leukemia

Hyper CVAD combined with imatinib, with an allogeneic stem cell transplantation as soon as possible in the first complete remission. If treatment is chosen, imatinib can be used in elderly patients either alone or combined with steroids as an induction for palliative indication.


Follow-up

Intensive chemotherapy treatment leads to significant granulocytopenia and thrombocytopenia. Therefore, frequent blood tests are necessary.

While the patient is hospitalized and receives aggressive combination treatment, and between later courses, hemoglobin, rod and segmental nucleated granulocyte counts, as well as platelets, should be checked at least twice a week after a course of chemotherapy until bone marrow regeneration.

Side effects

During the intensive treatment period, the patient will, in periods from weeks to months, require hospitalization as a result of the treatment due to infections, the need for transfusions, and/or organ failure. Large amounts of antibiotics and blood products are used.

Liberal use of thrombocyte concentrates in combination with optimal doses of antimicrobial and antifungal agents is a prerequisite for safe treatment. Chemotherapy of this intensity unfortunately leads to death in some patients, due to sepsis or other complications during the first months of treatment. This applies especially to older patients.

Nutrition

Nutritional problems occur, more or less, among patients receiving this treatment. This is due to nausea, vomiting, mucositis, diarrhea, dry mouth, pain, constipation, and changes in smell and taste senses. Many will require intravenous nutrition. Good nutritional guidance is important.  

Pain

Vincristine can cause neuromuscular manifestations. This often starts with sensory disturbances and paresthesia. Neuritis pain and serious delayed motor disturbances can occur with continued treatment. The neuromuscular side effects are muscle weakness, muscle atrophy, disappearance of deep delayed reflexes, bone pain, and difficulty walking which is sometimes significant, jaw pain, painful swallowing, and constipation. Vincristine can also lead to ptosis. The side effects are usually completely or partly reversible, but can last longer for some.

Mucositis

Mucositis, both in the mouth and other mucosa, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic mouth hygiene should be performed during the entire treatment. 

Nausea

Nausea improves 1–2 days after a treatment. Different chemotherapy agents cause nausea to varying degrees. The most emetic drugs are doxorubicin, daunorubicin, and cyclophosphamide.

Gastritis

Due to large doses of steroids, the patient is at risk for gastritis/gastric ulcer. Hydrogen blockers or proton-pump inhibitors are used routinely as prophylaxis during high dose steroid medication.  

Change in appearance/alopecia

Hair loss, often in tufts, will occur 2–3 weeks after starting chemotherapy. The patient will often develop an appearance resembling Cushing's disease from the use of steroids.

Change in self-image

This treatment is often a great burden for the patient, both physically and psychologically. This may alter the patient’s self-image.

Criteria for remission

Complete remission is defined as:

  • Hb > 10 g/dl
  • Granulocytes > 1.5 x 109/l
  • Thrombocytes > 100 x 109/l
  • No blasts in peripheral blood, spinal fluid, and absence of previously affected extramedullary localizations.
  • The bone marrow should have tri-linear hematopoiesis and blast cells < 5 %

Recurrence

Recurrence from earlier complete remission is diagnosed when blast cells with typical appearance and immunophenotype constitute 5% or more in bone marrow or are detected spinal fluid or other extramedullary localizations.

Other treatment alternatives:

  • Autologous stem cell support (HMAS) in first remission
  • For acute T-lymphoblastic leukemia with standard risk, HMAS can be assessed as an alternative to maintenance treatment.
  • Allogeneic stem cell transplantation

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