Acute myeloid leukemia medical therapy
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The mainstay therapy from acute myeloid leukemia is induction chemotherapy and usually includes a combination of an anthracycline and cytarabine. Induction chemotherapy sometimes includes etoposide. The decision about consolidation therapy depends on the risk assessment of acute leukemia. Relapsed acute myeloid leukemia is treated with a variety of other chemotherapeutics. Novel FDA-approved agents include midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and ivosidenib. Supportive care measures include transfusions and hydration.
Treatment of acute myeloid leukemia consists primarily of chemotherapy and is divided into two phases: induction and post-remission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. Maintenance therapy involving targeted therapy is used in some situations. Specific treatment plans may be used, depending on the type of leukemia that has been diagnosed. Many different chemotherapeutic plans are available for the treatment of acute myeloid leukemia. Overall, the strategy is to control bone marrow and systemic (whole-body) disease while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission (lessening of the disease) and a lower risk of disease resistance. Consolidation or "maintenance" treatments may be given to prevent disease recurrence once remission has been achieved. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with added drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase. It is important for the patient to understand the treatment that is being given and the decision-making process behind the choice.
Initial treatment of acute myeloid leukemia usually begins with induction chemotherapy using a combination of drugs such as daunorubicin (DNR) or idarubicin plus cytarabine (ara-C). In some cases, etoposide is added to induction chemotherapy. The combination of an anthracycline (such as daunorubicin or idarubicin) plus cytarabine is known as the 3+7 regimen, as this consists of 3 days of the anthracycline plus 7 days of continuous cytarabine infusion. All sub-types from the French-American-British classification except FAB M3 are given induction chemotherapy with cytarabine and an anthracycline. Other alternatives, including high-dose ara-C alone, may also be used. Because of the toxic effects of therapy, including myelosuppression and an increased risk of infection, induction chemotherapy may not offered to the very elderly. Induction chemotherapy usually requires a hospitalization for approximately 1 month to receive the chemotherapy and recover from its side effects. The induction chemotherapy agents are described in detail below:
|Therapy||Mechanism of Action||Dosing||Adverse Effects|
Inhibits DNA polymerase during S phase of cell cycle, via cytarabine-5'-triphosphate incorporation into DNA
100-200mg/m2 IV as a continuous infusion for 3 days
12mg/m2 IV daily for 3 days, given over 10-15 minutes
80mg/m2 IV on days 1-6
Induction chemotherapy is known as "7 and 3" because the cytarabine is given as a continuous IV infusion for seven consecutive days, while the anthracycline is given for three consecutive days as an IV push. Up to 70% of patients will achieve a remission with this protocol.
The M3 sub-type of acute myeloid leukemia, also known as acute promyelocytic leukemia, is almost universally treated with the drug ATRA (all-trans-retinoic acid) in addition to induction chemotherapy. Care must be taken to prevent disseminated intravascular coagulation (DIC), complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. APL is eminently curable with well-documented treatment protocols.
The goal of the induction phase is to reach a complete remission. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected with available diagnostic methods (i.e., <5% leukemic cells remain in the bone marrow). Complete remission is obtained in about 50%–75% of newly diagnosed adults, although this may vary based on the prognostic factors described above.
The durability of remission depends on the prognostic features of the original leukemia. In general, all remissions will fail without consolidation (post-remission) chemotherapy, and consolidation has become an important component of treatment.
Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further post-remission or consolidation therapy is given, almost all patients will eventually relapse, typically after 4-8 months. Therefore, more therapy is necessary to eliminate non-detectable disease. It is best to give consolidation therapy very soon after complete remission is achieved from induction therapy. If there is a delay between the end of induction therapy and the start of consolidation therapy, there is a higher risk that the leukemia will re-surge.
The specific type of post-remission therapy is individualized based on a patient's prognostic factors (see above) and general health.
- Favorable-risk disease: For good-prognosis leukemias (i.e. inv(16), t(8;21), and t(15;17)), patients will typically undergo an additional 3–5 courses of intensive chemotherapy, known as consolidation chemotherapy. Consolidation chemotherapy usually consists of high-dose cytarabine (HIDAC) and carries a 5% treatment-related mortality. HIDAC dosing is 3g/m2 every 12 hours on days 1, 3, and 5 (total of 6 doses per course). This regimen is given once per month for at least 3 cycles. Alternatively, HIDAC 1-1.5g/m2 twice daily for 5 days can be given. For patients above the age of 60, HIDAC 2g/m2 is given. For patients above the age of 70, HIDAC 1.5g/m2 is given. HIDAC should only be started after a first complete remission (CR1) is documented and toxicities from induction chemotherapy have resolved. Steroid eye drops should be given 4 times daily until 24 hours after the completion of HIDAC to prevent cytarabine-induced chemical conjunctivitis. Cerebellar testing for dysdiadochokinesis or past-pointing should be done every 12 hours during therapy. Toxicities include cytopenia, cerebellar dysfunction, conjuncitival dysfunction, hyperbilirubinemia, and fatigue.
- Unfavorable-risk disease: For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related acute myeloid leukemia), allogeneic stem cell transplantation is usually recommended if the patient is able to tolerate a transplant and has a suitable donor.
- Intermediate-risk disease: The best post-remission therapy for intermediate-risk acute myeloid leukemia (normal cytogenetics or cytogenetic changes not falling into favorable-risk or unfavorable-risk groups) is less clear and depends on the specific situation, including the age and overall health of the patient, the patient's personal values, and whether a suitable stem cell donor is available.
Relapsed acute myeloid leukemia
Upon confirmation of relapsed disease, the following should be performed for most patients:
- Goals of care discussion
- Molecular testing via next-generation sequencing
- Donor search for stem cell transplant if appropriate
The chemotherapy regimens used in relapsed/refractory acute myeloid leukemia include:
- FLAG-IDA: Fludarabine, araC, G-CSF, idarubicin
- G-CLAC: G-CSF, clofarabine, araC
- HIDAC: High-dose araC. This is given as 2-3g/m2 every 12 hours for 8-12 doses. It may be effective in 35-40% of patients. This should not be used if HIDAC was used for initial induction. Clinicians must watch for cerebellar and conjunctival symptoms while on HIDAC.
- 7+3 induction: This regimen consists of 7 days of cytarabine and 3 days of anthracycline. This is more useful for patients with complete remission more than 1 year. The rate of second complete remission (CR2) is 50%.
- MEC: mitoxantrone, etoposide, araC. The complete response rate is 40%
- MEC with intermediate-dose cytarabine: Cytarabine at an intermediate dose of 0.5g/m2 every 12 hours for 6 days can be given, based on Amadori et al., JCO 1991 showing safety and efficacy of MEC for RRAML
- Gemtuzumab ozogamycin: This is used for CD33+ AML. It is given at 3mg/m2 on days 1,4,7. Patients should be monitored for venoocclusive disease, prolonged thrombocytopenia; hemorrhage, and teratogenicity.
- Azacitidine plus sorafenib: This is used for FLT3-ITDmutant AML based on phase II data (Ravandi et al., Blood 2013)
- Hypomethylating agents
Novel FDA-Approved Agents
In general, these recent FDA approvals largely stem from the identification and characterization of unique molecular subtypes. The years 2017 and 2018 were landmark years in AML, as 8 new therapies were brought to the market after a 40-year period of stagnation.
- Target: The target of midostaurin is the FLT3 receptor tyrosine kinase. With regards to the pre-leukemic evolution of the hematopoietic stem cell, the FLT3 mutation is one of the late driver mutations in AML. The FLT3 mutation occurs in about 30% of cytogenetically normal AML.
- Mechanism of action: Midostaurin is a multi-kinase inhibitor that inhibits FLT3 receptor signaling and cell proliferation. Importantly it also inhibits KIT, VEGFR2, and PDGFRa/b. It is therefore non-specific and thus has various adverse effects.
- Clinical trial data: In the midostaurin trial, also known as CALGB 10603 or the RATIFY alliance trial, 717 patients were randomized to either standard chemotherapy plus midostaurin or standard chemotherapy plus placebo. Patients were stratified based on FLT3 mutation status (namely, tyrosine kinase domain mutation or internal tandem duplication, with either high allelic ratio or low allelic ratio). Patients also received midostaurin maintenance if they were in remission after consolidation. Primary endpoint was overall survival. There improvement in median overall survival and event-free survival. The beneficial effect was seen across all subgroups stratified by FLT3 status.
- FDA approval: It is FDA approved for newly diagnosed AML with a FLT3 mutation, at a dose of 50mg PO twice daily on days 8-21, as well as during consolidation at a dose of 50mg PO twice daily on days 8-21 alongside high-dose cytarabine. It is also used as maintenance therapy at a dose of 50mg PO twice daily for 12 months.
- Adverse effects: Nausea, hypocalcemia, neutropenic fever, increased ALT, mucositis, vomiting, headache
- Target: Enasidenib targets the mutant isocitrate dehydrogenase 2 (IDH2) enzyme. The IDH2 mutation is a early mutation in the pre-leukemic evolution of the hematopoietic stem cell. The IDH2 mutation occurs in about 12-15% of patients with AML and is more commonly found in cytogenetically normal AML.
- Mechanism: Under normal conditions, the IDH enzyme catalyzes the reaction of isocitrate to alpha-ketoglutarate, and this reaction leads to the generation of reductive bio-equivalents in the form of NADPH, which combats oxidative stress. However, in patients with the IDH2 mutation, this mutation confers neomorphic enzyme activity that leads to generation of the oncometabolite 2-hydroxyglutarate. Through a variety of epigenetic mechanisms, this leads to differentiation arrest. Enasidenib, or AG-221, is an oral selective inhibitor of the mutant IDH2. Enasidenib can be thought of a differentiation agent, similar to all-trans retinoic acid in acute promyelocytic leukemia.
- Clinical trial data: The trial that led to the approval of this agent was a first-in-human phase 1/2 trial that assessed the maximally tolerated dose, safety, and efficacy in patients with IDH2-mutant AML. Enasidenib 100mg PO daily was selected for the expansion phase, and continuous daily treatment was well tolerated. Results showed that, with each treatment cycle, there was an increasing proportion of patients who achieved complete remission. Overall response rate was 40% and median response duration was 5.8 months. Complete remission rate was 19%, and in the 19% of patients who achieved complete remission, the overall survival was 19 months. Median overall survival was 9.3 months.
- FDA approval: The FDA indication is for relapsed/refractory AML with IDH2 mutation at a dose of 100mg PO daily, administered continuously until unacceptable toxicity or disease progression. It should be given for at least 6 months.
- Adverse effects: Differentiation syndrome (to any degree of severity) occurs in 10% of patients. However, only 7% of patients develop grade 3 or higher differentiation syndrome. This syndrome includes edema, weight gain, shortness of breath. During the initial period after giving enasidenib, the white count actually rises and some may mistake this as disease progression, but this is actually pseudoprogression. Indirect hyperbili occurs in 12% patients. Nausea is common.
- Liposomal daunorubicin/cytarabine (CPX-351):
- Target: This agent targets DNA replication.
- Mechanism of action: CPX-351 is a dual-drug liposomal formulation that contains cytarabine and daunorubicin in a 5:1 molar ratio. Cytarabine is a nucleoside analog, and daunorubicin is an anthracycline that inhibits topoisomerase II and intercalates into DNA. The liposomal formulation helps deliver these cytotoxic agents into leukemia cells to a greater extent than normal cells. The liposome allows for persistent exposure of the drugs in the bone marrow.
- Clinical trial data: This was an open-label phase III trial consisting of 309 patients who were randomized to receive either CPX-351 or standard cytarabine/anthracycline chemotherapy for both induction and consolidation. The liposomal dose of cytarabine was 100mg/m2 and dose of daunorubicin was 44mg/m2, and this was given on days 1, 3, and 5 of induction. The liposomal formulation improved median overall survival compared to standard chemotherapy (9.5 months vs. 5.9 months). Liposomal daunorubicin/cytarabine also improved the overall remission rate compared to standard chemotherapy (47% vs. 33%). The safety profile was similar. Following the FDA approval, the European Commission recently approved in September 2018.
- FDA approval: This is FDA approved for newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). For cycle 1 of induction, it is given on days 1, 3, and 5. For cycle 2 of induction if needed, it is given on days 1 and 3. For consolidation, there is a 35% dose reduction.
- Adverse effects: hemorrhage, neutropenic fever, rash, edema, copper toxicity, cardiac toxicity
- Gemtuzumab ozogamicin:
- Target: This agent targets CD33, a protein expressed on the surface of 85-90% of myeloid cells.
- Mechanism of action: Gemtuzumab ozogamycin is an antibody-drug conjugate consisting of anti-CD33 plus the caliceamicin derivative ozogamicin. After internalization of the antibody-drug conjugate, ozogamicin causes DNA strand scission in the leukemia cells.
- Clinical trial data: The original trial for gemtuzumab ozogamycin used a dose of 9mg/m2. There was a 26% complete remission rate with the initial 9mg/m2 dose. However, gemtuzumab ozogamycin was taken off the market in 2010 due to safety and efficacy concerns, then reintroduced a lower dose and specifically for use in CD33-positive AML, based on the ALFA-0701 trial, a randomized phase III study of about 280 patients with de novo AML. In this trial, a low dose of fractionated gemtuzumab ozogamycin was used (3mg/m2 on days 1, 4, and 7), given the hematologic toxicity and veno-occlusive disease risk with 9mg/m2). The total induction dose was 9mg/m2 (since there were 3 doses of 3mg/m2), but the key difference was the fractionation of the regimen. The experimental group also received gemtuzumab ozogamycin on day 1 of each of 2 consolidation cycles so the total dose was 15mg/m2. The results showed 81% complete remission rate compared to 75% for standard chemotherapy. The beneficial effect was not restricted to any particular subgroup, though patients with the FLT3 mutation benefited the most.
- FDA approval: The FDA approval is for both newly diagnosed CD33-positive AML and relapsed/refractory AML. It is used during induction and during consolidation and continuation. It can be used in combination with standard chemotherapy or as monotherapy. We now give fractionated doses which allows for a higher total dose of gemtuzumab ozogamycin to be delivered while minimizing toxicity.
- Adverse effects: These include delayed platelet count recovery (thrombocytopenia) and veno-occlusive disease which is due to the ozogamycin component.
- Target: Ivosidenib targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. The IDH1 mutation is a early mutation in the pre-leukemic evolution of the hematopoietic stem cell. The IDH1 mutation occurs in about 6-10% of patients with AML.
- Mechanism of action:: Ivosidenib or AG120 is an oral mutant IDH1 inhibitor. Its mechanism parallels that of enasidenib. Ivosidenib prevents production of the oncometabolite 2-hydroxyglutarate and leads to differentiation of cells.
- Clinical trial data: This was a phase 1 open-label dose-escalation and dose-expansion study. In this trial, 179 patients with relapsed/refractory AML and IDH1 mutation were treated with ivosidenib 500mg PO daily. Treatment with ivosidenib resulted in a low frequency of grade 3 or higher adverse events (QT prolongation in 8% of patients and differentiation syndrome in 4% of patients). Leukocytosis also occurred after initiation of treatment, similar to enasidenib. The efficacy outcomes for ivosidenib were very similar to enasidenib. The overall response rate was 41%. The rate of composite complete remission was 30%, and the rate of complete remission was 21%. The median duration of response was in the range of 6-9 months. Transfusion independence was achieved in 35% of patients. The IDH1 mutant clone was eradicated in 21% of patients.
- FDA approval: Ivosidenib 500mg PO daily is approved for relapsed/refractory AML with the IDH1 mutation. Treatment should continue for at least 6 months to allow response.
- Adverse effects: QT prolongation (occurs in in 8% of patients), differentiation syndrome (edema, weight gain, shortness of breath), hyperleukocytosis
- Target: The target of glasdegib is the Hedgehog pathway. This pathway is essential for embryonic development and for cancer cell growth.
- Mechanism of action: Glasdegib is an inhibitor of Hedgehog signaling. It prevents cancer cell growth.
- Clinical trial data: In a phase II study, glasdegib in combination with anthracycline and cytarabine was shown to be well-tolerated and showed a 46% complete response rate.
- FDA approval: It is FDA approved in combination with low-dose araC for newly diagnosed AML in adults age 75 or older or who have comorbidities that preclude the use of intensive induction chemotherapy. The dose is 100mg daily on days 1-28 of each 28-day cycle. AraC is given at a dose of 20mg subcutaneously on days 1-10.
- Adverse effects: Increased creatinine, QT prolongation, hyponatremia, fatigue, hypomagnesemia
- Target: The target of gilteritinib is the FLT3 receptor tyrosine kinase. With regards to the pre-leukemic evolution of the hematopoietic stem cell, the FLT3 mutation is one of the late driver mutations in AML. The FLT3 mutation occurs in about 30% of cytogenetically normal AML.
- Mechanism of action: Gilteritinib is an inhibitor of FLT3 receptor signaling and cell proliferation. It is more specific than midostaurin and has less off-target effects. However, the medication also inhibits AXL.
- Clinical trial data: The ADMIRAL trial is still ongoing and the recent data is currently unavailable but will be available shortly. The CHRYSALIS study is Phase 1/2 trial of gilteritinib in relapsed/refractory AML and showed a 52% overall response rate.
- FDA approval: It is FDA approved for relapsed/refractory AML with a FLT3 mutation, at a dose of 120mg PO daily. The treatment should be continued for at least 6 months.
- Adverse effects: Myalgia, increased transaminases, fatigue, fever, dyspnea, increased bilirubin
- Target: The target of venetoclax is the anti-apoptotic protein BCL-2.
- Mechanism of action: Venetoclax is an inhibitor of the anti-apoptotic protein BCL-2. Venetoclax thus promotes apoptosis in cancer cells.
- Clinical trial data: A recent phase 1B trial showed a complete response rate of 61% in patients who received venetoclax alongside a hypomethylating agent.
- FDA approval: It is FDA approved in combination with azacytidine or decitabine or low-dose araC for the treatment in adults age 75 or older who are newly diagnosed with AML or who have comorbidities that preclude induction chemotherapy. The venetoclax dose schedule involves a ramp up phase: 100mg on day 1, 200mg on day 2, 400mg on days 3 and beyond.
- Adverse effects: Leukopenia, lymphopenia, neutropenia, hypocalcemia, diarrhea, tumor lysis syndrome
Stem Cell Transplantation
Patients with newly diagnosed disease also may be considered for stem cell transplantation (SCT). The source of hematopoietic stem cells may be either bone marrow, umbilical cord blood, or peripheral blood. Allogeneic bone marrow transplant (allo-BMT) is reserved primarily for patients under 65 years of age who have poor-risk genetic features and adequate performance status to tolerate transplant. They also require a compatible stem cell donor. People who receive allo-BMT 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 per microliter.
Treatment of Relapse after Stem Cell Transplant
For patients who develop relapse after allo-BMT, a second allo-BMT or donor lymphocyte induction can be done. The median survival is 3-4 months if no treatment is given after an initial failed allo-BMT. Worse outcomes are seen if there is a short interval between first SCT and relapse, graft-versus-host disease after first allo-BMT, older age, poor performance status, and lack of complete remission at time of the second allo-BMT. It is best to reduce the graft-versus-host disease prophylaxis in second allo-BMT in order to maximize the graft-versus-leukemia effect. There is equal overall survival at 2 years for either second allo-BMT or donor lymphocyte induction. The choice of how to proceed is physician-dependent.
- Second allo-BMT: If relapse occurred after more than 1 year after the initial allo-BMT, a second allo-BMT can be done. Prior to a second allo-BMT, chemotherapy must be given to achieve a complete remission again (CR2). Reduced-intensity conditioning regimens can be used for the second allo-BMT. The response rate for a second allo-BMT is 50%. Treatment-related mortality is high and relapse rate is high.
- Donor lymphocyte infusion: If relapse occurred within 1 year of the initial allo-BMT, donor lymphocyte infusion is a better option than second allo-BMT. For donor lymphocyte infusion, the complete remission rate is 20-35%. This strategy works best in patients with presence of minimal residual disease (MRD). Active graft-versus-host disease is a contraindication to donor lymphocyte infusion. The 2-year overall survival is 21% after receiving donor lymphocyte infusion (compared to 9% for patients who do not receive donor lymphocyte infusion).
- Cryoprecipitate transfusion: Cryoprecipitate is commonly given to patients with acute promyelocytic leukemia who have disseminated intravascular coagulation. Low fibrinogen levels (less than 100 mg/dl) warrant transfusion of cryoprecipitate. Cryoprecipitate contains factor I, factor VIII, and von Willebrand factor.
- Adverse effects: Risks of cryoprecipitate transfusion include volume overload (low risk) and transfusion reaction. In rare cases, sepsis can occur from contaminated product.
- Packed red blood cell transfusion: Red blood cell transfusion is commonly done in patients with acute promyelocytic leukemia. Transfusion is indicated when the hemoglobin level decreases below 7 g/dl.
- Adverse effects: Risks of red blood cell transfusion include volume overload, allo-immunization, iron overload, and infection (if the product is contaminated). Allo-immunization is usually prevents with clerical checks and proper blood banking techniques. Iron overload occurs after many repeated transfusion and can be prevented via the use of iron chelators such as deferiprone, deferasirox, and deferoxamine.
- Platelet transfusion: Platelet transfusion is indicated when the platelet count decreases to less than 10,000 cells per microliter. This low platelet count occurs especially when a patient received induction chemotherapy, such as cytarabine or anthacycline.
- Granulocyte colony stimulating factor (G-CSF): G-CSF is sometimes uses to help improve the neutrophil count in patients with acute promyelocytic leukemia. It is important to use G-CSF only when there is no active leukemia, as G-CSF can stimulate the proliferation of leukemic blasts. Patients who receive G-CSF are usually those who have had a favorable anti-tumor response to chemotherapy but have not recovered their normal blood counts. G-CSF helps enhance normal blood cell count recovery.
- IV hydration: Patients with leukemia undergoing chemotherapy frequently require significant amounts of hydration with IV normal saline to prevent hypotension and to help excrete cytotoxic medications.
- Antibiotics: Antibiotics with broad spectrum coverage (e.g. third-generation cephalosporins with or without vancomycin) should be given to all patients with neutropenic fever.
- Dietary measures: A neutropenic diet consists of no fresh fruits and no fresh vegetables. All foods should be cooked well including meat.
Follow-up therapy for such patients may involve:
- Supportive care: This is highlighted above and includes intravenous hydration, transfusions, nutrition support, and antibiotics. In some cases, oral antibiotics (e.g., ciprofloxacin) are used as follow-up measures, especially in patients who have prolonged neutropenia.
- Monitoring of labs: In the outpatient setting, patients require routine monitoring of the complete blood count (CBC) with differential. For patients on treatment, monitoring may need to occur twice weekly.
Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. How it is handled depends primarily on the type of leukemia. Patients who are pregnant are also at risk for hemorrhage affecting the fetus, as platelet counts may decrease with chemotherapy.
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