The diagnosis of AML is a medical emergency that requires referral of the patient to a tertiary referral center with expertise in the management of this disease and its complications. In British Columbia adult patients with an established or probable diagnosis of AML should be referred to the Leukemia/BMT Program at the Vancouver General Hospital. Children should be referred to the BC Children’s hospital.
CBC and differential
Electrolytes, BUN, creatinine, uric acid, liver function tests
INR, PTT and fibrinogen
Bone marrow aspirate and biopsy with cytogenetic analysis and flow cytometry for blast cell immunophenotyping. Additional molecular testing may be done depending on the results of cytogenetic analysis (see below under Prognosis).
Please note: to ensure that all necessary testing is done for diagnostic and prognostic purposes bone marrow testing is done at Vancouver General Hopsital on all newly diagnosed AML patients regardless of whether or not prior marrow examination has been done. Thus, if the diagnosis of AML is obvious from the peripheral blood (e.g. high peripheral blood blast cell count) the patient should be referred to the Leukemia/BMT Program without performing a bone marrow examination.
The diagnosis of AML requires:
More than 20% blasts in the bone marrow differential
Further refinement of the diagnosis to allow classification of the subtype of AML by WHO criteria requires the results of immunophenotyping and cytogenetics (J Clin Oncol 17:3835-3849, 1999).
At diagnosis, the most important subtype recognition is acute promyelocytic leukemia (APL). Although this is a highly curable AML subtype it carries with it a high risk of hemorrhagic complications and requires specific therapy. See specific Cancer Management Guidelines for APL.
At diagnosis, the average age of patients with AML is 68 years. Survival and likelihood of cure with conventional therapy decreases with age such that although ~40% of adults under 60 years old can be cured that proportion is less than 10% in patients over 60. Those greater than age 70 have a particularly grim prognosis with median survival from diagnosis of less than 6 months. Patients with an antecedent hematologic disease (e.g. myelodysplastic or myeloproliferative disorder) or treatment-related AML also have a less favorable prognosis than patients with de novo AML.
The most powerful disease prognostic indicator is bone marrow cytogenetics. Using the classification developed by the MRC (UK) (1) chromosome abnormalities classify patients as good, intermediate or poor risk. The frequency of adverse cytogenetic abnormalities increases with age. Almost half of AML patients have normal bone marrow cytogenetics at diagnosis. These are classified as intermediate risk. However, there are a growing number of submicroscopic mutations and rearrangements that may also affect prognosis. Currently the Leukemia/BMT Program is using detection of mutations in the FLT3 and NPM1 genes (performed by the BCCA Cancer Genetics Laboratory) to further refine prognosis among patients with intermediate risk cytogenetic changes (2). Patients with good risk cytogenetics are also tested for mutations in C-KIT which has a negative impact on prognosis for these patients. Below are the current risk categories utilized by the Leukemia/BMT group to stratify post induction therapy for AML patients. These are particularly important for patients who are potential stem transplant candidates.
t(8;21) or inv(16) in the absence of C-KIT mutation
Normal karyotype with good risk molecular testing, i.e. FLT3 ITD –ve; NPM1 mutation +ve
One or 2 cycles of 7+3 to enter complete remission (CR)
Cytogenetics (excluding cases with favorable karyotype):
The goals of therapy and the likelihood of success vary greatly in AML according to disease and patient characteristics. Thus, the treatment varies depending on the ‘Risk Categories’ described under Diagnosis as well as patient age and co-morbidities. For the purpose of clinical trials and Consensus Guidelines such as those developed by the National Comprehensive Cancer Network (NCCN) (www.nccn.org) in the USA treatment strategies are usually stratified by age and fitness to undergo allogeneic stem cell transplantation. While there is no absolute age restriction for stem cell transplantation this is a high risk procedure which often cannot be recommended for elderly patients or those with significant co-morbid illness.
The Leukemia/BMT Program participates in a variety of Phase 1 through Phase 3 clinical trials for which AML patients in different categories may be eligible. Below are the current treatment guidelines for patients not treated on such trials.
AML – transplant eligible
A. Induction chemotherapy
The first goal of therapy is achievement of ‘complete remission’ (CR) which is defined as less than 5% blasts in a post treatment marrow with an absolute neutrophil count >1.0X109/L, platelets ≥ 100X109/L and absence of transfusion requirements. Recommended remission induction chemotherapy includes cytarabine and an anthracycline. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy which includes cytarabine 100 mg/m2/d by continuous IV infusion for 7 days and daunorubicin 60 mg/m2/d for 3 days. A repeat bone marrow is done on ~ day 14 after the start of therapy to assess cytoreduction (see Algorithms). If significant residual leukemic blasts are present a second cycle of the same therapy is started immediately. A repeat marrow is done on count recovery or by day 30 if count recovery has not occurred. The probability of achieving CR with 1 or 2 cycles of 7+3 is ~70%. If CR is documented the patient proceeds to consolidation therapy as determined by their prognostic risk assessment. If CR is not obtained the patient receives salvage chemotherapy. There is no standard salvage regimen in this circumstance. For a number of years the Leukemia/BMT Program has used a salvage regimen consisting of etoposide (2.4 g/m2 by CIVI over 34h) and cyclophosphamide (2 g/m2/d on days 3-5). The probability of achieving CR with this therapy is ~50%. However, there are a number of other regimens that can achieve similar results including the well-known MEC (mitoxantrone, etoposide and cytarabine) protocol which has the advantage that it can be given as an outpatient and is generally less toxic (3). The overall probability of achieving CR for AML patients who are fit to receive induction and (if necessary) salvage chemotherapy is ~80%. Patients who fail to achieve CR after salvage chemotherapy may be offered participation in a clinical trial, if available. If a trial is not available or the patient refuses participation they receive palliative/best supportive care.
B. Post remission therapy
The goal of post remission therapy is the prevention of relapse. If such therapy is not given >80% of AML patients will relapse within a few months of achieving CR. There are 2 broad categories of post remission therapy; chemotherapy consolidation or stem cell transplantation, usually using cells from a healthy donor. Chemotherapy consolidation is well-tolerated but has a high risk of relapse particularly in patients with AML with poor risk prognostic features. The relapse risk is lower with donor stem cell transplant but the risk of treatment related death is high, varying between 20 and ~40% depending on the type of donor and the degree of matching between the donor and recipient as well as patient-specific risk factors. Thus, the risk must be weighed against the benefit for post remission strategies.
Patients with good risk prognostic features as defined under Diagnosis receive consolidation chemotherapy with 3 cycles of high-dose cytarabine at a dose of 3 gm/m2/d for 6 days. For patients beyond age 60 the cytarabine dose in reduced to 1.0 gm/m2/d for 5 days (INDAC) to reduce the risk of CNS toxicity. The probability of cure for such patients is ≥ 60%, thus the risk of donor stem cell transplant in CR1 is difficult to justify.
Patients with intermediate risk features receive HLA-matched myeloablative sibling stem cell transplant or volunteer unrelated donor transplant if a matched sibling is not available. In the absence of a matched sibling or unrelated donor 3 cycles of high-dose cytarabine is administered.
Patients with poor risk features receive a myeloablative matched sibling or alternative donor stem cell transplant (volunteer unrelated, haploidentical related donor or umbilical cord blood) if a donor can be identified because the probability of cure with chemotherapy alone is <10%. If no suitably matched donor is available, 3 cycles of high dose cytarabine is administered.
The probability of long-term disease free survival with fully-matched (10/10 antigen) related or unrelated donor stem cell transplant performed in CR1 overall is ~50%. Donor stem cell transplantation appears to overcome some of the negative prognosis associated with poor risk AML. There is a risk of relapse post transplant that varies with the prognostic features of the leukemia. Reduced intensity conditioning regimens are used for elderly AML patients who are considered otherwise fit. However, it is the minority of older patients who are stem cell candidates due to lack of a suitable donor or comorbid issues. In addition, AML in the elderly often has poor risk features that increase the risk of relapse following reduced intensity regimens.
C. Therapy of relapsed disease
AML patients frequently develop relapsed disease after the completion of all planned therapy. There is no standard ‘best’ therapy in this situation and the prognosis is poor. Currently, the Leukemia/BMT program offers clinical trial participation to all such patients if such a trial is available. If the patient refuses participation or a suitable trial is not available the patient may receive re-induction chemotherapy. This may be INDAC or a combination such as the MEC regimen. The probability of achieving a second CR is ~30% overall but varies with the length of CR1 (longer CR1 predicts greater likelihood of CR2). If CR2 is obtained and the patient has not previously received a donor transplant the patient would receive a transplant if a donor can be identified. The risk of treatment-related complications and relapse post transplant are higher when a donor transplant is done beyond CR1. In selected cases (typically where CR1 was long and the leukemia had other good risk features) an autologous stem cell transplant may be performed. If CR2 is not obtained the patient would receive palliative/supportive care.
AML, not transplant eligible (typically elderly and/or unfit)
A. Induction chemotherapy for the ‘fit’ elderly
Outcomes are generally poor for elderly AML patients and have not changed for ~30 years. Thus, it is appropriate to consider entry into clinical trials at diagnosis for such patients. If an appropriate clinical trial is not available or the patient refuses participation conventional therapy can be offered. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy as described above for younger AML patients for the ‘fit’ elderly. A repeat bone marrow is done on ~ day 14 after the start of therapy to assess cytoreduction. If significant residual leukemic blasts are present a second cycle of the same therapy is started immediately if the patient’s general condition allows this to be done safely. The probability of achieving CR with 1 or 2 cycles of 7+3 is ~50% i.e. lower than the remission rate achieved for younger patients. If CR is documented the patient may proceed to consolidation therapy. Patients who fail to achieve CR are offered participation in a clinical trial, if available. If a trial is not available or the patient refuses participation they receive palliative/best supportive care.
B. Post remission therapy
The goal of post remission therapy is the prevention of relapse. Unfortunately, this is an elusive goal in the elderly/unfit. ~90% of elderly AML patients who achieve CR1 will eventually relapse. Thus, the benefit of any post remission therapy must be carefully weighed against the risk of morbidity and occasional mortality associated with the treatment. Chemotherapy consolidation is generally offered to elderly AML patients who achieve CR1 and who tolerate induction therapy well. Outside of a clinical trial protocol this usually consists of 2 additional cycles of 7+3 chemotherapy similar to that used for induction. Rarely fit, elderly patients in CR1 with a fully matched related or unrelated donor may be candidates for consolidation using a reduced intensity conditioning transplant (RICT).
C. Therapy of relapsed disease
The duration of CR1 for most elderly AML patients is less than one year. Since second remissions are typically more difficult to achieve and, when achieved, are much shorter than the first, re-induction therapy is rarely offered to elderly AML patients. Selected patients may be appropriate candidates for clinical trials, if available. Most patients receive palliative/best supportive care.
D. Therapy for the AML in the ‘unfit’ elderly.
Patients ≥70years of age or younger patients with serious co-moribidity should rarely be offered standard induction chemotherapy and often the most appropriate management consists of palliative/best supportive care (transfusions, hydrea) delivered ‘closer to home’ if living outside the lower BC mainland.
Patients wishing more active treatment may be eligible for clinical trials of novel agents.
Occasional patients who wish chemotherapy and for whom no trials are available/appropriate may be offered 5-azacytidine (AZA). There is now data from a randomized trial comparing AZA to intensive induction, supportive care and low dose cytarabine for patients >65 years of age which has demonstrated overall improved outcomes with AZA in patients with >30% bone marrow blasts (4). Similar encouraging data was previously reported for elderly AML patients with 20 – 30% marrow blasts where a median 8 months improvement in overall survival as compared to supportive care or low dose cytarabine was reported (5). AZA is generally well-tolerated but inconvenient to administer (s.c. injections 7 of 28d for as long as response is sustained). The goal of therapy is to reduce transfusion requirements and slow progression of the disease.
Occasional patients may also benefit from low dose cytarabine according to the following criteria:
Newly-diagnosed AML by WHO criteria
Good or intermediate risk cytogenetics by MRC criteria
Able to administer subcutaneous cytarabine at home and pick-up medication from BCCA pharmacy
Patients who have poor risk cytogenetics, a poor performance status (ECOG >2) or who are unable to self-administer s.c. cytarabine are poor candidates for this therapy (6). Patients receive a maximum of 4 cycles of low dose cytarabine (20mg bid s.c. X 10d every 4 – 6 wks). Treatment stops regardless of response after 4 cycles. Treatment stops earlier if CR is achieved after fewer cycles or prohibitive toxicity develops defined as:
↓ ANC with sepsis requiring IV antibiotics and/or hospital admission or
↓ platelet count with platelet refractoriness and/or bleeding
The probability of achieving CR with low dose cytarabine is ~20% in this patient group. These remissions rarely last more than a few months. The rare patient who achieves a CR with duration > 12 mos may be eligible for retreatment on relapse.
Lubieniecka JM, Graham J, Heffner D, Mottus R, Reid R, Hogge D, Grigliatti TA, Riggs WK. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front Genet. 2013 Nov 11;4:231. PMID: 24273552
Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. PMID: 23591789
Rosen DB, Harrington KH, Cordeiro JA, Leung LY, Putta S, Lacayo N, Laszlo GS, Gudgeon CJ, Hogge DE, Hawtin RE, Cesano A, Walter RB. AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin. PLoS One. 2013;8(1):e53518. PMID: 23320091
Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res. 2013 Jun;37(6):697-704. PMID: 23522913
Brandwein JM, Geddes M, Kassis J, Kew AK, Leber B, Nevill T, Sabloff M, Sandhu I, Schuh AC, Storring JM, Ashkenas J. Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus. Am J Blood Res. 2013 May 5;3(2):141-64. Print 2013. PMID: 23675565
Chalandon Y, Barnett MJ, Horsman DE, Conneally E, Nantel SH, Nevill TJ, Nitta J, Shepherd JD, Sutherland HJ, Toze CL, Hogge DE. Influence of Cytogenetic Abnormalities on Outcome after Allogeneic Bone Marrow Transplantation for Acute Myeloid Leukemia in First Complete Remission. Biol Blood Marrow Transplant 8:435-443, 2002.
Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE et al Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 123: 3239-3246, 2014.
Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pineux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs H-G, Heuser M, Damon L, Powell BL, Gaidano G, Carella A-M, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA Acton G, Mehta C, Stuart RK, Kantarjian HM. Voxaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukemia (VALOR): a randomized, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 16:1025-36, 2015.
Cortes JE, Goldgerg SL, Feldman EJ, Rizzeri DA, Hogge DE et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer 121:234-42, 2015.
Minden MD, Hogge DE, Weir SJ, Kasper J et al. Oral diclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol 89:363-368, 2014.
Song S, Christova R, Perusini S, Alizadeh S, Bao R-Y, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M, Joseph B, Subramaniam R, Aman, A, Chau A, Hogge DE, Weir SJ, Kasper J, Schimmer AD, Al-awar R, Wrana JL Attisano L. Wnt Inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Research 71:77628-39, 2011.
Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot J-F. Phasae II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for los O6-methylguanine DNA methyltransferase expression. Brit J Haem 167:664-670, 2014.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ & Burnett AK. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116(3):354-365, 2010.
Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. N Engl J Med 358:1909-18, 2008.
Greenberg PL et al Mitoxantrone, etoposide and cytarabine with or without valspodar in Patients with relapsed or refractory acute myeloid leukemia and high risk myelodysplastic syndrome: A phase III trial (E2995). J Clin Oncol 22:1078-1086, 2004.
Dombret H et al International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291-299, 2015
Fenaux et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562-569, 2010.
Burnett A, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A Comparison of Low-Dose Cytarabine and Hydroxyurea With or Without All-trans Retinoic Acid for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome in Patients Not Considered Fit for Intensive Treatment. Cancer 109:1114-24, 2007.