Summary in English

Acute myeloid leukemia (AML) is a disease with diverse genetic features of the leukemic cells and with variable outcome. In Sweden, 350 new adult patients are diagnosed per year – there are slightly more males than females and the ages range from 18 years of age to nonagenarians. The incidence increases with age and the median age at diagnosis is 71 years. Most patients have de novo AML, but one fourth have a previous hematologic disease, with AML evolving from myelodysplastic syndromes (MDS) or myeloproliferative neoplasia (MPN) or AML induced by cytotoxic treatment for other malignant diseases (therapy-related AML; t-AML).

The Swedish AML group (for participants, see www.svenskaamlgruppen.se) has published national care programs since 2005, including basic background and recommendations for diagnosis, treatment and supportive care. The present document is an updated version produced in collaboration with the Swedish Regional Cancer Centres (www.cancercentrum.se). The content of the care program is based on published AML data, on the clinical experience of Swedish hematologists with special interest in AML, and on the Swedish AML registry, which has been collecting data on all Swedish AML-patients since 1997. Evidence is classified according to the GRADE Working Group [1] when appropriate.

Most patients up to the age of approximately 75 years should be considered for intensive combination chemotherapy with the aim to induce complete remission. Elderly patients with secondary AML, high-risk genetics or significant co-morbidites should rather receive treatment with hypomethylating agents such as azacitidine, with or without venetoclax. Those with severe comorbidities may prefer primary palliative treatment, with or without cytoreductive medications. In all patients that might become considered for intensive treatment, the AML diagnosis should be based on morphologic and immunophenotypic features of bone marrow aspirates as well as on genetic characteristics of the leukemic blasts. The latter should be based on chromosome banding analysis as well as on molecular genetic analyses, such as “next-generation sequencing” of relevant genes supplemented with fluorescence in situ hybridization and/or reverse transcription polymerase chain reactions analyses when needed. Storage of bone marrow or blood leukemic cells in biobanks is strongly recommended.

The initial clinical evaluation includes ascertainment/documentation of comorbidity, performance status, organ functions, and heredity. A central venous line should be placed if intensive treatment is scheduled. Most patients will start AML-specific treatment before the genetic risk classification is complete; the median delay from diagnosis to start of intensive treatment in Sweden is 3 days. However, the aim of treatment may be dependent on the genetic risk and comorbidity, and some patients may need supportive care for infection before being eligible for treatment decision.

A clinical trial is always the first choice if feasible and if there is a relevant one open for inclusion. The recommended initial intensive treatment for AML outside a clinical study is DA, i.e., daunorubicin, i.v. infusion 60 mg/m²/8h daily for 3 days in combination with cytarabine, i.v. infusion 1 g/m²/2h b.i.d daily for 5 days. The long infusion of daunorubicin is used to minimize the risk for cardiac toxicity. In patients with FLT3- mutated AML, addition of midostaurin should be considered. Supportive care includes transfusions with erythrocytes and platelets as needed, antiemetics, fluids, and allopurinol. Infection prophylaxis includes fluconazole (or posaconazole if increased risk for aspergillus), acyclovir and ciprofloxacin. Second-line treatment, such as ACE or FA-Ida might be considered if needed.

Patients with acute promyelocytic leukemia (APL) are treated according to a separate protocol (included in the care program) based on all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

Bone marrow aspiration is performed after hematopoietic recovery, or day 28 at the latest. For most patients, a second identical course should be given as consolidation. The protocol recommends a maximum of 4 courses, with the 3rd slightly attenuated, and the 4th optional and with cytarabin only. Elderly patients with intermediate- or high-risk genetics receive a maximum of 2 consolidations.

Allo-hSCT is estimated to reduce the risk of leukemia relapse to half, but with significant risk for treatment-related complications. The decision to attempt allo-hSCT is thus dependent on individual risk for relapse with and without allo-hSCT, and on individual estimates of transplant-related mortality and morbidity. Thus, continuing evaluation of the status of the patient and of the AML disease, as well as donor availability and patient/donor match, is required before final decision. For patients without limiting severe comorbidity (Sorror score <3), including advanced age, a donor search should be initiated early, and preferentially when the tolerance of and outcome after the primary induction can be evaluated, and the genetic risk classification has been determined. Patients with low-risk genetics are usually not eligible for allo-hSCT in first complete remission but may be so if measurable residual disease (MRD) is present, either using flow cytometry or targeted genetic analyses. If there are healthy siblings these should be typed first in order to proceed timely with donor registry search if needed. Haploidentical donors may be utilized in selected cases.

Patients with proper indication and wish for allo-hSCT, and with acceptable donor available, should be planned for allo-hSCT soon after consolidation, although full AML treatment may be given before allo-hSCT is performed due to logistic reasons. Conditioning regimen (standard myeloablative or reduced intensity protocol), stem cell source (blood or bone marrow), and type of immunosuppression are chosen among established protocols according to the individual situation, including EBMT-score.

MRD assessment by 8/10-color flow cytometry of bone marrow aspirates is recommended at remission evaluation following the second cycle of chemotherapy as well as at end of treatment for patients with a possibility to undergo allo-hSCT. Low risk patients with MRD-negativity will usually not undergo allo-hSCT. In addition, MRD assessment prior to allo-hSCT should be used to guide withdrawal of immunosuppression and the use of donor lymphocyte infusions following allo-hSCT. Some genetic abnormalities, mainly core-binding factor (CBF) AML gene fusions and NPM1 mutations, can be assessed with high-sensitivity analyses, which will supplement the basis for decision-making.

Maintenance treatment with histamine and low-dose interleukin 2 for selected patients in first complete remission is referred to in the protocol. Second-line treatments, strategies for intensive relapse treatment, and the use of additional chemotherapeutics are also discussed. Primary and subsequent palliation with or without cytoreduction is summarized.

More focus is now put on newer therapies, including kinase inhibitors, such as midostaurin for FLT3-mutated AML, gemtuzumab ozogamicin in CBF AML and the widening indications for hypomethylating agents.

Many AML-related aspects and problems are addressed, such as fertility preservation, tumor lysis prevention, treatment of CNS leukemia and myelosarcoma, and dosing in patients with renal failure. Psychosocial issues, social security, rehabilitation, and nursing aspects on nutrition and care of central lines are covered.

The requirements for health care providers dealing with intensive AML treatment are listed, such as continuous availability of experienced staff, possibilities for giving chemotherapy and transfusions during weekends, immediate management of complications such as neutropenic fever, established collaboration with other specialist units, e.g., infectious diseases, lung diseases, dentist, intensive care and diagnostic laboratories.

A few quality indicators, with preliminary targets aimed for regular evaluation per hospital and region, have been defined in collaboration with the Swedish Society of Haematology. These include the proportion of patients reported to the AML registry within 3 months and 12 months from diagnosis (targets > 70 % and > 95 %, respectively), the proportion of patients up to 80 years with genetic evaluation (target > 80 %), and thirty-day overall survival (target > 80 %). In addition, time intervals including days from complete remission to allo-hSCT, overall survival at 1 and 3 years, cells sampled in biobanks and patients included in clinical studies will be reported.

All newly diagnosed AML patients, except those opting out (i.e., actively deciding not to be included) are reported in the web-based system INCA (https://cancercentrum.se/samverkan/cancerdiagnoser/blod-lymfom-myelom/akut-myeloisk-leukemi-aml-inklusive-akut-oklassificerad-leukemi-aul/kvalitetsregister/) porting to the compulsory national cancer registry (https://www.socialstyrelsen.se/en/statistics-and-data/registers/national-cancer-register/).

At diagnosis, patient history, comorbidity and performance status, and base line blood and marrow findings including genetics, and treatment intention are reported. For patients eligible for intensive treatment the details and treatment outcome are also registered. Transplantations are reported in a separate form. Follow-up data include remission duration, therapeutic aims, and outcome after relapse. Survival is regularly checked from the national tax registration. Missing reports are actively requested from the clinicians. Several reports of data have been published in Swedish (see www.sfhem.se) and English [2].

1. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.
2. Juliusson G, Hagberg O, Lazarevic VL, Olander E, Antunovic P, Cammenga J, et al. Improved survival of men 50 to 75 years old with acute myeloid leukemia over a 20-year period. Blood. 2019;134(18):1558-61.