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Bilaga VIII: Summary in English

1 Summary of the Swedish national AML care program for adult patients.

AML is a disease with diverse genetic features of the leukemic cells and with variable outcome. In Sweden, 350 new patients are diagnosed per year, slightly more males than females, in ages from infants to very old. 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 myelodysplasia or myeloproliferative neoplasia or AML induced by cytotoxic treatment for other malignant diseases (therapy-related AML). 

2 The care program

The Swedish AML group (participants - see www.svenskaamlgruppen.se) has published national care programs since 2005, including basic background and recommendations for diagnosis, treatment and other management. This document is an updated version produced in collaboration with the Swedish Regional Cancer Centres. The content of the care program is based on published AML data and on the clinical experience of Swedish haematologists with special interest in AML, but also on the Swedish AML registry, which has collected data on all Swedish AML-patients diagnosed since 1997. Evidence is classified according to the GRADE Working Group (BMJ 2004; 328:1490) when appropriate.

3 Initial management

Most patients up to the age approximately 80 years should be considered for intensive combination chemotherapy aiming to induce complete remission. Patients with severe comorbidity 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 a bone marrow aspirate as well as genetic characteristics of the leukemic blasts. The latter should be based on chromosome banding analysis as well as next-generation sequencing of relevant genes using panels or whole-exome sequencing, supplemented with fluorescence in situ hybridization when needed. Storage of bone marrow or blood leukemic cells in a biobank is strongly recommended.

The initial clinical evaluation includes 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. 

4 Intensive treatment

A clinical trial is always the first choice if feasible and there is a relevant one open for inclusion. The recommended initial intensive treatment for AML outside a clinical study is DA, i.e., daunorubicin, IV infusion 60 mg/sqm/8h daily for 3 days, in combination with cytarabin, IV infusion 1 g/sqm/2h b.i.d daily for 5 days. The long infusion of daunorubicin is used to minimize the risk for cardiac toxicity. 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, FLAG-Ida or HAM, might be considered if needed.

Patients with APL are treated according to a separate protocol (included in this care program) based on ATRA and arsenic trioxide (ATO).

Bone marrow aspirate 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.

5 Allogeneic stem cell transplantation

Allo-SCT is estimated to reduce risk of leukaemia relapse to half, but with significant risk for treatment-related complications. The decision to attempt allo-SCT is thus dependent on individual risk for relapse with and without allo-SCT, 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 are determined. Patients with low risk genetics are usually not eligible for allo-SCT in first complete remission, but may be so if residual measurable disease is present, either using flow cytometry or specific genetic techniques. If there are healthy siblings they should be typed first, in order to proceed timely with donor registry search if needed. Haploidentical donors may be utilized in selected cases, or as a part of the scheduled Nordic trial comparing the outcome with registry donors vs haploidentical family donors.

Patients with proper indication and wish for allo-SCT, and with acceptable donor available, should be planned for allo-SCT soon after chemo-consolidation, although full AML treatment may be given before SCT 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.

6 Measurable residual disease (MRD) determination

MRD-assessment by 8-color flow cytometry on bone marrow is recommended at remission evaluation following the second cycle of chemotherapy, as well as after end of treatment, for patients with low risk-/intermediate genetics and a possibility to undergo allo-SCT. Thus, low and intermediate risk patients with MRD-negativity could be saved from allo-SCT, and MRD-positive patients encouraged proceeding with allo-SCT. In addition, MRD-assessment prior to SCT should be used to guide withdrawal of immunosuppression and the use of donor lymphocyte infusions following allo-SCT. Some gene mutations, mainly in core-binding factor leukemias and NPM1-mutated AML, can be assessed with high-sensitivity analyses, which will supplement the basis for decision-making.

7 Other treatments

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.

8 Special problems

Many AML-related aspects and problems are addressed, such as fertility preservation, tumour lysis prevention, treatment of CNS leukaemia 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.

9 Health care requirements

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 specialists units, e.g., infectious diseases, lung diseases, dentist, intensive care, diagnostics.

10 Quality indicators

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-SCT, overall survival at 1 and 3 years, cells sampled in biobank and patients included in clinical studies will be reported.

11 AML Registry

All newly diagnosed AML patients, except those opting out (i.e. actively denying,) are reported in the web-based system named INCA, which also handles reporting to the compulsory national cancer registry. At diagnosis, patient history, comorbidity and performance status, and base line blood and marrow findings including genetics, and treatment intention is reported. For patients eligible for intensive treatment the details and treatment outcome are reported. Transplantations have a separate report form. Follow-up includes remission duration and therapeutic aim and outcome at relapse. Survival is regularly checked from the national tax registration. Missing reports are actively requested from the clinician. Several reports of data have been published in Swedish (see www.sfhem.se) and English, see Blood 2012; 119:3890.