Clinical Management Guideline for Acute Myeloid Leukaemia

Transcription

1 Clinical Management Guideline for Acute Myeloid Leukaemia Document Control Prepared by: Mark Drummond, Anne Parker, John Murphy Approved by: RCAG Prescribing Advisory Subgroup Issue date: December 2009 Review date: December 2011 Version: Version 1.0

2 Contents 1. Initial Presentation Initial Management... 4 If APL suspected... 4 All AML patients Patients < 60yrs (or selected fit pts > 60yrs)... 4 Prognostic Information (<60yrs)... 6 a) Cytogenetically / molecularly determined risk group:...6 b) Conventional MRC approach (from MRC AML 10 & 12 trial data):.. 6 c) AML 17 Risk Score:... 7 Further Management during intensive therapy... 7 Choice of Intensive Therapy... 8 Assessment of Response... 8 Definitions of Response... 8 Indications for Consideration of Allogeneic SCT in 1 st CR:... 9 Management of Refractory / Relapsed Disease Outwith Study... 9 a) Refractory Disease... 9 b) Management of Relapse Patients > 60yrs or Frail a) Intensive Therapy b) Non-Intensive Therapy Follow Up Following Completion of Therapy Supportive Care References & Additional Reading (Hyperlinked) Summary Flow Chart CMG for Acute Myeloid Leukaemia Page 2 of 12

3 1. Initial Presentation 1. History to include symptoms of infection, bleeding +/- bruising, occupation, previous chemotherapy/ radiotherapy exposure, neurological symptoms, comorbidities & siblings. 2. Examination include fundi, skin & gums for infiltration 3. Assess performance status 4. Measure height & weight 5. If patient is aged < 26 years discuss at Regional MDT & consider transfer to Teenage Cancer Unit at BOC and discussion with teenage cancer team including Clic Sergeant SW and Clinical Nurse Specialist (contact via switchboard or direct ). 6. Laboratory Tests a. FBC manual differential & film b. Coagulation screen Fibrinogen, D dimers c. U+E d. LFT e. Urate f. LDH g. G+S h. ECG i. CMV serostatus if potential HSCT allograft candidate (generally <60yrs or >60yrs in AML16 trial Intensive Pathway). j. Tissue typing if potential HSCT allograft candidate. k. Check HIV, Hep B, Hep C status. l. Consent for Research Blood Sample (50mls if peripheral blasts) using Generic Consent form. Tel to inform research team (Paul O Gorman) and keep in 4 0 C overnight if required. m. Infection screen if clinically infected including blood cultures, MSU, stool sample n. Bone marrow aspirate. o. Bone marrow trephine- only if dry tap or no particles in aspirate. Carry out trephine roll in this situation, put part of sample into cytogenetics medium and agitate, plus part of sample into formalin. p. Cytogenetics preferably on bone marrow but PB can be used. If no aspirate available and no/ low circulating blasts send trephine sample in media. q. Immunophenotyping (including sample to GGH for central markers to establish baseline leukaemia-associated phenotype / MRD marker in case of subsequent transplant). r. Molecular biology sample (bone marrow). NB cytogenetics fails to detect 15% of patients who would fall into the good risk group. s. LP if neurological symptoms and imaging normal flow cytometry, cytospin, MC+S, glucose, protein. Needs to get to flow lab within 4 hours. 7. Imaging a. CXR b. CT/ MR scan if neurological symptoms 8. Discuss patient at MDT (Local or Regional) CMG for Acute Myeloid Leukaemia Page 3 of 12

4 2. Initial Management If APL suspected 1. Correct coagulation aggressively maintain fibrinogen >1.0g/dl with cryoprecipitate, and plts > 50 x10 9 /l, normalise PT & PTT with FFP. This should happen even if not clinically haemorrhagic. 2. Start ATRA 45mg/m 2 immediately (including presentations out of hours) if suspicious of diagnosis & monitor for ATRA syndrome. 3. If WCC >10 Idarubicin doses should be brought forward by one day in patients presenting with WBC>10, with first dose given within a few hours of starting ATRA. Consider giving prophylactic dexamethasone 10mg IV 12- hourly, although evidence lacking for this prophylactic approach. 4. If ATRA syndrome suspected clinically (unexplained fever, weight gain, respiratory distress, pulmonary infiltrates, pleural or pericardial effusion) start dexamethasone 10mg i.v. 12 hourly (to continue for a minimum of 3 days and until disappearance of symptoms & signs). ATRA should be temporarily interrupted only in severe cases. 5. Arrange urgent cytogenetics: telephone to alert lab to urgent sample. If sample is received before 12pm FISH can be performed on the same day. All AML patients 1. Treat any infection according to local antibiotic policy for the immunocompromised 2. Start allopurinol, acyclovir 400mg bd, azole prophylaxis (withhold if myelotarg being considered), ciprofloxacin 500mg bd if does not require iv antibiotics 3. Correct coagulation abnormalities MUST be done aggressively if APL suspected (see above) 4. Monitor K+ levels 5. Rehydrate as required, maintain good diuresis with iv fluids if necessary 6. Assess re requirement for leucopheresis confusion, retinal changes, headache. Do NOT leucopherese if APL suspected 7. Correct Hb if clinically indicated UNLESS signs of leucostasis. If WCC high eg >100 do not transfuse unless patient is symptomatic and then only slowly. Use CMV neg products until CMV status known in HSCT potential candidates 8. Discuss any clinical trials available eg AML 17, AML 16 and conventional chemotherapy. Allow patient time to read PIS. 9. Consent for agreed therapy 10. It is important to commence definitive chemotherapy promptly in young patients (<60yrs) as outcomes are better if treatment is started within 5 days of diagnosis Patients < 60yrs (or selected fit pts > 60yrs) 11. Assess re risk of tumour lysis syndrome if LDH >2xULN, WCC >50, Urate >0.5 consider rasburicase (particularly if monoblastic). Daily U+E, Ca 2+, PO 4, urate until WCC <10. NB if already receiving rasburicase urate will be falsely low. 12. Echo if previous history of cardiac problems or previous chemotherapy CMG for Acute Myeloid Leukaemia Page 4 of 12

5 13. Fertility counselling re loss of fertility for premenopausal women and men, counselling re risk of partners pregnancy for men whilst on chemotherapy. Discuss sperm storage if deemed appropriate. 14. Tissue typing sample + VUD form if potential allograft candidate a. This includes patients >60 entering AML16 intensive arm a. Details of siblings to Clinical Apheresis Unit CMG for Acute Myeloid Leukaemia Page 5 of 12

6 Prognostic Information (<60yrs) This can be determined in 3 different ways: a) Cytogenetically / molecularly determined risk group: Risk Group Karyotype marker* Molecular marker Good risk Intermediate risk Poor risk t(15;17) t(8;21) inv(16) t(16;16) Normal cytogenetics Abnormalities NOT included in good or poor risk groups >2 abnormalities t(9;22) q- 7q- 11q23 except for t(9;11) t(6;9) inv(3) PML/RARA AML1/ETO CBFB/MYH11 Normal cytogenetics with NPM1 or CEBPA (& Flt-3 negative). All these patients require molecular analysis (Flt-3, NPM1, CEBPA). Normal cytogenetics with Flt3 ITD *In the event of a failed marrow aspirate it is vital that either a trephine or PB sample (if adequate circulating blasts) is sent to cytogenetics lab. If metaphase preps fail it is necessary to get as full a FISH & molecular profile as possible. Suggest discuss directly with relevant lab in light of morphological / clinical features to guide testing. NB molecular markers for t(8;21) and inv(16) are NOT done as part of AML17 b) Conventional MRC approach (from MRC AML 10 & 12 trial data): Good risk: Any patient with favourable genetic abnormalities t(8;21), inv(16), t(15;17),irrespective of other genetic abnormalities or marrow status after Course 1. Standard: Any patient not in either good or poor risk groups. Poor risk: Any patient with more than 15% blasts* in the bone marrow after Course 1, or with adverse genetic abnormalities: -5, -7, del(5q), abn (3q) or complex (5 or more abnormalities) and without favourable genetic abnormalities. Risk Group 5 Year Survival 5 Year Relapse rate Good 76% 25% Standard 48% 52% Poor 21% 73% CMG for Acute Myeloid Leukaemia Page 6 of 12

7 NB: *In AML12, patients with >15% blasts after cycle 1 have a poor outlook (5 year survival of 26%), while partial remitters (5-15% blasts) do only slightly worse than complete remitters (5 year survivals of 44% and 56% respectively). c) AML 17 Risk Score: See associated Excel file for calculation. Developed from AML12 data, tested prospectively on AML 15 cohort as below: Pending further clarification from trial data it is reasonable to manage patients as per risk group determined by any or all of the above methods. Further Management during intensive therapy 1. In APL or cases with propensity for fibrinolysis / DIC (eg monocytic lineage) twice daily coagulation screen to include fibrinogen and D Dimers until WCC<1.0 or coagulation returned to normal whichever is achieved last. 2. In patients with monocytic lineage leukaemia and high WCC ie. >50 consider giving Dexamethasone 8mg daily to reduce risk of pneumonitis. 3. Regular FBC, U&E, LFT to assess requirement for blood products (see local policies), renal function and drug toxicity 4. If the patient develops a pyrexia >38 0 C they should be treated according to local policies for neutropenic sepsis 5. Irradiated blood products are ONLY required for patients who have been given CLOFARABINE or FLUDARABINE 6. CMV negative blood products are ONLY required if CMV neg AND candidate for HSCT (note that all CMV negative blood products are now irradiated) 7. G-CSF should not be used routinely, but may be commenced in patients who are slow to recover or have significant infections. NB this may make BM interpretation at the time of count recovery more difficult CMG for Acute Myeloid Leukaemia Page 7 of 12

8 Choice of Intensive Therapy See flow chart for treatment summary. Ideally pts suitable for intensive therapy should be entered into the age appropriate clinical trial (for those >60yrs see below). The standard approach outwith study is DA 3+10 followed by DA 3+8 (i.e. 2 induction cycles) followed by two cycles of HD ARA-C (1.5g/m 2 ). The latter appears to be at least as effective as the conventional MACE / MiDAC approach (AML 15 data, unpublished) and is more straightforward (although the latter regimes are an acceptable alternative). Assessment of Response 1. This should be done once the patient has neutrophil count> 0.5 x 10 9 /l 21 days from the end of chemotherapy without count recovery. If a hypoplastic BM this should be repeated every 7-10 days until recovers circulating blasts are identified in the peripheral blood 2. This should be done by Bone marrow aspirate morphology (trephine is NOT required unless dry tap) Cytogenetics ONLY if previously abnormal Molecular studies ONLY if previously abnormal Immunophenotyping (FU sample to GGH if sent at diagnosis) 3. This only requires to be repeated after subsequent courses if they are more than 28 days from the end of chemotherapy without count recovery circulating blasts are identified in the peripheral blood Cytogenetics ONLY if abnormal after previous course Molecular studies have MRD marker Immunophenotyping ONLY if MRD marker 4. After completion of cycle 1 assign risk group as detailed above. Definitions of Response 1. Complete Remission (CR): The bone marrow is regenerating normal haemopoietic cells and contains <5% blast cells by morphology in an aspirate sample with at least 200 nucleated cells. Additionally there is an absolute neutrophil count of more than 1.0 x 10 9 /l and platelet count of at least 100 x 10 9 /l. 2. Complete Remission with incomplete recovery (CRi): Fulfilling all criteria for CR except for residual neutropenia (<1.0 x 10 9 /l) or thrombocytopenia (<100 x 10 9 /l). 3. Partial Remission (PR): The bone marrow is regenerating normal haemopoietic cells and blast count has reduced by at least half, to a value between 5 and 25% leukaemic cells. 4. Resistant Disease (RD): The bone marrow shows persistent AML, and patient survives at least 7 days beyond end of course. CMG for Acute Myeloid Leukaemia Page 8 of 12

9 Indications for Consideration of Allogeneic SCT in 1 st CR outwith trial: Age >35 yrs & preceding MDS or Poor Risk Age < 35 yrs, either Standard or Poor Risk (not good risk patients) who are NPM1 negative. This is an evolving indication: please discuss individual patients with BMTU. Management of Refractory / Relapsed Disease Outwith Study a) Refractory Disease Patients who do not respond to induction therapy i.e. fail to have a blast count <15% should be considered for allosct. Prior remission induction should be attempted with alternative regimen such as FLAG-Ida. b) Management of Relapse Such patients should be discussed at relevant MDT and clinical trial considered if available. It is important to consider relevant prognostic factors before attempting salvage therapy in this setting (see below). Early relapses (< 6 months) do particularly poorly. 3 main factors are relevant: 1. Duration of first remission* 2. Patient age 3. Cytogenetics at the time of original presentation The decision to treat the patient with relapsed disease should take into account prognostic factors. The HOVON prognostic index 2 (see table and subgroups below) can be used to define outcome risk and should be used to aid decision making. Three prognostic sub-groups can be defined. Patients with prognostic scores of may be considered for palliation or experimental therapy. Group A: Overall survival 70% at 1 year and 46% at 5 years Score 1-6 Group B: Overall survival 49% at 1 year and 18% at 5 years Score 7-9 Group C Overall survival of 16% at 1 year and 4% at 5 years Score CMG for Acute Myeloid Leukaemia Page 9 of 12

10 HOVON Prognostic Factor Points Relapse-free interval from first complete remission, months >18 months months 3 6 months 5 Cytogenetics at diagnosis t(16;16) or inv(16)* 0 t(8;21)* 3 Other 5 Age at first relapse 35 years years 1 > 45 years 2 Stem-cell transplantation before first relapse No SCT 0 Previous SCT (allogeneic or autologous) 2 Although the optimal salvage regimen for patients with relapsed disease is unknown, most regimens rely upon high-dose cytarabine in combination with other chemotherapeutic agents e.g. FLAG or FLAG-Ida, or as single agent. Patients deemed suitable for intensive salvage therapy should be discussed with the Transplantation team. * In patients experiencing late relapse (> 2years from 1 st CR) consolidation with an autograft can be considered in place of allogeneic SCT. 4. Patients > 60yrs or Frail a) Intensive Therapy The decision to treat with intensive (curative) therapy or palliate is a key one and is made on an individual basis. In general pts over the age of 60 may be considered for intensive therapy if they have a good PS (ECOG 0-2): if a patient is clearly a candidate for intensive therapy it is reasonable to start induction treatment in the absence of cytogenetic data. Ideally treatment should be on a clinical trial (eg intensive arm of AML 16 or AML17); the optimal induction therapy for these patients remains unknown (DA 3+7 is standard). Local experience is that FLAG is well tolerated in this setting but there is no evidence that it is superior. 2-3 cycles of therapy are likely to be optimum. For poor risk pts consider RIC if remission is achieved. Management of such patients should largely be as described for < 60 yrs above. b) Non-Intensive Therapy This is appropriate for frail (ECOG > 2) or elderly patients. Where possible enter patients into AML 16 non-intensive arm. Standard treatment is LD ARA C, 20mg bd for 10 days. The CR rate is 18% with this therapy, although pts who have poor risk cytogenetics are unlikely to respond and may be considered for supportive care (+/- hydroxycarbamide) only (AML 14 results 3 ). It is therefore appropriate to delay definitive management while cytogenetics are awaited. CMG for Acute Myeloid Leukaemia Page 10 of 12

11 5. Follow Up After Completion of Therapy 1. Stop prophylactic medication unless previous fludarabine/ clofarabine. In this circumstance it seems reasonable to continue PCP prophylaxis for 6 months. 2. Regular FBC 3. Consider venesection programme after 4-6 months if Hb in normal range, and if pt treated with curative intent If ferritin >1000 and &/or Transferrin Saturation > 50%. Ferritin >1000 and deranged LFTs 4. Review 1 monthly for 6 months post therapy 2 monthly until 1 year post therapy 3-4 monthly until 3 years post therapy 6 monthly to 4 years and then consider annually Consider referral to late effects clinic (if available) from 4 years post therapy 6. Supportive Care As a minimum the following policies should be available to the clinical care team Blood product transfusion Antimicrobial prophylaxis and treatment Care of Neutropenic sepsis Tumour lysis Mouth care Long term indwelling catheter care 7. References & Additional Reading (Hyperlinked) Guidelines on management of AML (BCSH) Practical Guidelines for Oncology Acute myeloid leukaemia (NCCN) Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Sanz, M.A. et al (2009) Blood, 113, AML 17 website AML 16 website Guidelines on the management of invasive fungal infection during therapy for haematological malignancy (BCSH) Guidelines On The Insertion And Management Of Central Venous Access Devices In Adults (BCSH) Obtaining Consent for Chemotherapy (BCSH) 1. Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood. 2009;113: CMG for Acute Myeloid Leukaemia Page 11 of 12

12 2. Breems DA, Van Putten WLJ, Huijgens PC, et al. Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse. J Clin Oncol. 2005;23: Alan KB, Donald M, Archie GP, et al. 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. 2007;109: Summary Flow Chart See over: CMG for Acute Myeloid Leukaemia Page 12 of 12

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