Clinical Management Guideline for Adult Acute Lymphoblastic Leukaemia

Transcription

1 Clinical Management Guideline for Adult Acute Lymphoblastic Leukaemia UNCONTROLLED WHEN PRINTED NOSCAN Haematology MCN has agreed the information contained within this document to guide the management of adult patients with a Lymphoid Malignancy only: any patients who have been entered in a clinical trial should be managed according to the appropriate trial protocols. Document control Prepared by NOSCAN Haematology MCN Approved by PRESENTLY UNDER REVIEW Issue date May 2016 Review date September 2016 Version V1.0 [May 2016] V1.0 [May 2016] Page 1 of 16

2 Contents Page Diagnostic Management 3 Clinical 3 Laboratory Tests 3 General 3 Specific 5 Multi-disciplinary team discussion 5 Therapeutic Management 5 General 6 Specific 6 Risk Stratification at (around) diagnosis 6 Induction therapy 6 Risk Stratification during induction therapy 8 Risk Stratification at the end of induction therapy 8 Post-induction therapy 9 Supportive care during therapy 9 Management of Refractory/Relapsed Disease 11 Follow Up 12 References 12 Appendix 13 V1.0 [May 2016] Page 2 of 16

3 Diagnostic Management Clinical 1. Comprehensive history that includes symptoms indicative of infection, hyperleucocytosis, organ (including central nervous system) infiltration, current and previous co-morbidity, siblings/con-sanguinity, occupation, previous/current medication including previous chemotherapy/ radiotherapy exposure, any intrauterine devices in females, religious beliefs (eg Jehovah s Witness). 2. Comprehensive physical examination including fundal examination and testicular exam in males, signs of superior vena cava obstruction 3. Document height, weight and BMI. 4. Performance status 5. If the patient is <25 years old, contact Board appropriate CLIC Sergeant Social Worker, and/or Clinical Nurse Specialist for Teenagers and Young Adults (TYA) with Cancer. Laboratory Tests General 1. Full blood count manual differential & film 2. Coagulation screen, Fibrinogen, D dimers 3. Routine biochemical profile (U+E, LFT, Bone) 4. Urate, glucose, phosphate, lactate dehydrogenase 5. Group and save, requesting Hepatitis E virus negative blood components in transplant eligible patients. 6. CMV serostatus if potential candidate for allogeneic stem cell transplantation (generally <60yrs or >60yrs in clinical trial). 7. Tissue-typing and signed VUD form to Glasgow for all patients under the age of 65 years (as per acute leukaemia quality performance indicators, QPI, /programme_resources/cancer_qpis.aspx ). 8. Check HIV, Hep B, Hep C status. 9. Pregnancy test if sexually active, pre-menopausal female. 10. Infection screen if clinically indicated, including blood, stool and urine cultures, swabs of relevant anatomical sites. V1.0 [May 2016] Page 3 of 16

4 11. Baseline chest x-ray and ECG, echocardiogram/muga scan if suspicion of cardiac disease and patient potentially suitable for curative therapy. 12. CT neck, chest, abdomen, pelvis if clinical evidence of lymphadenopathy or mediastinal widening on chest x-ray. 13. CT/MRI brain if suspicion of CNS disease. 14. Lumbar puncture: if neurological symptoms are present but CT head is normal, an experienced operator should perform a lumbar puncture and send samples for cytospin, flow cytometry, microbiological and biochemical analysis. If infection is considered to be an unlikely cause for the symptoms, consent the patient for administration of intrathecal methotrexate. Specific In patients where the treatment delivered is potentially curative, the complete diagnostic panel recommended by the acute leukaemia QPIs should be performed on a bone marrow aspirate ( t/programme_resources/cancer_qpis.aspx and Appendix 1) The complete diagnostic panel includes the following Morphology Immunophenotyping Cytogenetics Molecular markers Storage of genetic material (DNA and RNA) for routine diagnostic testing The storage of genetic material will enable testing for and enable minimal residual disease (MRD) monitoring in patients under the age of 25 years. Exceptions to performing the acute Leukaemia QPI diagnostic panel on marrow aspirate include patient refusal or when tissue availability precludes certain investigations. In these situations, the diagnostic panel should be performed on peripheral blood. V1.0 [May 2016] Page 4 of 16

5 Bone marrow trephine is not mandatory, but, in patients with a dry-tap, bone marrow trephine will be important for the diagnosis. Perform a trephine roll in this situation. Consider placing a small portion of the tissue into culture (cytogenetics) medium followed by gentle agitation and send for cytogenetic analysis. The remainder of the trephine should be sent in formalin to histopathology. Multi-disciplinary team discussion Patients with ALL should be discussed by a multidisciplinary team (MDT) at diagnosis, with a repeat discussion at approximately 6 weeks once information on the complete diagnostic panel and response to induction therapy is available. Therapeutic Management 1 General Adequately hydrate the patient. Monitor K+ levels, but do not add supplemental intravenous potassium if evidence of tumour-lysis. Correct Hb if clinically indicated. If WCC high eg >100 or signs of leucostasis, transfuse cautiously. CMV negative blood products are not mandatory. If there is evidence of a coagulopathy, maintain fibrinogen >2.0g/dl with cryoprecipitate/ fresh frozen plasma (FFP) and aim to normalise PT & aptt. Maintain a platelet count of > 30 x10 9 /l even if the patient is not clinically haemorrhagic. If haemorrhagic, maintain plts > 50 x10 9 /l. Treat infection according to unit antibiotic policy. Start prophylactic allopurinol, aciclovir 400mg bd, ambisome (1mg/kg Mon/Wed/Fri) and ciprofloxacin 250mg bd. If LDH >2xULN, WCC >50 and Urate >500µmol/L, consider rasburicase depending on risk of tumour lysis and perform twice daily U+E, Ca2+, PO4, urate until WCC <10. If rasburicase commenced, send specimen for urate testing on ice. 2 Prior to the start of definitive treatment Fertility counselling regarding loss of fertility for men and premenopausal women. Offer sperm storage and counselling regarding risk of partner s pregnancy for men whilst on chemotherapy. If previous history of cardiac problems or previous chemotherapy, perform Echo/MUGA scan prior to chemotherapy. V1.0 [May 2016] Page 5 of 16

6 3 Specific All eligible patients with newly diagnosed ALL should be offered participation in a clinical trial (if available) and managed according to trial protocol. The management recommended below is based on best current practice and should be considered only for patients not enrolled in a clinical trial. Informed consent for therapy should be sought from all patients, and a signed copy of the consent form filed in the patient s case notes. Risk Stratification at (around) diagnosis Philadelphia positive ALL is the only sub-type of ALL that requires modified induction therapy with the addition of a tyrosine kinase inhibitor (see below for details) For Philadephia negative patients, Patients aged years (refer to latest ALL 2011 protocol) Patients aged years (refer to latest UK ALL14 protocol) Patients aged >60 years (no additional risk-stratification required) Induction therapy Philadelphia positive ALL (all age groups) Follow a treatment schedule that includes combination chemotherapy with tyrosine kinase inhibition with imatinib (as per latest UK ALL14 or 60+, intensive or nonintensive). Consider omission of Daunarubicin from the schedule to reduce toxicity and if patient is being planned for allogeneic stem cell transplantation. For Philadephia negative patients, Patients aged years: Follow the latest ALL 2011 schedule using standard duration of dexamethasone (6mg/m 2 /day orally for 28 days), with the Asparaginase options being: 1. Pegylated (PEG)-Asparaginase (Oncaspar) which has recently been licenced under additional monitoring in the European Union. V1.0 [May 2016] Page 6 of 16

7 2. Erwinia Asparaginase (Erwinase, licensed, marketed and distributed by OPi pharmaceuticals). Erwinase can be used in place of PEG-Asparaginase if there is a Systemic hypersensitivity reactions to PEG-Asparaginase: this includes patients with generalised rash with or without anaphylactic symptoms, but not those with only local pain or redness at the site of injection. Each dose of PEG-Asparaginase should be replaced with 6 doses of 20,000 Units/m 2 Erwinase given on Mondays, Wednesdays and Fridays. Erwinase should be administered by intra-muscular injection and for older patients requiring large volumes, the individual dose may be split between two injection sites. Patients with CNS disease at diagnosis (>5/mm 3 lymphoblasts in the CSF) should receive weekly intrathecal methotrexate until two consecutive clear CSFs have been obtained. Patients in whom the CSF is clear by day 29 will continue MRD directed therapy. Cranial irradiation should be avoided. Patients aged years: Follow UK ALL14 protocol without using Rituximab or Nelarabine for B-lineage and T-lineage ALL respectively. In the case of traumatic lumbar puncture (> 10 red blood cells per microlitre), patients should be treated as having CNS disease IF they still have blasts within the peripheral blood at the time or have blasts in the CSF. In this case or where there is existing evidence of established CNS disease, intrathecal therapy with methotrexate should be escalated to twice per week and given at this frequency until the cytospin is clear of blasts. Such patients should also receive cranial irradiation, prior to consolidation, if they are not going to receive myeloablative allogeneic transplant. The asparaginase options are as for patients between years. Patients aged >60 years (Follow the Intensive or Non-intensive arms of the 60+ trial as appropriate) Risk Stratification during induction therapy This is applicable only to patients between years, mainly to facilitate the management of patients who may fall into the MRD-No Result category at the end of induction (see below). Assess marrow at day 8 of induction and class as slow early responder (SER) if the blast percentage 25% blasts. If the blast percentage is <25%, the patient can be classed as a rapid early responder (RER). Risk stratification at the end of induction therapy V1.0 [May 2016] Page 7 of 16

8 Stratify all patients as responders/non-responders based on marrow morphological features. In patients aged years only, use minimal residual disease (MRD) levels to stratify patients achieving morphological complete remission into the following categories: MRD Low Risk: these include patients with good-risk cytogenetics [t(12;21) and high hyperdiploidy] who achieve MRD levels of <0.1% and all others to the exclusion of those with high-risk cytogenetics (see below) with MRD levels of <0.005%. No change in Regimen or further MRD measurement is required for these patients. MRD risk: these patients (excluding those with good-risk cytogenetics) have MRD levels 0.005% at day 29. Consider augmented BFM consolidation (Regimen C consolidation) and have further MRD assessment upon count recovery from consolidation at week 14. Based on the week 14 results, the MRD risk status will be re-assigned (see below). MRD No Result: these patients have no MRD result at day 29 due to inadequate samples or no MRD marker. Patients with RER continue Regimen B while dose escalation with Regimen C should be considered in those with a SER. Patients with Philadelphia negative high-risk cytogenetics [MLL rearrangement, near haploidy, low hypodiploidy, iamp21, and t(17;19)] should transfer to Regimen C independent of MRD results with post-consolidation MRD being used to guide further management. If these patients fall into an MRD No Result category, discuss the management at the MDT. The role of MRD analysis in patients >25 years is unclear and additional data are required before recommendations for MRD-directed therapy can be made. Post-induction therapy Philadelphia positive ALL (refer to UK ALL1V or 60+ Intensive or Non-Intensive schedules) and proceed to allogeneic stem cell transplantation where applicable. For Philadephia negative patients, Patients aged years: follow the ALL 2011 protocol and be guided by end-ofinduction MRD analysis. In patients achieving MRD low risk, proceed to consolidation with Regimen B of the protocol. Patients with MRD risk may be switched to Regimen C, which has been shown to be associated with improved event-free survival, if not overall survival at 5 years. V1.0 [May 2016] Page 8 of 16

9 Post consolidation, re-evaluate MRD status, and if <0.5%, continue to follow Regimen C, with all patients receiving Capizzi interim maintenance. Patients with higher levels of MRD should be considered for allogeneic stem cell transplantation with optimal pre-transplant treatment to be guided by the relapse/refractory protocol. All patients continuing to receive Regimen B or C should receive a single schedule of delayed intensification and maintenance therapy with pulsed dexamethasone, vincristine and intrathecal methotrexate (pending results of the ALL 2011 trial). Cycles of maintenance therapy lasting for 12 weeks should be stopped exactly 2 years (for females) or 3 years (for males) from the start of interim maintenance. Patients aged years: follow the UK ALL14 protocol and consider allogeneic stem cell transplantation in appropriate patients using criteria stipulated in the trial. The maintenance cycles of therapy (lasting for 12 weeks each) continues for a total of two years regardless of patient gender. Patients aged >60 years (refer to 60+ Intensive or Non-Intensive schedules as appropriate) Supportive care during therapy As per unit policy for blood product and anti-microbial (including Pneumocystis jiroveci) prophylaxis and support, line and mouth care. Dietician review and nutritional support. Psychological support if required. Management of Refractory/Relapsed Disease The prognosis of relapsed or refractory ALL is poor and there are limited data for specific treatment recommendations. The default position in younger patients (25-60 years) without significant co-morbidity and an allogeneic stem cell donor has been to attempt salvage therapy and proceed to allogeneic transplantation in patients achieving a remission. Despite the poor post-transplant outcomes in these patients, the absence of appropriate alternative treatment options continues to make this an option to discuss with the Transplantation team. Options in patients with relapsed disease (depending on duration of first remission) thus include re-induction with chemotherapy (FLAG-Ida, UKALL14 induction schedule) or consideration of blinatumomab. In patients with relapsed/refractory Philadelphia-positive ALL, therapy with alternative tyrosine kinase inhibitors may be suitable in some patients and should be discussed at the MDT. V1.0 [May 2016] Page 9 of 16

10 Long-term follow up There is recognition of longer-term sequelae of therapy in patients whose treatment has been curative. Age-appropriate information may be provided to patients (eg Aftercure: A guide for teenage & young adult survivors of childhood cancer) and it is intended that a leaflet on survivorship issues relevant to the patient will be sent to the general practitioner once the patient is discharged from hospital-based follow-up. Patients who have received cranial irradiation, stem cell transplantation or have experienced treatment toxicity (avascular necrosis) may benefit from longer-term hospital follow up. References UKALL14 A randomized trial for adults with newly diagnosed acute lymphoblastic leukaemia UKALL 2011 Trial United Kingdom National Randomisation for Children and Young Adults with Lymphoblatic Leukaemia and Lymphoma 2011 UKALL60+ A Phase 2 study for older adults with Acute Lymphoblastic Leukaemia Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C, Moorman AV, Wade R (2014). Augmented post-remission therapy for a minimal residual diseasedefined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 15: Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S (2013). Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 14: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH (2014). UKALLXII/ECOG2993: addition of imatinib to a standard V1.0 [May 2016] Page 10 of 16

11 treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. 123: V1.0 [May 2016] Page 11 of 16

12 Appendix 1 ID Age Curative Yes No Date of diagnosis Date of last dose of chemotherapy Performance Status QPI 1 (curative) Morphology Immunophenotype Cytogenetics Molecular Storage Yes No Not applicable QPI 2 (curative) WHO Diagnosis (ICD code) QPI 3 (all patients) MDT at diagnosis MDT at week 6 QPI 4 (curative, ALyL <25) MRD marker sent QPI 5 (curative) ALyL death within 35 days QPI 7 (curative non-transplant) Death in CR in year 1 QPI 8 (curative, <60y) Clinical trial QPI 9 (curative <65y) Tissue-type sent QPI 10 (curative >60y) Clinical trial QPI 11 (non-curative) Clinical trial V1.0 [May 2016] Page 12 of 16

13 Appendix 2: ECOG Performance Scores ECOG PERFORMANCE STATUS* Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead *Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol Dec;5(6): V1.0 [May 2016] Page 13 of 16

14 1. Bernstein, S.H., et al., Natural history of CNS relapse in patients with aggressive non- Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG the Southwest Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, (1): p Boehme, V., et al., CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood, (17): p McMillan, A., et al., Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology. British journal of haematology, (2): p Hill, Q.A. and R.G. Owen, CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood reviews, (6): p McMillan, A., Central nervous system-directed preventative therapy in adults with lymphoma. British journal of haematology, (1): p Fonseca, R., et al., Testicular lymphoma is associated with a high incidence of extranodal recurrence. Cancer, (1): p Zucca, E., et al., Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, (1): p Gholam, D., et al., Primary breast lymphoma. Leukemia & lymphoma, (7): p Shimada, K., et al., Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients. Cancer science, (6): p MacKintosh, F.R., et al., Central nervous system involvement in non-hodgkin's lymphoma: an analysis of 105 cases. Cancer, (3): p Savage, K.J., et al., MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood, (17): p van Besien, K., et al., Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood, (4): p Haioun, C., et al., Incidence and risk factors of central nervous system relapse in histologically aggressive non-hodgkin's lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d'etudes des Lymphomes de l'adulte. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, (6): p Villa, D., et al., Diffuse large B-cell lymphoma with involvement of the kidney: outcome and risk of central nervous system relapse. Haematologica, (7): p V1.0 [May 2016] Page 14 of 16

15 15. Ghielmini, M. and E. Zucca, How I treat mantle cell lymphoma. Blood, (8): p Pro, B. and G. Perini, Central nervous system prophylaxis in peripheral T-cell lymphoma. Blood, (26): p Dunleavy, K. and W.H. Wilson, How I treat HIV-associated lymphoma. Blood, (14): p Schmitz, N., et al., CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, (5): p Tilly, H., et al., Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-hodgkin lymphoma. Blood, (13): p Abramson, J.S., et al., Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer, (18): p Evans, W.E., et al., Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion. Clinical pharmacology and therapeutics, (3): p Perez-Soler, R., T.L. Smith, and F. Cabanillas, Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Cancer, (5): p V1.0 [May 2016] Page 15 of 16

16 Appendix 3 - Systemic Anti Cancer Therapy (SACT) regimens [The following section details are presently under review] NOSCAN Haematology MCN has agreed the maximum routine starting doses and treatment durations in the management of Adult Acute Lymphoblastic Leukaemia across the North of Scotland as follows: Note: Where available, Clinical Trials should always be considered the preferred option for eligible patients Asparaginase as per detailed on page 6 [ Combination therapy ] still to be detailed Dexamethasone - 6mg/m² administered orally (once daily in morning) Continue for 28 days Imatinib Methotrexate (Intrathecal) Nelarbine Rituximab V1.0 [May 2016] Page 16 of 16