Acute Lymphoblastic Leukaemia Guidelines Approved by Pathway Board for Haematological Malignancies Coordinating author: Adele Fielding, Royal Free London NHS Trust Date of issue: 12.03.2015 Version number: v1.0 These guidelines should be read in conjunction with the latest National Cancer Drug Fund information, and all applicable national /international guidance. The prescribing information in these guidelines is for health professionals only. It is not intended to replace consultation with the Haematology Consultant at the patient s specialist centre. For information on cautions, contra- indications and side effects refer to the up- to- date prescribing information. While great care has been taken to see that the information in this section is accurate, the user is advised to check the doses and regimens carefully and if there is any uncertainty about the guidance provided, you should discuss your queries with a Haematology Consultant or Senior Pharmacist. No set of guidelines can cover all variations required for specific patient circumstances. It is the responsibility of the health care practitioners using them to adapt them for safe use within their institutions and for the individual needs of patients. London Cancer ALL Guidelines 2015-16 v1.0 1
Overview - main points in ALL management 1. ALL is an eminently curable disease in young patients that becomes harder to treat with age - less patients are cured as age advances and therapeutic complications are increasingly common. 2. All patients should be treated with age- appropriate therapy. 3. Since the disease is rare, treatment is complicated and there are many areas of controversywhere best practice is not defined, patients should be treated within a clinical trial wherever possible. 4. Experienced specific and supportive care is required; a European Working Group on Adult ALL recommendation suggests that patients should be treated in centres which see at least five new patients per annum. 5 Adherence to the detail and timing of scheduled schemes of treatment is important. Minimising therapeutic delays positively impacts outcome. Recognising complications of therapy quickly and being aware which complications require treatment cessation and which do not is vital. 6. Allogeneic bone marrow transplant is currently a common element of patient management for patients aged 25 years and over. Hence, all patients and siblings aged 25 and older should be tissue- typed at diagnosis and an unrelated donor search carried out if there are no sibling donors. In practice, this means informing the appropriate Transplant Centre at diagnosis about all age- appropriate new diagnoses of ALL. Currently, those aged between 25 and 65 years old and all patients who are Ph+ should be considered as possible transplant candidates at diagnosis. 7. Appropriate specimens should always be taken before therapy is started. Cytogenetic testing is standard of care, Minimal Residual Disease assessment is also now standard practice. This requires a diagnostic specimen to be sent centrally to the Adult MRD Laboratory at the Royal Free Hospital (for UKALL14, UKALL60+), Molecular Haematology at the Royal London Hospital (for BLT patients not on study) or Paediatric MRD laboratory at GOSH (for UKALL2011), in order to identify patient- specific markers at diagnosis. 8. Clinical trials currently open within the Network are listed in red typeface AGE- SPECIFIC THERAPEUTIC APPROACHES 1. Patients aged 18 25 years. Patients aged 0-18 years should be referred to the joint primary treatment centre (UCLH/GOS) and patients aged 19-25 years should be offered treatment at UCLH or a local TYA designated centre. Patients aged less than 25 years should be offered the opportunity to enter UKALL2011. UKALL2011 does not accommodate patients with Philadelphia positive (Ph+) disease. Hence, if patients of this age group have Ph+ disease they need to receive imatinib as soon as possible and they must be considered for allogeneic transplant. Such patients are eligible for entry UKALL14 in which the lower age limit for patients with Ph+ALL is 18 years. Younger patients should be offered entry into the ESPHALL study. 2. Patients aged 25-65 years. London Cancer ALL Guidelines 2015-16 v1.0 2
Patients with both Ph- and Ph+ disease within this age group should be offered entry to UKALL14. Between the age of 60 and 65, some patients will not be considered suitable for intensive therapy and this should be assessed on a case by case basis. 3. Patients aged 65 and over and those aged 55 and over who are not fit for UKALL14. Patients should be offered the opportunity to enter UKALL60+. If trial entry is not acceptable patients should be treated according to age and clinical status. Ideally, patients should receive induction therapy of sufficient intensity to achieve complete remission. If patients can tolerate repeated cycles of inpatient chemotherapy, a reasonable approach would be to use two cycles of induction chemotherapy followed by one cycle of CNS directed prophylaxis with high dose Methotrexate dose dependent on renal function and patient performance status. If patients are not fit for consolidation therapy they should be placed directly onto maintenance therapy. All patients being treated with curative intent should receive at least six doses of Methotrexate intrathecally, if tolerated. Patients with Philadelphia positive disease should receive Imatinib at a dose of 600 mgs per day orally, wherever tolerated, ideally in combination with steroid. A combination of imatinib with a maintenance schedule might offer benefit, but there are no good data to support this. SPECIFIC THERAPEUTIC PROBLEMS 1. Relapsed ALL Relapsed ALL is a difficult therapeutic situation to manage. The treatment of any patient with relapse should bear in mind what the maximum potential benefit for the patient could be and balance this against the risk of treatment related morbidity and mortality. The only curative approach to the treatment of relapse is allogeneic bone marrow transplant. The achievement of a CR is a prerequisite for this. Patients with relapsed B precursor ALL should be offered the opportunity to enter a clinical trial. Patients less than 18 years of age should be offered the R3 trial. Three studies for older patients with relapsed B- precursor ALL are presently available within the UK. Each trial has different entry criteria and may be valuable for different patient populations. It is possible for patients to cycle through more than one relapse trial, if this is clinically appropriate and desirable to the patient. - TOWER (Royal Free) offers patients with relapsed ALL the opportunity to receive Blinatumomab randomised against standard of care Outside a trial, in some situations it may be appropriate to take a palliative approach. In other situations, aggressive re- induction therapy will be appropriate. It is clear that following relapse, patients who are younger and have had longer durations of first remission are more likely to do well and it is in these patients in whom the most aggressive approaches should be pursued. Allogeneic bone marrow transplantation is the only known curative therapy for relapsed ALL and aggressive approaches should have the overall aim of achieving complete remission so that the patient can receive a bone marrow transplant. If the patient has already received a bone marrow transplant a second transplant will rarely be appropriate and consideration should be given to entering Phase 1 and 2 trials of novel therapy. The rate of second complete remission is approximately 50%. There are no data to indicate the best choice of re- induction regimen. If patients are ineligible for, or do not wish to enter a trial, FLAG- IDA is a commonly used and appropriate choice of re- induction regimen for those who are fit. Nelarabine is licensed for the treatment of relapsed T- ALL. It is used as a single agent and is a reasonable choice for re- induction in these circucmstances. London Cancer ALL Guidelines 2015-16 v1.0 3
2. Relapsed Philadelphia Positive ALL In the case of Ph+ disease, paradoxically, relapse may be easier to treat, at least in the short term. A specimen should be sent to determine whether there are any mutations in the BCR- ABL kinase domain (test can be carried out at Imperial College London or by the Wessex Genetics Service), to guide choice of subsequent TKI. p210 quantification is typically available locally. p190 quantification is available at the Royal London Hospital and in the MRD laboratory at the Royal Free Hospital. Dasatinib should be initially be offered to patients with relapsed Ph+ ALL where there is no contra- indicating mutation in the BCR- ABL KD. 3. Central nervous system relapse or other isolated extramedullary relapse Extramedullary relapse is invariably associated with subsequent bone marrow relapse even if the two are not concomitant. If treatment is with curative intent, systemic therapy needs to be give as well as local therapy. In the case of CNS relapse, intrathecal therapy should be given until blasts are no longer detectable in the CSF. The choice of agent depends upon the clinical situation, CNS irradiation is also an important component of therapy but should not be given in conjunction with MTX. For this reason cytarabine and steroid may be the appropriate choice immediately following CNS relapse. CNS irradiation carries a potential for cognitive impairment and this needs to be discussed with the patient 4. Suspicion of BCR- ABL- like ALL For patients with no poor- risk factors and inexplicably bad response to conventional therapy, it may be apprropriate to consider this entity as a subset of patients may responsd to TKI or JAK inhibitors. However, there is no conventional funding stream to support this so requests would be on a case- by- case basis. An approach to invesgtigation of this entity is given as an appendix. SUPPORTIVE CARE Supportive care is very important for all patients with ALL. There are many aspects to consider and they are carefully documented in UKALL2011 and UKALL14. These protocols are available for download and should be consulted for precise details of appropriate supportive care, even if patients are not entering the clinical trial. PATIENTS NOT WISHING TO ENTER CLINICAL TRIALS All patients should be strongly encouraged to enter a clinical trial wherever possible, because of the rarity of the disease and the importance of gathering appropriate information in areas of controversy. Additionally, patients may benefit directly from entering clinical trials by receiving novel therapies. It is not appropriate that a patient is not offered treatment on a clinical trial simply because the trial is not open at the presenting centre. Patients should always be offered the opportunity to be referred to a centre where the appropriate clinical trial is open. It is strongly discouraged that the protocols described in clinical trials are followed without the patients entering the trial concerned. If patients do not wish to enter the currently available trials, or their physicians think that these are inappropriate, an individual treatment decision will need to be made taking into account the patients age, immunophenotype, cytogenetics and initial treatment response by minimal residual disease. Specific advice on individual patients who do not wish to enter clinical trials having had the opportunity to do so will gladly be provided by Dr Adele Fielding (0207 8302833, a.fielding@ucl.ac.uk at the Royal Free Hospital. If Dr Fielding is unavailable, individual advice may be obtained from other members of the UK NCRI Adult ALL Group. Drs Rachel Hough (UCLH) and Clare Rowntree (Cardiff) can provide expert advice on London Cancer ALL Guidelines 2015-16 v1.0 4
the management of young adults and adolescents. Dr David Marks (Bristol) will provide expert advice on the treatment of adults with ALL and particularly issues relating to bone marrow transplantation. Dr Bella Patel (St Bartholomew s Hospital) can provide expert advice on aspects of minimal residual disease. Dr Matthew Smith (St Bartholomew s Hospital) can provide expert advice on the treatment of relapsed ALL. Appendix: an approach to diagnosis of BCR- ABL- like ALL using conventional cytogenetics London Cancer ALL Guidelines 2015-16 v1.0 5
London Cancer ALL Guidelines 2015-16 v1.0 6