HAEMATOLOGY CLINICAL GUIDELINES (LANCASHIRE & SOUTH CUMBRIA) May Review date: March 2016 (or earlier if new guidance published)

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1 HAEMATOLOGY CLINICAL GUIDELINES (LANCASHIRE & SOUTH CUMBRIA) May 2015 Review date: March 2016 (or earlier if new guidance published) 1

2 Index: Page No Chronic Lymphocytic Leukaemia 3 Precursor Acute Lymphoblastic Leukaemia 10 Acute Myeloid Leukaemia (AML) 12 Myelodysplastic Syndrome 16 Chronic Myeloid Leukaemia 18 Chronic Myeloproliferative Disorders Myelofibrosis Polycythaemia Vera Essential Thrombocythaemia Investigation and management of patients with hairy cell leukaemia (HCL) Investigation and management of patients with T-cell Prolymphocytic Leukaemia Investigation and management of patients with large granular lymphocyte leukaemia (LGL) 42 Guidelines on the diagnosis and management of Multiple Myeloma 46 Lymphoma 79 2

3 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF CHRONIC LYMPHOCYTIC LEUKAEMIA These guidelines are to be used in conjunction with the BCSH guidelines (Oscier, et al 2012) Diagnosis: The diagnosis of chronic lymphocytic leukaemia (CLL) is based on lymphocyte morphology, the presence of more than 5 x 10 9 /l circulating clonal B cells for > 3 months and characteristic immunopenotype. CLL is a chronic leukaemia of CD 5+ B-cells. Monoclonal B-lymphocytosis (MBL-CLL) is diagnosed in individuals with less than 5x 10 9 /l monoclonal CD5+ lymphocytes present without other symptoms (lymphadenopathy, organomegaly, cytopenias and general symptoms). A typical case of CLL is characterised by the presence in the blood film of mainly small lymphocytes with clumped heterochromatin but variation in morphology can occur. Smear cells may be present. Lymph node examination reveals a diffuse infiltration with lymphocytes with pseudofollicle formation. For the diagnosis follow HMDS guidelines. Investigations: Essential: Full blood count Immunophenotyping of peripheral blood Direct antiglobulin test (DAT) and reticulocyte count Serum immunoglobulines Renal and liver biochemistry (including urate) 3

4 Calculation of Binet stage (See Tab 1) Viral screen for hepatitis B and C and HIV Other recommended tests: Bone marrow test is not necessary in patient with stage A CLL. CT scans are not recommended at diagnosis TP 53 deletion test is mandatory pre-treatment and before subsequent treatment Bone marrow test should be performed In case of phenotypically atypical CLL For investigation of cytopenia in CLL Before initiating chemotherapy Lymph node biopsy is indicated in cases when diagnosis is no certain and/or the suspicion of transformation CT scan/us are recommended If the presence of splenomegaly is uncertain on physical examination To assess lymphadenopathy before therapy For the disease assessment when bulky lymphadenopathy is present in abdomen to diagnose progression 4

5 Prognosis The number of serum factors is known to have prognostic significance In CLL cases: LDH, beta 2 microglobulin, soluble CD23, thymidine kinase, cytogenetic analysis (FISH 17p and possibly 11q), IgVH mutation, CD38 and ZAP-70. Measurement of biomarkers is not recommended for patient with CLL outside clinical trials The most important in clinical practice is detection of a TP 53 abnormality (deletion or mutation) as this will determine which type of treatment is appropriate see below. The presence of a TP 53 abnormality is not an indication for starting chemotherapy in otherwise asymptomatic patient. Management of CLL MBL-CLL: These patients have a low risk of developing progressive disease. The clinical assessment of CLL symptoms is indicated (B symptoms, lymphadenopathy, splenomegaly). The monitoring of FBC is recommended every 3-6 months in the first year and if stable once a year later (preferably in the local surgery with clinical protocol provided). Early stage (Binet s stage A) Clinical assessment and FBC monitoring preferably in GP surgery with provided clinical protocol containing indication for re referring to haematologist. No treatment indicated regardless of prognostic markers. Indications for treatment: 1. Anaemia (Hb < 10 g/dl) and thrombocytopenia (<100 x 10 9 /l) due to bone marrow infiltration by CLL 2. Progressive splenomegaly (>6 cm below costal margin) 3. Progressive, symptomatic lymphadenopathy (cluster >10cm diameter) 4. Progressive lymphocytosis with the increase of lymphocyte number more than 50% over 2-months or lymphocyte doubling time less than 6 months, 5. Autoimmune anaemia and thrombocytopenia not responsive to steroid therapy 5

6 6. B symptoms: weight loss more than 10% in previous 6 months, extreme fatigue, fever >38 o for more than 2 weeks without evidence of infection Initial therapy for advanced, symptomatic CLL. TP 53 negative The choice of treatment depends on age, performance status and comorbidities of the patient. F-CR regimen is recommended as a front line therapy for fit patients outside clinical trials (recommended by NICE and IWCLL) Patients can be considered for the FLAIR trail open in Blackpool (Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab - A randomised trial of FCR v R + long term ibrutinib in fitter patients with CLL. Unfit patients may be offered chlorambucil or bendamustine chemotherapy but entry of patients into trials of these two agents in combination with anti CD 20 antibodies is strongly recommended. Combination of Chlorambucil and Ofatumumab can be prescribed through The Cancer Drugs Fund. Some patients in the unfit group may tolerate the FCR-lite regimen with reduced dose of fludarabine and cyclophosphamide. Initial therapy for advanced, symptomatic CLL TP 53 positive Approximately 7% of CLL patients will have deletion of chromosome 17p or TP 53 mutation/dysfunction. They do not respond well to fludarabine-based therapy and should be considered for TP 53 independent therapy. The most appropriate for that group of cases would be treatment offered in clinical trials. Outside clinical trials, alemtuzumab as a single agent or in combination with high dose of steroids (when large lymph nodes present) is an option. Subcutaneous alemtuzumab is better tolerated. At present this medication is only available in UK now through a Patient Access Scheme. 6

7 The allotransplant option should be considered in patients aged below 65 with good performance status. Treatment of relapsed CLL. The treatment choice of therapy depends on: -The duration of the first remission, -Age and performance status, -First line treatment regimen and -TP 53 status (the test should be repeated before the subsequent line therapy) 1 Fit patient, relapse < 12 months no TP 53 deletion FCR when not given as first line, when fludarabine resistant consider clinical trials. If they are not available the patient should be offered bendamustine with rituximab treatment and assessed for allotransplant. Other options may be CHOP- R and ofatumumab therapy. Ibrutinib treatment should be considered in patients over 70 without comorbidities and over 60 with comorbidities as available through The Cancer Found. 2, Fit patient relapsed months with no TP53 abnormality should be consider clinical trials. If they are not available Bendamustine with Rituximab or Alemtuzumab may be given. Allotransplant should be considered. Another option is immunotherapy with Ofatumumab in patient resistant to both: Rituximab and Alemtuzumab. 3 Fit patient with relapsed CLL after 24 months since the last treatment should be considered for clinical trials. If not available: Rituximab with Bendamustine may be given or FCR repeated.. 7

8 When TP 53 deletion is present high dose of methylprednisolone with alemtuzumab treatment is indicated, again the trial option should be investigated and allotransplant considered for fit patient. Ibrutinb therapy can be given through The Cancer Drugs Fund. Ofatumumab may be the effective (but response last only for the short time) only treatment option in patients resistant to Alemtuzumab. Less fit patient: In a case of fludarabine resistance and/or TP53 abnormality, the patient should be considered for clinical trials in the first instance. When trials are not available the patient could be offered Bendamustine in combination with rituximab. The combination of Idelalisib with Rituximab is available for prescription through the Cancer Drugs Fund. When a TP 53 abnormality is present, alemtuzumab with high dose methylprednisolone can be considered The other option of treatment in this context is ofatumumab. FCR lite with an attenuated dose of cyclophosphamide and fludrabine may be effective and well tolerated option in selected cases of relapsed CLL. When a patient is sensitive to alkylating agents, chlorambucil (combination with rituximab may be advisable but the fouding is not provided and evidence in literature is scarce) Unfit patient can be offered best supportive car and referred to palliative care. Supportive care: 1. Transfusion of blood products (irradiated lifelong for fludarabine or alemtuzumab treated patients) 2. Infections: All patients should be screened for Hepatitis B, C and HIV prior starting chemotherapy 3. Antimicrobial prophylaxis against Pneumocystis jivoreci and herpes simplex and zoster is advocated for patients receiving immunochemotherapy 4. Patients treated with alemtuzumab should be monitored regarding CMV reactivation and receive antifungal prophylaxis 5. Intravenous immunoglobulin infusion can be indicated in patients with recurrent infections and low IgG level. (antibiotic prophylaxis may be considered when needed as well) 8

9 Treatment of autoimmunity: Autoimmune haemolytic anaemia and/or thrombocytopenia are common in patients with CLL. These can be be treated with Prednisolone 1 mg/kg for 2-4 weeks. The second option could be Rituximab 375 mg/m2 weekly for 4 weeks. Cyclosporin or mycophenolate mofetil can be given as a third line therapy. Failure of treatment for autoimmunity may be an indication to chemotherapy treatment in CLL. Table 1 Binet staging system Binet Stage A B C Features <3 Lymphoid area >3 Lymphoid area Haemoglobin < 100g/l or platelet count<100 x 109/l List of trials for CLL patient available in Network 1. RIAltO: A randomised Investigation of Alternative Ofatumumab-containing regiments in less fit patients with CLL. (opened at RBH) 2. FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab - A randomised trial of FCR v R + long term ibrutinib in fitter patients with CLL. Author Dr M Rockika Ratified by LSCCN Haematology NSSG 15 th March 2015 Review date: March

10 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL) General Points: The comments regarding transfer to Blackpool without performing a bone marrow examination when the diagnosis of acute leukaemia is strongly suspected applies for ALL. Often ALL can only be distinguished from AML by flow cytometry. MRD assessment is a critical part of the management of adult ALL. Bone marrow samples should be sent to Adele Fielding s lab in London at diagnosis and post phase II induction as an absolute minimum. Samples are sent post phase I induction if part of the UKALL14 trial but these results are not disclosed. MRD assessment should occur regardless of whether the patient enters a clinical trial. Tissue typing of all patients <65 years old should be performed at presentation, with samples sent to Sheffield & the HSCT lab in Manchester. All patients with confirmed ALL should be discussed at the network MDT once cytogenetic analysis is available. Patients should have holistic support with clinical nurse specialist input and written information about their disease Patients with white cell counts >50 can deteriorate rapidly. All patients with suspected acute leukaemia with white cell counts >50 and potentially suitable for intensive chemotherapy should be discussed with the attending consultant at Blackpool. This conversation should take place as soon as acute leukaemia is suspected, 24 hours per day. This should not wait until the following day. The advantage of this approach is that early complications can be addressed and early transfer to Blackpool arranged. Note that Blackpool has a ring-fenced bed at all times that can be used to facilitate the urgent transfer of patients from around the Network with suspected acute leukaemia. Management of patients aged 16 end of 18 th year: All patients in this age group should be treated at the Young Oncology & Adolescents Unit (YOU) at the Christie Hospital. Management of patients aged 19 but less than 25: Patients aged up to their 25 th birthday with ALL should essentially be treated on a paediatric protocol. Essentially though from a practical point of view these patients should be referred to Blackpool in the first instance to establish a diagnosis. Philadelphia negative ALL - patients should be referred to the Christie Hospital in Manchester to consider entry into the UKALL 2011 trial. Philadelphia positive ALL these patient are not eligible for the UKALL 2011 trial. Patients aged can enter into the UKALL14 trial. If they decline this trial, then 10

11 they should receive two courses of induction chemotherapy with Imatinib, followed by an allogeneic procedure at the first opportunity. Patients in this age group should be given the choice of having this treatment at the Young Oncology & Adolescents Unit (YOU) at the Christie Hospital, or more locally within Lancashire at Blackpool Victoria. Management of patients aged >25 but less than 60: These patients should be offered entry into UKALL14. If they decline the trial, they should be treated as per protocol but without the addition of the monoclonal antibodies. Patients aged 55 or over can enter the ALL60+ if they are considered unsuitable for the UKALL 14 trial. Management of patients aged >60 but less than 65: These patients are eligible for entry into both UKALL14 and the ALL60+ trials. Management of patients aged greater than 65: These patients should be evaluated in Blackpool & offered entry in the ALL60+ trial. Patients with Philadelphia positive disease can be treated successfully with high dose Imatinib combined with steroids outside a trial. Philadelphia negative disease in elderly patients is a difficult situation. Three agent induction without the use of asparaginase may reduce early mortality. Attenuation of induction chemotherapy e.g. omission of day 29 chemotherapy may be required. Omission of consolidation may also be required, moving directly to standard maintenance. CNS directed therapy should be considered as for patients under the age of 65. Treatment of relapsed ALL: These patients should be discussed once again at the Network MDT. There is no current trial within the network. There may be a role for entry into trials involving monoclonal antibodies, but this would need exploration with other centres around the country. Relapsed ALL has a very poor prognosis. Flag-Ida may have a role in this situation. Allogeneic transplantation should occur in CR2 if this has not already been performed. Author Dr P Cahalin Ratified by LSCCN Haematology NSSG 15 th March 2015 Review date: March

12 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF ACUTE MYELOID LEUKAEMIA (AML) General points: In general, patients up to the age of 70 are usually candidates for intensive chemotherapy. If acute leukaemia is strongly suspected (e.g. pancytopenia with circulating blasts, or large numbers of circulating blasts on the blood film) these patients should be referred directly to Blackpool. They will usually need a bone marrow examination for trial purposes and if the diagnosis is obviously an acute leukaemia, the bone marrow should be left until the patient arrives in Blackpool. It may take up to a week for the cytogenetics to become available & the formal report to come back from HMDS. Once the bone marrow has been done in Blackpool, the patient could return home if not unwell or febrile and have local blood count monitoring until the results become available. Blackpool is happy to see all other patients with acute myeloid leukaemia to discuss treatment options and this can even be done on the telephone. Cases of acute promyelocytic leukaemia are a haematological emergency. They should be referred at the slightest suspicion to Blackpool, 24 hours a day. Notably, these patients usually present with a pancytopenia. Clotting tests including D-Dimers are of crucial importance in raising suspicion of this very treatable condition. Suspected APML patients should be referred at the slightest indication of such via telephone communication to Blackpool to arrange urgent transfer to Blackpool. All patients therefore presenting with a pancytopenia, or those with circulating blasts, should have a full coagulation profile performed as soon as possible, and this must include fibrinogen & D-Dimers. All patients with confirmed AML should be discussed at the network MDT once cytogenetic analysis is available. Patients should have holistic support with clinical nurse specialist input and written information about their disease Patients with white cell counts >50 can deteriorate rapidly. All patients with suspected acute leukaemia with white cell counts >50 and under the age of 75 should be discussed with the attending consultant at Blackpool. This conversation should take place as soon as acute leukaemia is suspected, 24 hours per day. This should not wait until the following day. The advantage of this approach is that early complications can be addressed and early transfer to Blackpool arranged. Note that Blackpool has a ring-fenced bed at all times that can be used to facilitate the urgent transfer of patients from around the Network with suspected acute leukaemia. 12

13 Definitive treatment for non-apml patients: 1. Patients under the age of 60: These patients are usually always eligible for intensive chemotherapy and entry into the AML19 trial, when it opens. If a patient declines entry into the AML19 trial or is not eligible, then standard DA chemotherapy should be given. Risk stratification is critical in AML. All cases of suspected / proven acute myeloid leukaemia should be have samples sent to HMDS. Cytogenetics should be performed on every case. If there is a dry tap, a trephine core should be sent in cytogenetic medium for cytogenetic analysis. If there is a dry tap but circulating blasts, then 20mls of blood should be sent for cytogenetic analysis & HMDS review. Patients in the AML19 trial will have a risk score allocated after their response to induction chemotherapy is known. This will determine whether or not they are poor risk and proceed to a stem cell transplant. The situation for non-trial patients is more complicated. Poor risk patients in terms of cytogenetics should proceed to stem cell transplantation in first remission; equally well good risk patients should not proceed to transplantation in first remission. The situation is more complicated in AML defined as standard risk using cytogenetics. The evaluation of the AML 17 risk score in these nontrial patients may help the decision making process. Evidence from the AML 15 trial showed that standard risk patients with a sibling donor do benefit from a sibling allograft in first remission and therefore these patients should proceed to transplant in 1 st CR. The evaluation of patients for potential allografts should start in all patients under the age of 70 on admission to Blackpool. These patients should have samples sent to Sheffield & the HSCT lab in Manchester for tissue typing at presentation. 2. Patients in the age group years: The majority of these patients again will be candidates for intensive chemotherapy and should be considered for the AML18 trial. Comments for patients under the age of 60 generally apply to this age group i.e. same day referral where the diagnosis is strongly suspected. Non-trial patients who are eligible for intensive chemotherapy should have DA3+10. Patients under the age of 70 should be considered for a reduced intensity allograft in first remission if suitable. The evaluation of patients for potential allografts should start in all patients under the age of 70 on admission to Blackpool. These patients should have samples sent to Sheffield & the HSCT lab in Manchester for tissue typing at presentation. 3. Patients in the age range years: These patients can often be treated with an intensive or non intensive approach. 13

14 The decision to go down either route depends upon their past medical history, other comorbidities and the patient s wishes. It also depends on leukaemia related factors such as cytogenetics and the rate of their disease progression. In general these patients should be seen in Blackpool for assessment. If they are not very proliferative then they can usually be seen as an outpatient; however if they clearly have very proliferative disease with rapidly rising white cell counts, then they should be referred via a telephone call for inpatient assessment, as outlined in General Points It is particularly preferable to wait for cytogenetic results in this age group to risk stratify the patient appropriately, unless the white cell count is >20 at presentation or rising rapidly. 4. Patients in the age range 80+ years: These patients are usually never suitable for intensive chemotherapy, given the very high mortality rate. These patients should either be treated with a palliative approach, low dose Cytarabine off trial or consideration of the LI1 trial. Azacitidine for those patients with 20 30% blasts may also be another option, with the advantage of being able to give this at a local level. The only reason to refer these patients to Blackpool is therefore for consideration of entry of these patients into the LI-1 trial. This should be done as an outpatient referral. Full HMDS review and cytogenetic analysis should usually be made available before referral. If the patient is not fit for outpatient assessment here in Blackpool, then a supportive approach should be adopted in the local hospital until they are able to be discharged. Before referring to Blackpool, it should be made very clear to the patient and their family that the only point of referral to Blackpool is to consider the entry into a national trial. They must be willing to commute backwards and forwards to Blackpool on a 4 6 weekly basis. If the patient is not willing to do this then clearly there is no rationale for referral to Blackpool in the first place. The use of Hydroxycarbamide is permitted to control elevated white cell count at the local hospital before patients go into the LI-1 trial. Responsibilities of Blackpool are:- o To assess the patient for suitability for non-intensive chemotherapy o To offer them the possibility of the LI-1 trial according to organ dysfunction o To enrol them into the LI-1 trial if that is their wish o To arrange low dose cytarabine if randomised to this by the district nurses or the family at a local level, including the return of cytotoxic waste o To arrange an end of treatment assessment to evaluate response Responsibility of the local hospital are:- o All blood count monitoring o All blood product support o All admissions for neutropenic sepsis & other supportive care o Palliative treatment and end of life care, if appropriate 14

15 Clearly the aim of treatment in these very elderly patients with acute leukaemia is maximising quality of life and that local care and support is the best way of providing this. In the AML14 trial, no patients treated with low dose Cytarabine who had complex cytogenetics achieved CR. In the non-intensive part of the AML16 trial thus far, there does appear to be a very small CR rate of approximately 5 10% with low dose cytarabine for such patients. If such a patient does not wish to enter the LI-1 trial, then it may be preferable to offer best supportive care with white cell count control with Hydroxycarbamide. Definitive treatment for APML patients: Please note the comments above regarding prompt assessment of the coagulation & same day referral to Blackpool. Molecular monitoring in APML patients is critical and should start at diagnosis with blood and bone marrow sent to David Grimwade s lab in London. This should occur regardless of whether the patient enters a clinical trial. Patients deemed fit for intensive chemotherapy should be offered AML19, when it opens. If a patient declines entry into the AML19 trial or is not eligible, then standard AIDA chemotherapy should be given. The APL Coagulopathy study should be offered to the patient. Patients with APML over the age of 60 represent a difficult problem. They cannot be entered into the AML18 trial but if fit, could be considered for the AML19 trial. APML patients not entered into this trial can be considered for the ATRA + arsenic combination or a modified AIDA approach. Relapsed or refractory patients: These patients should be discussed once again at the Network MDT. Refractory patients in the AML 19 trial will usually be deemed to be high risk and should be offered the high risk randomisation. Relapsed patients who were in AML17 can be offered the high risk arm of AML 19 and enter the trial at this point. FLAG-Ida chemotherapy remains the preferred option for treating relapsed or refractory AML outside a clinical trial. All patients should be discussed with the transplant centre to consider stem cell transplantation in CR2. Relapsed APML or molecular positivity following end of consolidation chemotherapy arsenic trioxide followed by stem cell transplantation. Author Dr P Cahalin Ratified by LSCCN Haematology NSSG 15 th March 2015 Review date: March

16 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF MYELODYSPLASTIC SYNDROME These guidelines are a summary of the 2013 BCSH Guidelines on Myelodysplastic syndrome. Diagnosis: The diagnosis of MDS should be considered in all unexplained cytopenia(s) Cytogenetics should be performed in all such cases Management recommendations for myelodysplasia have largely evolved through the IPSS and, as such, are driven by the IPSS system. Low risk MDS are those patients with IPSS low/intermediate I disease; high risk MDS includes those patients with IPSS intermediate II/high risk disease No recommendations can be made to predict response to recommended therapy in relation to the revised IPSS scoring system, which should be used to evaluate prognosis in all patients, but not yet to guide therapy. All patients with confirmed myelodysplasia should be discussed at the network MDT once cytogenetic analysis is available. Patients should have holistic support with clinical nurse specialist input and written information about their disease The IPSS score should be calculated for all patients before the MDT discussion Management of low risk disease: As above, all such patients should be discussed at the network MDT One can consider a trial of erythropoietin if required Consider horse ATG if age less than 60 years with either normal cytogenetics or trisomy 8 Deletion 5q disease consider trial of erythropoietin as first line therapy. If this fails, or the patient is not deemed suitable for this trial, consider lenalidomide if there is an isolated deletion 5q with transfusion dependence. This is NICE approved. Deletion 5q disease with transfusion dependence & one additional cytogenetic abnormality can be treated with lenalidomide through the Cancer Drugs Fund. Consider all low risk patients who might be a potential allograft candidate for this potentially curative therapy early. In particular, low risk patients but with life-threatening cytopenias such as significant neutropenia, should have be offered a transplant consultation. Low risk patients may progress, with changes in their blood counts, such falling haemoglobin, transfusion dependence, worsening neutropenia or thrombocytopenia. If this occurs, patients should have a re-assessment marrow examination to decide further treatment options, as well as having further MDT review. Elderly low risk patients who have deteriorating counts should not therefore be simply placed on azacitidine without a repeat marrow assessment. 16

17 Management of high risk disease: This is essentially decided according to whether or not a patient will be eligible for allogeneic stem cell transplant. As always, these patients must be discussed at the network MDT, when the cytogenetic analysis is known and the IPSS score has been calculated. If patients are deemed to be transplant eligible, the next decision is based around the blast percentage. If blasts are less than 10%, one could consider an up-front allogeneic transplant without preceding chemotherapy. This may necessitate a direct referral to Manchester Royal Infirmary for this purpose. In this situation, consideration should be given to entry into the FIGARO trial at Manchester Royal, which compares the novel conditioning regimen FLAMSA-BU with standard conditioning regimens. However if blasts are greater than 10%, these patients will need induction chemotherapy before stem cell transplantation, and as such they should be referred to Blackpool to be seen in the outpatient clinic for such a discussion. If a patient is deemed not eligible for allogeneic stem cell transplantation, the options are as follows: 1. Supportive care alone with blood product support and treatment of infection with antibiotics. 2. Azacitidine 3. One could consider intensive chemotherapy without stem cell transplantation if (a) no significant co-morbidities, (b) there is a good performance status and (c) the karyotype is not high risk. Author Ratified by LSCCN Haematology NSSG Dr P Cahalin 15 th March 2015 Review date: March

18 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF CHRONIC MYELOID LEUKAEMIA Diagnosis: The question of whether or not initial assessment on the peripheral blood is acceptable is controversial. There are those that argue that the management of CML is now driven by response assessments and that therefore previously identified prognostic factors are now less important. This is the view that has been taken for the current national CML trial, SPIRIT 3. However, others argue that an initial bone marrow examination should be performed at diagnosis. This is to completely exclude the possibility of blast phase (although rare at diagnosis and usually obvious from the peripheral blood findings). Advocates of bone marrow examination at diagnosis argue that it is useful to identify additional chromosomal abnormalities (ACA) at diagnosis, so that a comparison can be made to the diagnostic sample if they are identified at a later date. Therefore, blood or marrow should be sent to HMDS Leeds Consideration could be given to sending blood or marrow for cytogenetics to the Christie Hospital, especially if a rapid confirmation is required, as usually FISH results can be obtained within 48 hours. No samples should now be sent to Manchester Royal Infirmary for the exclusion or confirmation of CML. There is no need to perform a bone marrow trephine at diagnosis. To have confirmed chronic phase disease, all of the following criteria should be met: o less than 15% blasts in the blood, o less than 30% blasts plus promyelocytes in the blood, o less than 20% basophils in blood, o greater than 100 x 10 9 /L platelets o no evidence of an extramedullary leukaemic involvement, with the exception of hepatosplenomegaly. Once the diagnosis has been confirmed, there should be discussion at the network MDT. Patients should have holistic support with clinical nurse specialist input and written information about their disease Treatment: Hydroxycarbamide can be used for a short time before initiating a tyrosine kinase inhibitor. Clinical trial participation should be offered to all newly diagnosed patients with CML. The current trial for this is SPIRIT 3, and Dr Cahalin would be pleased to accept referrals to discuss this trial with newly diagnosed CML patients. At present, there is no evidence to state that imatinib should be superseded by other tyrosine kinase inhibitors as first line treatment for chronic myeloid leukaemia. The initial starting dose should be 400 mg daily. 18

19 However, NICE have permitted the use of nilotinib as 1 st line use in CML. Whether this upfront use is better than initial treatment with imatinib and then swapping to nilotinib if imatinib fails remains to be seen. The crucial importance of compliance should be emphasised right from the initial diagnosis. Patients should have access to clinical nurse specialist support, as well as receiving written and verbal information on the disease & imatinib / nilotinib. Monitoring: These are based on the European LeukaemiaNet recommendations for the management of chronic myeloid leukaemia 2013, published in Blood (volume 122: ). Blood should be taken at 3, 6 and 12 months following the initiation of imatinib and sent to HMDS Leeds for molecular monitoring. There is no indication to perform ongoing bone marrow examination for monitoring purposes, as peripheral blood BCR ABL monitoring is sufficient. All patients in the Network should have on-going monitoring samples sent to HMDS, regardless of when they were diagnosed. This means that no samples should now be sent for molecular monitoring at Manchester Royal Infirmary. All on-going monitoring for these patients historically monitored in Manchester Royal should now occur in Leeds. Information about the original breakpoint should be provided with the first sample being sent to Leeds, or even just stating on the first request form Previously monitored in Manchester please discuss with Manchester lab to get breakpoint information. At 3 months, failure of imatinib is defined by the non-achievement of a complete haematological response. An optimal level would be having a BCR ABL level less than 10%. A warning that a patient may not be progressing as desired would be complete haematological response with a BCR ABL level greater than 10%. At 6 months, an ideal BCR ABL level would be less than 1%. Failure would be defined as having a BCR ABL level of great than 10% at this time point. A warning would be having a BCR ABL level between 1 and 10% at this time point. After 12 months on imatinib, the optimal achievement would be that of a major molecular response, i.e. a BCR ABL level less than 0.1%. Failure would be defined as having a BCR ABL level greater than 1%, equivalent to not having achieved a complete cytogenetic response. BCR ABL level between 0.1 to 1% would be a warning that the patient would not be progressing as optimally desired. Many patients however remain entirely stable in the long-term with levels between 0.1 and 1%. At subsequent time points, confirmed loss of a major molecular response in two consecutive tests, one of which will have a BCR ABL level greater than 1%, would confirm failure. Throughout the treatment, again compliance to imatinib or nilotinib therapy should always be emphasised. 19

20 Failure of imatinib requiring a second generation tyrosine kinase inhibitor: The patient s case should be re-discussed at the Network MDT Firstly, compliance to imatinib should be explored in detail. Blood should be sent for BCR ABL1 kinase domain mutation testing at HMDS Leeds. The patient and any siblings should have tissue typing performed. The second generation tyrosine kinase inhibitor to be used will usually be nilotinib, as this has NICE approval for this indication. As per monitoring on imatinib, there are ELN defined time points with regard to optimal response, a warning response or failure of a response to a second generation tyrosine kinase inhibitor. At three months, no complete haematological response is a failure of a second line TKI. An optimal response would be an achievement of a BCR ABL level less than 10%, with a warning response corresponding to a BCR ABL level of 1 10%. At six months on a second generation TKI, an optimal response would be a BCR ABL level less than 10%. Failure would be an inability to achieve a BCR ABL level greater than 10% at this time point. At 12 months on a second generation TKI, the optimal response would be a BCR ABL less than 1%. Failure at this time point would correspond to a BCR ABL of greater than 10%. Note that the current ELN guidelines state that allogeneic stem cell transplantation remains the recommendation of all eligible patients that require a third line tyrosine kinase inhibitor. This may be because of failure of and/or intolerance to two previous tyrosine kinase inhibitors. Author Ratified by LSCCN Haematology NSSG Dr P Cahalin 15 th March 2015 Review date: March

21 GUIDELINES FOR INVESTIGATION AND MANAGEMENT OF PRIMARY MYELOFIBROSIS (PMF) Diagnostic criteria for primary myelofibrosis (PMF) - BCSH 2012 Diagnosis requires A1+A2 and any two B criteria A1 A2 B1 B2 B3 B4 B5 B6 Bone marrow fibrosis 3 (on 0-4 scale) Pathogenetic mutation (eg Jak2, CALR or MPL), or absence of both BCR-abl and reactive causes of bone marrow fibrosis Palpable splenomegaly Unexplained Anaemia Leuco -erythroblastosis Tear drop poikilocytes Constitutional symptoms* Extramedullary haematopoiesis (histology) *Drenching night sweats, weight loss >10% over 6 months, unexplained fever > 37.5C or diifuse bone pain. Diagnostic criteria for post PV and post ET myelofibrosis - BCSH 2012 Diagnosis requires A1+A2 and any two B criteria A1 A2 B1 B2 B3 B4 B5 B6 Bone marrow fibrosis 3 (on 0-4 scale) Previous diagnosis of PV or ET New palpable splenomegaly or increase of spleen size 5cm Unexplained Anaemia with 20g/l drop from baseline Leuco erythroblastic blood film Tear drop poikilocytes Constitutional symptoms* Extramedullary haematopoiesis (histology) *Drenching night sweats, weight loss >10% over 6 months, unexplained fever > 37.5C or diifuse bone pain. 21

22 Prognostic Criteria* Variable IPSS DIPSS DIPSS+ Age >65 Constitutional Sy HB < 100 g/l WCC >25 X 10 9 /l Circulating blasts 1% Transfusion Dep Plts < 100 X 10 9 /l Karyotype (unfavourable) Unfavourable Karyotype: +8; -7/7q-; i(17q);inv (3);-5/5g-; 12p-;11q23 rearrangement IPSS: low risk, 0 points; intermediate-1 risk, 1 point; intermediate-2 risk, 2 points; high risk, 3 to 5 points; DIPPS: low risk, 0 points; intermediate-1 risk, 1 to 2 points; intermediate-2 risk, 3 to 4 points; high risk, 5 to 6 points; DIPPS-plus: low risk, 0 points; intermediate-1 risk, 1 point; intermediate-2 risk, 2 to 3 points; high risk, 4 to 6 points. IPSS is only validated at diagnosis, whilst the DIPSS/DIPSS+ is dynamic Risk Group IPSS MS(years) DIPSS MS(years) DIPPS+ MS(years) Low 11.3 NR 15.7 INT INT HIGH MS Median Survival, NR Not reached 22

23 Management of myelofibrosis: General points 1. All patients should be risk stratified using the IPSS at diagnosis or DIPSS+ at any other time to assess prognosis and guide treatment strategies. 2. Patients with an IPSS risk of intermediate 2 or high should be assessed for their suitability to undergo an allogeneic stem cell transplant. If deemed unsuitable for a transplant option then they should be considered for a trial or treatment targeted to their symptoms. 3. Patients with IPSS low risk/intermediate 1 without symptoms can be observed. 4. Patients with IPSS low risk/intermediate 1 with symptoms should be considered for a trial or treatment targeted to their symptoms. 5. All patients should be discussed at MDT with appropriate histology/molecular studies reviewed at HMDS Leeds. 6. All patients should have holistic support with clinical nurse specialist input and written information about their disease. Treatment: Symptomatic splenomegaly Medical Management: 1 st line Hydroxycarbamide, Ruxolitinib (available via the Cancer Drug Fund for intermediate /high risk Primary myelofibrosis, Post ET/PV Myelofibrosis who are deemed unsuitable for a stem cell transplant) 2 nd line Immunomodulatory agents Thalidomide and prednisolone. (consider lenalidomide if anaemia and platelets > 100) Surgical management: Routine splenectomy is inappropriate due to its high risk of morbidity and mortality. It should be restricted to carefully selected patients with extensive pre-operative assessment. The laparascopic route is not suitable due to high risk of bleeding. Typical indications would include: Drug refractory symptomatic splenomegaly Drug-refractory anaemia Symptomatic portal hypertension Severe catabolic symptoms. 23

24 Radiotherapy: Radiotherapy can be considered for patients who are deemed unsuitable for surgery and have an adequate platelet count (>50 X 10 9 /l) Anaemia Options include: Red cell transfusion programme (iron chelation not routinely recommended). Erythropoietin trial in patients with inappropriately low erythropoietin levels (< 125 u/l) Androgens Danazol first line for a minimum of 6 months before assessing response Immunomodulators Thalidomide and prednisolone, Lenalidomide Constitutional Symptoms Consider Myelosuppression or Ruxolitinib for symptoms that are impinging on quality of life. (available via the Cancer Drug Fund for intermediate /high risk Primary myelofibrosis, Post ET/PV Myelofibrosis who are deemed unsuitable for a stem cell transplant) Myelosuppression Indications for myelosuppressive treatment include : 1. Control of hyperproliferative symptoms 2. Splenomegaly and hepatomegaly 3. Leucocytosis and or thrombocytosis Hydoxycarbamide is the first line choice. Inteferon alfa and anagrelide are alternative options in selected cases. Author Ratified by LSCCN Haematology NSSG Dr S Kolade 15 th March 2015 Review date: March

25 Investigation algorithm for myelofibrosis: Suspected myelofibrosis Clinical features: Splenomegaly; anaemia;leucoerythroblastic blood film; constitutional symptoms; ^LDH; TDP s ; extramedullary haematopoeiss If not progression of known ET/PV then molecular studies required Jak 2, CALR, MPL, (BCR-abl if negative) Note: MPL not routinely done at HMDS needs to be specifically requested if Jak2 and CALR negative Bone marrow biopsy with trephine for assessment of reticulin. Cytogenetic assessment Diagnosis confirmed ( see text) Prognosis - History of constitutional symptoms/transfusion FBC/Blood film/peripheral blood CD34 count Karotype 25

26 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF POLYCYTHAEMIA VERA Investigation algorithm: Hct > 0.52 in men Hct > 0.48 in women 1. History and Examination 2. FBC/Film 3. Renal and liver function 4. Ferritin/iron profile 5.JAK 2 V617F assay Jak2 V617 +ve Jak2 V617 -ve Serum EPO EPO - Low EPO - Normal or Raised Polycythaemia Vera 1. Jak2 exon 12 assay 2.Additional investigations (see appendix )* Consider other causes of erythrocytosis. Including apparent and investigate as appropriate (see appendix)** JAK 2 mutational assay should only be undertaken at HMDS LEEDS Note: A Hct > 0.56 in women and > 0.60 in men is evidence of true erythrocytosis 26

27 Diagnosis (Modified BCSH diagnostic criteria for polycythaemia vera ) JAK2-positive polycythaemia vera A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted) A2 Mutation in JAK2 Diagnosis requires both criteria to be present JAK2-negative polycythaemia vera A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women. A2 Absence of mutation in JAK2 A3 No cause of secondary erythrocytosis A4 Palpable splenomegaly A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells B1 Thrombocytosis (platelet count >450 X 10 9 /l) B2 Neutrophil leucocytosis (neutrophil count > 10 X 10 9 /l in non-smokers; >12.5 X 10 9 /l in smokers) B3 Radiological evidence of splenomegaly B4 Endogenous erythroid colonies or low serum erythropoietin Diagnosis requires A1 + A2 + A3 + either another A or two B criteria Treatment of Polycythaemia Vera 1. Risk Stratification : High risk A.Age > 60 B.Previous Thrombosis Low risk None of the above risk factors 27

28 2. Management: All patients should have cardiovascular risk factors reviewed and managed appropriately All patients should start on low dose Aspirin (75mg daily) unless contraindication (caution with platelet count above 1000 X 10 9 /l due to the risk of bleeding) Low risk patients Venesect to a target HCT < 0.45 (consider cytoreductive treatment if poor tolerance of venesection, symptomatic or progressive splenomegaly, significant thrombocytosis, progressive leucocytosis) High risk patients Cytoreductive treatment, +/- Venesection Cytoreductive treatment Age < 40-1 st line : Inteferon alpha ; 2 nd line Hydroxycarbamide Age > 40 1 st line : Hydroxycarbamide; 2 nd line Inteferon alfa, anagralide Consider radioactive phosphorus or Busulfan as second line treatment in those over 75 (increased risk of transformation to acute leukaemia) All patients starting on cytoreductive treatment or changing treatment must be discussed at an appropriate MDT. All molecular studies/ histology should be sent to HMDS Leeds for review. Previously diagnosed patients being represented to the MDT for change of treatment without results at HMDS Leeds, requires formal presentation of molecular studies for oversight by the MDT. Patients should have holistic support with clinical nurse specialist input and written information about their disease. Appendix 1 Secondary investigations of erythrocytosis: Red cell mass studies * Abdominal ultrasound* Bone marrow aspirate and trephine with cytogenetic analysis* Erythroid burst forming unit cultures* Arterial oxygen dissociation studies ** High affinity Hb variant studies** Sleep studies** Lung function tests** EPOR, VHL, PHD2 mutational analysis** Author Dr S Kolade Ratified by LSCCN Haematology NSSG 15 th March 2015 Review date: March

29 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF ESSENTIAL THROMBOCYTHAEMIA Proposed diagnostic criteria for essential thrombocythaemia. (BCSH) Diagnosis requires A1 A3 or A1 + A3 A5 A1 Sustained platelet count > /l A2 A3 A4 A5 Presence of an acquired pathogenetic mutation (e.g. in the JAK2, CALR or MPL genes) No other myeloid malignancy, especially PV*, PMF, CML or MDS No reactive cause for thrombocytosis and normal iron stores Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0 2/4 or grade 0/3) 1. * PV,polycythaemia vera ;excluded by a normal haematocrit in an iron-replete patient. 2. PMF, primary myelofibrosis ; indicated by presence of significant marrow bone marrow fibrosis (greater or equal to 2/3 or 3/4 reticulin) AND palpable splenomegaly, blood film abnormalities (circulating progenitors and tear-drop cells) or unexplained anaemia. 3. CML, chronic myeloid leukaemia; excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood. 4. MDS, myelodysplastic syndrome ; excluded by absence of dysplasia on examination of blood film and bone marrow aspirate. 29

30 * BCR-abl testing recommended if other molecular tests are negative and/or if positive and there are atypical features eg. basophilia **Bone marrow examination is recommended by the World Health organisation classification to confirm the diagnosis but may always be clinically indicated *** The requirement for cytogenetic analysis on the bone marrow be guided by blood and bone marrow morphology. Molecular testing should only be undertaken at HMDS Leeds Treatment of Essential Thrombocythaemia (ET) 1. Risk Stratification : High risk A.Age > 60 B.Previous ET related haemorrhagic or thrombotic event C. Platelet count > 1500 X 10 9 /l Intermediate risk A. Age with no high risk features Low risk A. Ag e<40 with no high risk features Microvascular complications not responding to aspirin should be stratified as high risk. 2. Management: All patients should have cardiovascular risk factors reviewed and managed appropriately All patients should start on low dose Aspirin (75mg daily) unless contraindication (caution with platelet count above 1000 X 10 9 /l due to the risk of bleeding) High risk patients should be started on cytoreductive treatment with a platelet target <400 X 10 9 /L Low and intermediate risk patients should generally not be started on cytoreductive treatment outside the context of a clinical trial or if they are symptomatic : progressive splenomegaly; erythromelalgia not responsive to aspirin; uncontrolled bleeding with high platelet counts. 30

31 Cytoreductive treatment 1 st line Hydroxycarbamide 2 nd line Anagrelide Consider interferon alfa in young patients and in high risk pregnancy Consider radioactive phosphorus or busulfan in those with short life expectancies (risk of leukaemic transformation) All patients starting on cytoreductive treatment or changing treatment must be discussed at an appropriate MDT. All molecular studies/ histology should be sent to HMDS Leeds for review. Previously diagnosed patients being represented to the MDT for change of treatment without results at HMDS Leeds, requires formal presentation of molecular studies for oversight by the MDT. Patients should have holistic support with clinical nurse specialist input and written information about their disease. Author Ratified by LSCCN Haematology NSSG Dr S Kolade 15 th March 2015 Review date: March

32 Diagnostic pathway for investigation of thrombocytosis Platelet count > 450 X10 9 /l Blood Film CRP/ESR Ferritin/iron profile Acute phase response Iron Deficiency Reactive Repeat FBC Repeat FBC Persistent unexplained thrombocytosis Molecular genetics: JAK2 V167F, MPL exon 10, CALR, BCR ABL* Bone Marrow ** Cytogenetic analysis *** Note:MPL needs to be specifically requested from HMDS Diagnosis 32

33 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF HAIRY CELL LEUKAEMIA (HCL) Introduction: Hairy cell leukemia (HCL) is an uncommon chronic B cell lymphoproliferative disorder characterized by the accumulation of small mature B cell lymphoid cells with abundant cytoplasm and hairy projections within the peripheral blood, bone marrow and splenic red pulp. Presents with splenomegaly and variable pancytopenia. Presentation: Presents with symptoms relating to splenomegaly or cytopenias (example; anaemia, thrombocytopenia, neutropenia, monocytopenia). Physical examination reveals palpable splenomegaly in 80 90% of cases. Hepatomegaly and lymphadenopathy are only present in 20 and 10% of patients respectively. Laboratory Findings: 60 80% of patients present with pancytopenia, approximate frequency as follows: Anemia 85% Thrombocytopenia 80% Neutropenia 80% Monocytopenia 80% Abnormal liver function tests 20% Hypergammaglobulinemia 20% Leukocytosis (total white cell count >10,000/microL) 10 20% Characteristic hairy cells in blood identified in 90% of patients. Bone marrow often dry tap due to fibrosis. Diagnosis usually from trephine with diffuse or interstitial infiltrate. Mast cells may be numerous. Extravasated red cells are frequently seen. Immunophenotype CD19, CD20, CD22 and CD25. Usually lack CD5, CD10, CD21 and CD23. Hairy cells characteristically express CD11c, CD103, CD123 (bright) and cyclin D1 (usually weak). Genetic features Majority of cases demonstrate BRAF mutation. HMDS will screen for this. Cytochemical Findings: Demonstration of tartrate-resistant acid phosphatase (TRAP) marrow slides (not as specific as flow cytometry). Now largely obsolete. 33

34 Investigation: Bone marrow aspirate, cell markers, trephine and peripheral blood sample / blood film ( EDTA ) to be sent to HMDS Leeds. HMDS Level 3 Bexley Wing St James Institute of Oncology Beckett Street Leeds LS9 7TF CT scan of neck, thorax, abdomen and pelvis as indicated. Hairy cell leukemia variant now considered to be a distinct entity from hairy cell leukaemia and will not be discussed in these guidelines. Management: Many patients are asymptomatic and can be observed for months or years after the diagnosis is established before requiring treatment. No clear advantage to early treatment. Indications For Treatment: Significant cytopenias. Absolute neutrophil count less than 1 with repeated infections. Symptomatic anaemia with a haemoglobin less than 10 or bleeding due to a platelet count less than 100. Symptomatic splenomegaly or symptomatic adenopathy. Constitutional symptoms (example fever, night sweats, fatigue, weight loss). Initial treatment: Cladribine see network protocols Pentostatin - see network protocols iv or sc preparations can be used. With purine analogues prophylaxis with Septrin and Acyclovir is recommended. This should be continued until the CD4 count is over 200 or for up to three months post completion of therapy. GCSF can be given but currently not recommended in the BCSH guidelines. Blood products should be irradiated indefinitely. 34

35 Single agent Rituximab at a dose of 375 mg/m 2 for four weeks can be considered in patients whose comorbidities preclude the use of nucleoside analogues. This treatment can also be considered in neutropenic patients due to hairy cell leukemia in whom the inevitable worsening of cytopenias for two to four weeks post treatment is considered high risk. Example :- those presenting with intercurrent infection, those requiring intensive care or frailty. Definitive treatment with nucleoside analogues can be considered later. Response assessment: Bone marrow aspirate, trephine, cell markers and peripheral blood ( EDTA ) should be assessed four to six months after completion of therapy once peripheral blood counts have maximally recovered. Samples should be sent to HMDS Leeds. Complete remission requires morphological absence of hairy cells in the blood and bone marrow and normalisation of any organomegaly and cytopenia. A partial response (PR) requires normalisation of peripheral counts, together with at least 50% reduction in organomegaly and bone marrow hairy cells and less than 5% circulating hairy cells. All other responses are known as non- responses (NR). Those patients not attaining complete remission following nucleoside analogue can be considered for a second course of treatment at the same dose at an interval of four to six months. Consideration should be given to the addition of rituximab. Eradication of minimal residual disease (MRD), in contrast to overtly persistent disease, should not be the aim of therapy except as part of a clinical trial. 35

36 Second-line treatment: Relapses after several years can be effectively treated with the same or alternate purine analogue. Consideration should be given to the addition of Rituximab 375 mg 2. The number of doses and schedule will differ according to clinician preference (concurrent or sequential) - see network protocols. Interferon Alpha can be considered although complete remissions are uncommon. Treatment with interferon alpha is now rarely used but can be considered in patients failing treatment with purine analogue. This has previously been used to improve pancytopenia in patients who are unable to tolerate subsequent purine analogue therapy with fewer infectious complications but this role has now been largely superceded by Rituximab. Common toxicities of interferon alpha include flu like symptoms, anorexia, fatigue, nausea, vomiting, diarrhoea, dry skin, peripheral neuropathy and central nervous system dysfunction including depression or memory loss. Elevated serum liver enzymes are the most common laboratory abnormality other than myelosuppression. Splenectomy: Possible indications for splenectomy in hairy cell leukemia include: Symptomatic splenomegaly (massive enlargement, pain, infarction, rupture) Pancytopenia which is still present after other treatments. As a temporising measure in symptomatic pregnant females. Splenectomy largely obsolete and purine analogues generally obviate the need for splenectomy in most other settings. Other experimental therapy to be discussed with tertiary centre. Anti-CD22 antibody (BL22) anti-cd25 antibody Resistant disease Only 4 percent of patients obtain no initial benefit. Consideration should be given to using a different purine analog from the one initially chosen in combination with rituximab.. Other options include IFNa, splenectomy, or one of the available monoclonal antibodies directed against B cell determinants on the malignant cell. 36

37 Management of pregnancy Prevalence of the disease in pregnant women is extremely low. There are limited data to guide treatment definitively. It seems reasonable, as for other patients, to avoid therapy in the absence of symptoms. If treatment is required, interferon alpha would be reasonable first line treatment. Author Dr DE Howarth Ratified by LSCCN Haematology NSSG May 2015 Review date: June

38 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF T-CELL PROLYMPHOCYTIC LEUKAEMIA (T-PLL) Introduction T-cell prolymphocytic leukaemia (T-PLL) is a rare T-cell neoplasm composed of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, lymph nodes and spleen. T- PLL comprises approximately 2% of mature lymphocytic leukaemias in adults. Mean age of presentation 65 years. Presentation Most patients with T-PLL present with elevated white blood count, hepatosplenomegaly (75%) and generalised lymphadenopathy (50%). Anaemia (36%) and thrombocytopenia (51%) can be seen. Skin infiltration and serous effusions (ie pleural) can occur. Laboratory Findings Peripheral blood lymphocytosis. Interstitial pattern of bone marrow infiltration. Skin infiltration most commonly involves the face. The spleen demonstrates dense lymphoid infiltrates in the red pulp, but often invade the splenic capsule. Lymph node involvement is diffuse with involvement of the paracortical areas. Immunophenotype CD52 (strong). Pan T-cell markers (CD2, CD3 and CD7). TDT not expressed. Expression of CD4 and CD 8 is variable. Co-expression of CD4 and CD8 is practically unique to T-PLL. Genetic Features T-cell genes receptor genes are clonally rearranged. Chromosome abnormalities are common. Rearrangements involving TCL1 are common and relatively specific to T-PLL. 38

39 Investigations Blood film slides, peripheral blood, bone marrow aspirate, trephine and bone marrow cell markers to be sent to HMDS Leeds, Level 3, Bexley Wing, St James Institute of Oncology, Beckett Street, Leeds LS9 7TF. CT scan of neck, thorax, abdomen and pelvis as indicated. Management Many patients are asymptomatic and can be observed. 30% of patients with T-CLL present with initially stable or slow progressive disease. It is however advisable to monitor these patients more closely than patients with other chronic leukaemias as progression can occur rapidly. Indications for Treatment Symptomatic anaemia, thrombocytopenia or neutropenia. Systemic symptoms such as weakness, night sweats, weight loss or fever. Skin infiltration, pleural effusion or central nervous system involvement. Progressive disease demonstrated by increasing lymphocytosis and/or rapidly enlarging lymph nodes, spleen and liver. Initial Treatment Alemtuzumab is initial treatment of choice. Intravenous route recommended (see network protocol). Premedication with paracetamol and Piriton recommended.slowly escalating doses advised in week one. Antibiotic prophylaxis against pneumocystis, viral infection and fungal infections are recommended (as per local practise). Cytomegalovirus quantitative PCR monitoring recommended on a weekly basis. Antibiotic prophylaxis recommended post-two months completion of therapy. Maximal duration of therapy - 18 weeks. Pentostatin, Fludarabine and Cladribine have utility. Pentostatin is the most commonly used purine analogue in this condition. Response of Pentostatin considered to be inferior to Alemtuzumab, although no direct comparisons in clinical trials. 39

40 Historical agents such as Chlorambucil and CHOP are now usually considered to be of low efficacy. Response Evaluation Six to eight weeks following initiation of therapy, peripheral blood, bone marrow aspirate, trephine and cells markers should be sent to HMDS Leeds and CT scan whole body as indicated. Repeat staging investigations on a six to eight weekly basis. Post-Remission Therapy All eligible patients should be referred to tertiary centre for consideration of either a bone marrow allograft ( Christie Hospital or Manchester Royal Infirmary ) or autograft ( Blackpool Victoria Hospital ). Initial referral should be made before initiation of therapy. Usual requirement to have obtained complete remission post-therapy. Maintenance therapy should not be given outside a clinical trial. Management of suboptimal response or refractory disease Alemtuzumab intravenously can be given in combination with Pentostatin. Alemtuzumab intravenously three times weekly for up to three months and Pentostatin 4mg m 2 given intravenously weekly for four weeks followed by alternate weekly administration for up to six months. Prophylactic antibiotics including antiviral, antifungal and antibacterial agents recommended for two months post-completion. High infection risk with this regime despite antibiotic prophylaxis. Single agent purine analogues can be considered. There is a dearth of literature and evidence concerning the management of suboptimal or refractory disease. Advise discuss with tertiary centre for possible clinical trial. 40

41 Management of Relapse T-cell PLL Repeat treatment with Alemtuzumab or purine analogue. Enrolment in clinical trial, as little information exists on the treatment of recurrent T-cell PLL Author Dr DE Howarth Ratified by LSCCN Haematology NSSG May 2015 Review date: June

42 GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF LARGE GRANULAR LYMPHOCYTE LEUKAEMIA (LGL) Introduction: Large granular lymphocyte leukaemia (LGL) is characterised by peripheral blood and marrow lymphocytic infiltration with LGL s, splenomegaly and cytopenias, most commonly neutropenia. The LGL is a morphological distinct lymphoid subset that is larger than most circulating lymphocytes and has characteristic azurophilic granules containing acid hydrolases. LGL s comprise 10-15% of normal peripheral blood mononuclear cells. LGL s arise from two major linages 85% are CD3 positive, CD57 positive, CD56 negative T- cells. The remaining 15% are CD3 negative, CD56 positive natural killer (NK) cells. Epidemiology: 2% to 5% of chronic lymphoproliferative disorder. Median age 60 years, associated with other disorders in 40% of cases particularly rheumatoid arthritis. Also association between MGUS, multiple myeloma, myelodysplastic syndrome and post bone marrow transplant. Clinical Features: Neutropenia (84%). Infections typically involve skin, oropharyngeal and perirectal areas but pneumonia can also occur. Opportunistic infections are uncommon. Anaemia (50%). Transfusion dependent (20%) ;association with autoimmune haemolytic anaemia and pure red cell aplasia. Thrombocytopenia (20%). B symptoms (30%). Diagnosis: Peripheral blood and slides, bone marrow aspirate, trephine and cell markers to be sent to HMDS Leeds: HMDS Leeds Level 3 Bexley Wing St James Institute of Oncology Beckett Street Leeds LS9 7TF 42

43 Peripheral blood - absolute lymphocyte count usually raised but may be normal. Absolute numbers of LGL s usually increased. Characteristic morphology. Bone marrow may be hypercellular, normocellular or slightly hypocellular with mild to moderate reticulin fibrosis. Monoclonal LGL s usually less than 50% of nucleated cells. Interstitial and or intrasinusoidal infiltration of clonal, CD8 expressing T-Cells accompanied by lymphoid aggregates or nodules comprised of reactive (polyclonal) T and B cells. Immunophenotype great majority of T LGL leukaemia s express CD3, CD8, CD16, CD57 and the alpha/beta T-cell receptor (TCR) but do not usually express CD4, CD56 or CD28. Clonal nature of T-cell LGL leukaemia most easily demonstrated by molecular studies of T-cell receptor. Identification of clonally rearranged T-cell receptor genes is the key factor in the diagnosis of T - LGL leukaemia (to be performed at HMDS Leeds). Serological findings: Rheumatoid factor, the most common abnormality (60%). Antinuclear antibodies 40 50%. Serum protein electrophoresis may show hypergammaglobulinemia and a polyclonal pattern in about one half of patients. Also association with MGUS. Imaging CT scan, US scan as indicated. Treatment: Not all patients with LGL leukaemia require treatment at the time of diagnosis. Active treatment for symptomatic disease only. Most cases have an indolent clinical behaviour with medium survival over ten years. Indications for treatment: Severe neutropenia (less than 0.5) Moderate neutropenia (absolute neutrophil counts <1 with recurrent infections) Symptomatic or transfusion dependent anaemia. Severe thrombocytopenia (very rare event <20) or bleeding and higher platelet threshold clinical decision. Associated autoimmune conditions (example rheumatoid arthritis) requiring therapy Initial Treatment: Immunosuppressive therapy. Methotrexate, Cyclophosphamide, Cyclosporine. These drugs can be combined with prednisolone as indicated. Single agent therapy with prednisolone however not recommended. 43

44 Methotrexate (up to 10 mg/m 2 weekly) with or without prednisolone is the most commonly used initial therapy especially for patients with neutropenia as a primary symptom. Response is seen in 50% of patients with time to response ranging from two to twelve weeks. Monitor FBC, renal and liver function tests. Low dose Methotrexate mg per week gradually increasing to mg per week over one to three months has similar efficacy. Cyclophosphamide (50 to 100 mg daily). Overall response rate 55 to 65% in previously untreated patients. One study showed efficacy along with prednisolone in the presence of pure red cell aplasia. Not a good option for neutropenic patients. Monitor FBC and renal function. Alkylating agent so advise regarding fertility, long term small risk of MDS, AML. Cyclosporine response rate 56% 5-10 mg/kg per day orally in two divided doses for at least three months. Adjusted therapeutic blood level of 200 to 400 ng/ml. Close monitoring of renal function. Low dose cyclosporine (1 to 1.5 mg/kg orally every 12 hours) with or without low dose GCSF led to a return of normal neutrophil count in one small study where the neutrophil count was less than 0.5 Toxicities include gastrointestinal disturbance, nephrotoxicity, hypertension, neurotoxicity and secondary malignancy. Blood pressure, creatinine, blood glucose, liver function tests, potassium and magnesium should be monitored. Methotrexate and Cyclosporine can be continued indefinitely as tolerated. Cyclophosphamide should not be administered for longer than six to twelve months for responders. Discontinuation of methotrexate and cyclosporine can be considered in patients who achieve complete remission for one to two years but studies show that the disease is likely to return slowly following cessation. Other treatments: GCSF can be considered for neutropenia only. Erythropoietin can be given for anaemia only. Both have poor success rates. 44

45 Blood transfusion consider chelation once ferritin > Treatment of relapsed or resistant disease Consider the use of one of the immunosuppressive drugs not previously used. Advise discussion with tertiary centre for possible clinical trials. Other drugs with anecdotal benefit: purine analogues, alemtuzumab, tacrolimus, azathioprine, anti lymphocyte globulin (ALG). Author Dr D E Howarth Ratified by LSCCN Haematology NSSG May 2015 Review date: June

46 GUIDELINES ON THE DIAGNOSIS AND MANAGEMENT OF MULTIPLE MYELOMA Contents 1) Methodology, epidemiology and clinical presentation 2) Diagnosis, prognostic factors and disease monitoring 3) Imaging techniques in myeloma 4) Management of common medical emergencies in myeloma patients 5) Myeloma bone disease 6) Renal impairment 7) Induction therapy including management of major toxicities and stem cell harvesting 8) Management of refractory disease 9) Allogeneic stem cell transplantation 10) Maintenance therapy 11) Management of relapsed myeloma References Appendices 46

47 1. Methodology, epidemiology and clinical presentation 1.1 Methodology: The production of these guidelines involved the following steps: Review of current BCSH guidelines Review of European Society of Medical Oncology(ESMO) Guidelines Review of International Myeloma Federation Guidelines Review of Recently published Network guidelines in the UK Review of NHS England proposed pathway for Myeloma Review by Network Haematologists involved in Myeloma care Review of HMRN Leeds epidemiology data 1.2 Incidence, prevalence and epidemiology in UK and LSCCN Incidence: 6-7/100,000 per annum ( cases per annum in the LSCCN Prevalence appears to be increasing as evidenced by improving survival rates (Brenner et al, 2009; Kumar et al, 2008). 1% of all cancers and 10% of all haematological malignancies mortality is 4.1/ /year The median age at presentation is approximately 70 years. Only 15% of patients are aged less than 60 years. Myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009). MGUS progresses to MM at a rate of 1% per year. Asymptomatic or Smouldering Myeloma (SMM) progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter (Kumar et al, 2009) 47

48 1.3 Clinical Presentation: Routine presenting clinical features include symptoms of: Calcium- Hypercalcemia Renal impairment Anaemia Bone disease Recurrent or persistent bacterial infection Hyperviscosity Incidental finding of paraproteinemia, raised ESR, Total protein, Globulin, Emergency presentation with Spinal cord compression, Hypercalcemia and renal failure require immediate investigations and treatment. Patients with suspected Myeloma require urgent Haematology referral in accordance with the LSCCN pathway. 2. Diagnosis, prognostic factors and disease monitoring 2.1 Investigation and diagnosis FBC, Blood Film, ESR, Coagulation screen, Group and save U+Es, LFTs, Calcium and albumin, CRP LDH β2-microglobulin Immunoglobulins with Electrophoresis and immunofixation of serum and urine with quantification of monoclonal protein Skeletal survey Bone marrow aspirate and trephine with plasma cell phenotyping by either immunohistochemistry or flow cytometry To be reviewed by the Network diagnostic centre which is Leeds HMDS Virology Hep B, Hepatitis C, HIV 1 and 2 48

49 Additional test that may be required are: Plasma viscosity (if suspected hyperviscosity) Serum free light chains (in light chain myeloma) 24 hour urine for Bence-Jones protein quantification Creatinine clearance MRI or CT scan. HLA Typing (If potential candidate for Allograft) 2.2 Diagnostic criteria and differential diagnosis The diagnosis (and differentiation from MGUS) should be made using the IMWG criteria as outlined in the BCSH guidelines for the Diagnosis and Management of Multiple Myeloma (Feb 2014). All diagnoses should be made or reviewed by the Multidisciplinary Team (MDT) (National Institute for Health and Clinical Excellence [NICE], 2003). Consider using the NUTS criterion to exclude Amyloidosis Neuropathy- Peripheral or Autonomic at the time of diagnosis Urine Dipstick for protein to exclude proteinuria Troponin T or BNP If high, proceed with an ECG and a ECHO to look for Amyloid Soft tissue involvement- Large tongue, Bruising related to Factor X deficiency 2.3 Monitoring and indications for starting therapy: Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI (IMWG 2003) Asymptomatic myeloma patients should be monitored under the supervision of a Consultant Haematologist.(BCSH Feb 2014) Monitoring of patients with asymptomatic myeloma should include regular (typically 3- monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). (BCSH Feb 2014) Repeat BM examination and skeletal imaging should be considered prior to the start of treatment (BCSH Feb 2014) 49

50 2.4 Prognostic factors and staging in symptomatic myeloma The International Staging System based on serum albumin and 2-microglobulin should be used Stage I: Serum β2-microglobulin < 3.5mg/l and serum albumin 35g/l Median survival- 62 months Stage II: Neither I or II Median survival- 45 months Stage III: Serum β2-microglobulin 5.5mg/l Median survival: 29 months FISH studies are recommended for all patients at diagnosis as they provide important prognostic information but their role in directing therapy remains uncertain. Newer techniques for prognostic assessment should continue to be utilised in the context of clinical trials to evaluate future incorporation in to routine clinical practice. 2.5 Measuring Response to Therapy Response to therapy should be defined using the IMWG uniform response criteria The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligosecretory disease 2.6 Rare myelomas Plasma Cell Leukaemia Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterized by the presence of >20% circulating plasma cells and/or an absolute level of > 2.0x109/l (Kyle et al, 1974). IgD, E and M Myelomas The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975) 50

51 Non-secretory myeloma The SFLC assay is informative in approximately two thirds of patients (Drayson et al, 2001). The clinical presentation is similar to standard myeloma, but anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al,2010 ; BCSH Feb 2014). 3. Imaging techniques The skeletal survey remains the screening technique of choice at diagnosis. The skeletal survey should include a postero-anterior (PA) view of the chest, anteroposterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views Computerized tomography (CT)scanning or magnetic resonance imaging (MRI) should be used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse. Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated. CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial 51

52 Bone scintigraphy has no place in the routine staging of myeloma Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in all symptomatic myeloma patients. 4. Management of common medical emergencies in myeloma patients 4.1 Hyperviscosity All patients with high protein levels should undergo fundoscopy, which may demonstrate retinal vein distension, haemorrhages and papilloedema. Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mpa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta and Singhal 2003). Management: Symptomatic hyperviscosity should be treated with therapeutic plasma exchange with saline fluid replacement If plasmapheresis is not immediately available but hyperviscosity symptoms are present, consider isovolaemic venesection with saline replacement as a holding measure Effective treatment of the underlying disease should be started as soon as possible 4.2 Hypercalcaemia Up to 30% of myeloma patients present with hypercalcaemia in the context of active disease. Exclude other causes like Hyperparathyroidism Management: CoCa Oral/IV Hydration CoCa- >2.9- IV Hydration +/- Diuretics, Bisphosphonate- Zoledronate is the bisphosphonate of choice. ( Reduced dose Pamidronate(30mg) to be considered in Renal impairment) 52

53 Refractory Hypercalcemia: If persistent beyond 72 hours, consider repeat Bisphosphonate therapy+/- Corticosteroids and Calcitonin. 4.3 Cord compression Compression of the spinal cord from extramedullary foci of disease occurs in 5% of patients with myeloma during the course of their disease (Kyle et al, 2003). The management should be in accordance with the MSCC pathway for the LSCCN with the involvement of the spinal cord co-ordinator If cord compression is suspected on clinical grounds, Start Dexamethasone 40 mg daily for 4 days with appropriate PPI cover. Urgent MRI should be performed and neurosurgical or spinal surgical / clinical oncology consultation obtained Local radiotherapy is the treatment of choice for non-bony lesions and should be commenced as soon as is possible, preferably within 24 h of diagnosis. A dose of 30Gy in 10 fractions is recommended Surgery is recommended for emergency decompression in the setting of bony compression and/or to stabilize the spine If cord compression is a presenting symptom, it is important to concurrently pursue a rapid diagnosis and to institute systemic therapy as soon as possible 4.4 Early Infection It has been reported that up to 10% of patients die of infective causes within 60 days of diagnosis (Augustson et al, 2005). Neutropenia is not usually a factor in early infection (Augustson et al, 2005) 24-h access to specialist advice for the patient and/or primary care team is crucial. Any febrile myeloma patient should be treated promptly with broad-spectrum antibiotics. Intravenous antibiotics are required for severe systemic infection or neutropenic sepsis as per the Neutropenic sepsis policy. Aminoglycosides should be avoided, if possible. 53

54 5. Myeloma bone disease 5.1 Clinical features of bone disease Bone disease occurs in 80-90% of myeloma patients. This can present as bone pain, pathological fractures/spinal cord compression and hypercalcaemia (Coleman 1997; Croucher and Apperley 1998; Terpos and Dimopoulos 2005). Skeletal events compromise mobility and day-to-day independence, decrease quality of life (Cocks et al, 2007; Terpos and Rahemtulla 2004; Vogel et al, 2004) and increase overall treatment costs. 5.2 Bone fractures Appropriate specialist input should to be sought Local radiotherapy is helpful for pain control Long bone fractures require stabilization and subsequent radiotherapy Large lytic lesions may cause skeletal instability an orthopaedic opinion should be sought and pre-emptive surgery considered in selected patients. Vertebral fractures may require specialized clinical interventions including vertebroplasty and kyphoplasty. Myeloma UK facilitated a Spinal Myeloma working group Pathway is attached below. 5.3 Bisphosphonates Bisphosphonate therapy is recommended for all patients with symptomatic multiple myeloma, whether or not bone lesions are evident(bcsh Feb 2014) Zoledronic acid should be the bisphosphonate of choice Sodium clodronate is less effective than zoledronic acid but has a significantly lower incidence of BONJ(Myeloma IXtrial- Morgan et,al, 2010 ) Duration of treatment is left at the discretion of the treating Haematologist based upon the clinical needs of each individual patient. However, this needs to be reviewed after 2 years. 54

55 Bisphosphonate break as advised by BNF after 4 years of therapy is recommended Renal impairment: Dose modifications as listed in the Appendix Dental evaluation should be carried out before starting IV bisphosphonate therapy 6. Renal Impairment 6.1 Incidence and pathophysiology Incidence is about 20-25% (Knudsen et al, 1994) at the time of presentation and about 50% at some time during their disease (Eleutherakis-Papaiakovou et al, 2007; Kyle 1975). It is possible to reverse renal insufficiency in approximately half of patients but the remainder will have some degree of persistent renal impairment and of these, 2-12 % will require renal replacement therapy (Clark et al, 1999). Patients presenting with renal failure have a high early death rate; of 367 newly diagnosed myeloma patients with serum creatinine >199 mmol/l, 29.4% died within 60 days of diagnosis (Augustson et al, 2005). It is therefore critically important to prevent renal failure, or if established, to reverse it as this will significantly improve survival (Knudsen et al, 2000). 6.2 Prevention of Renal Failure Early diagnosis of both new and relapsed myeloma enables early intervention and thus prevention of renal damage (Augustson et al, 2005; Drayson et al, 2006). Investigations for Amyloidosis need to be considered pro-actively NUTS Criterion Renal function is optimized by maintenance of a high fluid intake, at least 3 litres/day (MRC Working Party on Leukaemia in Adults, 1984) and all patients should be instructed as to the importance of this throughout the course of the disease. 6.3 Early Management of Renal Failure Vigorously rehydrate with at least 3 litres of normal saline daily Treat precipitating events eg hypercalcaemia, sepsis and hyperuricaemia and discontinue nephrotoxic drugs, particularly NSAIDs Administer high dose dexamethasone unless otherwise contraindicated pending initiation of definitive treatment which should be started without delay 55

56 Monitor SFLC levels Identify and treat infection vigorously Renal dose modification of drugs and particularly the bisphosphonates is critical 7. Induction Therapy 7.1 The broad aims of treatment in myeloma are: to control disease maximise quality of life to prolong survival These goals are achieved by a combination of specific disease-directed therapy and supportive care. It is important to tailor treatment to the individual patient. Although high-dose therapy (HDT) is recommended where possible, many patients will not be able to receive such therapy because of advanced age, specific problems or general poor performance status. 7.2 Treatment decisions should be made in the context of an MDT and should take into account individual patient factors and patient choice. Patients should be treated as part of national trials if available. NHS England is working on national guidance for Myeloma which advises that treatment decision needs to be made based upon whether a patient is transplant eligible or has renal impairment. LSCCN Myeloma Chemotherapy Regimens should be followed 7.3 Induction: Intensive patients (suitable for HDT and PBSCT) Induction therapy Myeloma Consider entering into intensive arm of Myeloma XI trial If not eligible, or patient does not want to enter trial, use Thalidomide containing regimes like CTD, MPT chemotherapy or the Bortezomib based therapy in the context of NICE TA 311(Apr 14) like Vel-Dex, VCD, VTD, VMP in accordance with the LSCCN chemotherapy protocols particularly in the context of renal impairment not responding to adequate hydration. 56

57 Treat until maximum response + 1 further cycle (min 4 cycles). VTE risk stratification should be used to select antithrombotic prophylaxis Eg: Aspirin 75mg or prophylactic doses of LMWH. Assess response after 2 cycles After maximal response mobilise with Cyclophosphamide and/or G-CSF (doses as per local protocols) Proceed to Melphalan PBSCT 200 mg/m2 (Renal dose modification: Melphalan 140mg/m2 if Creatinine >200umol/L 7.4 Induction therapy Plasma cell leukaemia Use either a Bortezomib based regime (eg PAD or VCD) for plasma cell leukaemia, or DT- PACE if any contraindication to Velcade containing regimen or failure to achieve a PR after 2 cycles of PAD. 7.5 Induction: Non-Intensive Patients (those not suitable for HDT) Consider entering into non-intensive arm of Myeloma XI trial If not eligible, or patient does not want to enter trial, use CTDa chemotherapy, if tolerated. Maximum of 9 courses. MPT may be preferred if patient intolerant of high dose steroids or requires simpler scheduled regimen. For both CTDa, VTD and MPT, VTE risk assessment followed by Aspirin 75mg or prophylactic doses of LMWH should be used as thromboprophylaxis. Bortezomib based regimes VTD, Vel/Dex, VCDa, VMP (velcade, melpahalan and prednisolone) should be used in patients either unable to tolerate or has contra-indications to thalidomide. All patients receiving Bortezomib should be monitored closely for peripheral neuropathy. See LSCCN Myeloma Chemotherapy Regimens for details. Our network has used the once weekly Bortezomib with equal efficacy and less toxicity as evidenced in several clinical trials. This should be used as an alternative schedule, particularly in older patients. 57

58 8. Intensification for non-responders (primary refractory disease) This represents about 5% of patients. They are defined as those with <25% reduction in paraprotein after 2 cycles of CTD or < 50% reduction after 4 cycles. These patients should change to a Bortezomib containing regimen. Treatment for these patients once identified, should be VCD chemotherapy, 2-6 courses until maximum response. If a Partial Response or greater seen, proceed to consolidation therapy with High dose Melphalan Auto PBSCT. If less than PR (ie less than 50% fall in paraprotein) with VCD or PAD consider treatment with VDT-PACE/ DT-PACE to further cytoreduce prior to Autograft Disease monitoring should be using modified EBMT/IMWG criteria 9. Allografts Seek Allograft opinion for patients who are <40 years old, 17p del, Plasma cell Leukaemia patients and for selected patients if early relapse post autograft or refractory to multiple lines of therapy, with good performance status. 10. Maintenance therapy The role of maintenance therapy remains unclear in the context of the new drugs. Therefore, its role is being assessed as a part of the Myeloma XI trial in the UK No benefit has been demonstrated for the role of maintenance with chemotherapy (Belch et al, 1988; Drayson et al, 1998). 11. First Relapse Aim to enter in clinical trial where possible. If no clinical trial is available, first relapse therapy will depend on whether the patient is suitable for a second autograft: Bortezomib cannot be used if it has been used previously as per the New Cancer Drugs Fund policy 58

59 11.1 Intensive Following results from Myeloma X trial, a second autograft should be performed at first relapse in patients: who were previously treated with standard chemotherapy and autologous transplantation with progressive disease 12 months from time of first transplant. with a Performance Status (PS) of 0-2 (ECOG). with adequate hepatic, renal, pulmonary and cardiac function. Patients should be offered a Bortezomib containing induction regimen such as PAD or VTD/VCD (up to 4 cycles) ahead of the transplant to reduce the disease burden. If frozen stem cells are stored these can be used. Otherwise re-mobilisation may be possible. High dose Melphalan conditioning is used as per first autograft (dependent on renal function) 11.2 Non Intensive If the patient is NOT suitable for a second autograft they should be offered Bortezomib (Velcade) as per NICE guidance ( This can be given with a steroid (usually Dexamethasone) and can also be combined with an alkylating agent such as cyclophosphamide (eg VCD) or as VTD Details of dosing and dose modifications may be found in the LSCCN Myeloma Chemotherapy Regimens. The response to Bortezomib will be measured after a maximum of four cycles of treatment, and treatment is continued only in people who have a complete or partial response If CR is achieved, treatment can be stopped after a further 2 cycles. Patients will receive up to a maximum of 8 x 21-day cycles. If bortezomib was given as first line treatment under the criteria above then a thalidomide or lenalidomide containing regimen may be offered as a second line option. 59

60 11.3 Second relapse Lenalidomide (Revlimid) and Dexamethasone as per NICE guidance if patient has had previous thalidomide. Patients should receive aspirin 75mg or low dose LMWH as thromboprophylaxis. If additional risk factors are present full dose LMWH or warfarin should be considered The manufacturer will provide free drug for any Lenalidomide used after 26 cycles of Therapy 11.4 Third or subsequent relapse Entry into a clinical trial should be considered whenever possible. Patients may be retried on a thalidomide containing regimen (eg CTD or MPT). Alternatively consider Pomalidomide, Dexamethasone or bendamustine, combined with thalidomide and dexamethasone Local radiotherapy Some patients may relapse with local disease, eg. spinal plasmacytoma, with little evidence of active disease elsewhere. Such patients, especially if they are beyond first relapse, may be treated with local radiotherapy, avoiding the additional toxicity of systemic therapy, which would be an option for subsequent disease re-activation.(bcsh Feb 2014) 60

61 References Augustson, B.M., Begum, G., Dunn, J.A., Barth, N.J., Davies, F., Morgan, G., Behrens, J., Smith, A., Child, J.A. & Drayson, M.T. (2005) Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United kingdom Medical Research Council trials between 1980 and Medical Research Council Adult Leukaemia Working Party. Journal of Clinical Oncology, 23, Belch, A., Shelley, W., Bergsagel, D., Wilson, K., Klimo, P., White, D. & Willan, A. (1988) A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. British Journal of Cancer, 57, Brenner, H., Gondos, A., & Pulte, D. (2009). Expected long-term survival of patients diagnosed with multiple myeloma in haematologica, 94(2), Cocks, K., Cohen, D., Wisloff, F., Sezer, O., Lee, S., Hippe, E., Gimsing, P., Turesson, I., Hajek, R., Smith, A., Graham, L., Phillips, A., Stead, M., Velikova, G. & Brown, J. (2007) An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. European Journal of Cancer, 43, Clark, A.D., Shetty, A. & Soutar, R. (1999) Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Reviews, 13, Coleman, R.E. (1997) Skeletal complications of malignancy. Cancer, 80, Croucher, P.I. & Apperley, J.F. (1998) Bone disease in multiple myeloma. British Journal of Haematology, 103, Drayson, M.T., Chapman, C.E., Dunn, J.A., Olujohungbe, A.B. & Maclennan, I.C. (1998) MRC trial of alpha2b-interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults. British Journal of Haematology, 101, Drayson, M., Tang, L.X., Drew, R., Mead, G.P., Carr-Smith, H. & Bradwell, A.R. (2001) Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood, 97, Drayson, M., Begum, G., Basu, S., Makkuni, S., Dunn, J., Barth, N. & Child, J.A. (2006) Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials. Blood, 108,

62 Durie, B.G., Harousseau, J.L., Miguel, J.S., Blade, J., Barlogie, B., Anderson, K., Gertz, M., Dimopoulos, M., Westin, J., Sonneveld, P., Ludwig, H., Gahrton, G., Beksac, M., Crowley, J., Belch, A., Boccadaro, M., Cavo, M., Turesson, I., Joshua, D., Vesole, D., 55 Kyle, R., Alexanian, R., Tricot, G., Attal, M., Merlini, G., Powles, R., Richardson, P., Shimizu, K., Tosi, P., Morgan, G. & Rajkumar, S.V. (2006) International uniform response criteria for multiple myeloma. Leukemia, 20, Eleutherakis-Papaiakovou, V., Bamias, A., Gika, D., Simeonidis, A., Pouli, A., Anagnostopoulos, A., Michali, E., Economopoulos, T., Zervas, K. & Dimopoulos, M.A. (2007) Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leukemia and Lymphoma, 48, Jancelewicz, Z., Takatsuki, K., Sugai, S. & Pruzanski, W. (1975) IgD multiple myeloma. Review of 133 cases. Archives of Internal Medicine, 135, Knudsen, L.M., Hippe, E., Hjorth, M., Holmberg, E. & Westin, J. (1994) Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group. European Journal of Haematology, 53, Knudsen, L.M., Hjorth, M. & Hippe, E. (2000) Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. European Journal of Haematology, 65, Kumar, S., Hayman, S., Buadi, F., Lacy, M., Stewart, K., Allred, J.,... & Dispenzieri, A. (2008, December). Phase II trial of lenalidomide (RevlimidTM) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. In Blood (ASH Annual Meeting Abstracts) (Vol. 112). Kumar, S., Flinn, I.W., Parameswaran, Hari, N., Callander, N., Noga, S.J., Stewart, A.K., Glass, J., Raje, N., Rifkin, R.M., Shi, H., Webb, I.J., Richardson, P.G. & Rajkumar, S.V. (2009) Novel three- and four-drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: encouraging results from the multi-center, randomized, phase 2 EVOLUTION Study. Blood (ASH Annual Meeting Abstracts), 114, Abstract 127. Kyle, R.A. (1975) Multiple myeloma: review of 869 cases. Mayo Clinic Proceedings, 50, Kyle, R.A., Maldonado, J.E. & Bayrd, E.D. (1974) Plasma cell leukemia. Report on 17 cases. Archives of Internal Medicine, 133, Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., Fonseca, R., Rajkumar, S.V., Offord, J.R., Larson, D.R., Plevak, M.E., Therneau, T.M. & Greipp, P.R. (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceedings, 78,

63 Landgren, O., Kyle, R. A., Pfeiffer, R. M., Katzmann, J. A., Caporaso, N. E., Hayes, R. B.,... & Rajkumar, S. V. (2009). Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood, 113(22), Mehta, J. & Singhal, S. (2003) Hyperviscosity syndrome in plasma cell dyscrasias. Seminars in Thrombosis and Hemostasis, 29, Morgan G., DaviesF., GregoryW., Bell S.E., SzubertA., Navarro CoyN., DraysonM., Owen R.G., Jackson G.H., Child J.A.(2010 ) Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study J Clin Oncol 28:7s, (suppl; abstr 8021) Morris, C., Drake, M., Apperley, J., Iacobelli, S.,van Biezen, S.,Bjorkstrand, B.,Goldschmidt,H., Jouet, J.P., Harousseau, J-L, Morgan, G., de Witte, T., Niederwieser, D., Gahrton, G. for the myeloma subcommittee of the chronic leukaemia working party of the EBMT (2010) Efficacy and outcome of autologous transplantation in rare myelomas. Haematologica, in press MRC working party on leukaemia in adults (1984) Analysis and management of renal failure in fourth MRC myelomatosis trial.. British Medical Journal, 288, National Institute for Health and Clinical Excellence. (2003) Improving outcomes in haematological cancers-the Manual. Available at: Terpos, E. & Dimopoulos, M.A. (2005) Myeloma bone disease: pathophysiology and management. Annals of Oncology, 16, Terpos, E. & Rahemtulla, A. (2004) Bisphosphonate treatment for multiple myeloma. Drugs Today (Barc), 40, Vogel, C.L., Yanagihara, R.H., Wood, A.J., Schnell, F.M., Henderson, C., Kaplan, B.H., Purdy, M.H., Orlowski, R., Decker, J.L., Lacerna, L. & Hohneker, J.A. (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist, 9,

64 APPENDICES Appendix 1 - Monitoring Response subcategory Stringent complete response (scr) Complete response (CR) Response criteria CR as defined below plus normal SFLC ratio Absence of phenotypically aberrant plasma cells by multiparameter Flow cytometry Negative immunofixation in serum and urine Disappearance of any soft tissue plasmacytomas <5% bone marrow plasma cells Very good partial response (VGPR) Serum and/or urine M protein detectable by immunofixation but not on electrophoresis or >90% reduction in serum M protein and urine M protein level <100mg/24hr Partial response (PR) >50% reduction of serum M protein and reduction in 24hr urinary M protein by >90% or to <200mg/24hr Stable disease (SD) Not meeting criteria for CR, VGPR, PR or progressive disease Progressive disease (PD) Requires at least one of the following >25% increase in serum M protein in 3 months (absolute increase must be >5g/l) >25% increase in urine M protein in 3 months (absolute increase must be >200mg/24hr) >25% increase in the difference between involved and uninvolved SFLC levels (applicable only to patients without measurable serum and urine M protein. Absolute increase must be >10mg/dl >25% increase in bone marrow plasma cell percentage (absolute percentage must be >10%) Development of new bone lesions or soft tissue plasmacytoma Development of hypercalcaemia 64

65 Appendix 2 Dose modifications of Bisphosphonates Bisphophonates Recommended dose reductions of bisphosphonates in renal impairment Creatinine Clearance Sodium clodronate Pamidronate Zoledronate >30mls /min No dose modification If Cr Cl: 30-60mls/min: The infusion rate should not exceed 90mg over 4 hours >60mls/min: 90mg over 2 hrs If Cr Cl: 30-39mls/min: 3mg 40-49mls/min: 3.3mg 50-59mls/min: 3.5mg 60mls/min: 4mg ml/min Half dose 30 mg to be given over 2-4 hours Not recommended < 10 ml/min Contra indicated 30 mg to be given over 2-4 hours Not recommended Appendix 3- Staging Staging is now done using the International Staging System (ISS) for Multiple Myeloma which defines 3 risk categories. However, the ISS should not determine the choice of therapy for individual patients. ISS Stage I Criteria Serum β2-microglobulin < 3.5mg/l and serum albumin 35g/l Median survival in months 62 months II Neither I or II 45 months III Serum β2-microglobulin 5.5mg/l 29 months Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4:14), t(14;16) and deletion 17p,t(14:20) and 1q gain demonstrated by FISH, confer an adverse outcome. At present, the consensus is that no clinical 65

66 or treatment decisions can be guided by genetic factors, however, centres may wish to assess FISH at diagnosis to provide prognostic information, and possibly influence treatment decisions in the future as new data emerges. When to treat Following a diagnosis of multiple myeloma, patients can be divided into those with either asymptomatic or symptomatic disease. Those who are asymptomatic require close monitoring by a Consultant Haematologist, however, early intervention or treatment is not required. Treatment with chemotherapy is indicated for the management of symptomatic myeloma (1) This is as defined by the presence of Myeloma-related organ or tissue impairment (ROTI) defined in table below: Myeloma-related organ or tissue impairment (ROTI) (International Myeloma Working Group, 2003) Clinical effects due to myeloma Increased calcium levels Renal insufficiency Anaemia Bone lesions Other Definition Corrected serum calcium >0.25mmol/l above the upper limit of normal or >2.75mmol/l Attributable to myeloma (exclude other causes) Haemoglobin 2 g/dl (1.2 mmol/l) below the lower limit of normal or haemoglobin <10 g/dl (<100 g/l or 6.2 mmol/l) Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12 months) 66

67 Appendix 4 NHS England Draft Treatment Algorithms 67

68 68

69 69

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72 Appendix 5 - Spinal Pathway Spinal Myeloma Working Group Pathway Patient with known history of myeloma presenting with persistent back or radicular pain/weakness NO ABNORMAL NEUROLOGY Myeloma with spinal involvement: pain/instability/progressive deformity, or, risk of neurological dysfunction. MRI SCAN WHOLE SPINE MDT Management Review ] (Surgeon, Haematologist, Radiotherapist and Radiologist) If concerned about stability CT SCAN (Sagittal and coronal reconstructions) Assess pars, facet joints, pedicles, posterior /anterior wall involvement to determine if instability is a concern. Conduct SINS assessment** If bony destruction is present on CT (suggesting spinal instability) consider brace or surgical intervention Δ Pain significantly affecting day to day functioning (or VAS pain score 6) Pain not significantly affecting day to day functioning (or VAS pain score 6) Epidural mass with risk of cauda equina or cord compression Cement Augmentation* /Radiotherapy or combination of both (according to MDT review) +/- Brace*** (if high risk of deformity) After 2-3 Cycles of chemo if on-going pain affecting QOL. Steroids, Radiotherapy, Chemotherapy Repeat MRI after 2/3 cycles of chemotherapy (Canal Clear?) Balloon Kyphoplasty creation of cavity, injection of cement with potential restoration of VB height Yes Assess for cement augmentation based on risk of VB collapse No MDT Management Review Continue Medical Management +/- brace*** * Antibiotic prophylaxis recommended for all patients undergoing cement augmentation (to avoid potential risk of severely debilitating discitis) ** Spinal Instability Neoplastic Score 72 *** Thermoplastic/TLSO brace if available to prevent progressive deformity +/- further vertebral body collapse Δ High risk patient e.g., patient with bilateral facet joint destruction, therefore posing risk of spondylolisthesis See appendix for clinical data pertaining to Balloon Kyphoplasty, Vertebroplasty and Radiotherapy

73 Spinal Myeloma Working Group Pathway Patient with known history of myeloma presenting with persistent back or radicular pain/weakness ABNORMAL NEUROLOGY Cord compression / cauda equina / signs & symptoms of neurological dysfunction MRI SCAN WHOLE SPINE CT scan (SINS assessment**) Soft Tissue involvement: Urgent liaison with MDT Bone Involvement Cord compression due to bone involvement Steroids, Radiotherapy, Chemotherapy Immediate neurological improvement 2-3 cycles Chemotherapy No Improvement (unusual) Spinal decompression +/- stabilisation (cement augmentation +/- metal work) MDT Management Review No Pain not significantly affecting day to day functioning (or VAS pain score 6) Repeat MRI (Canal Clear?) Yes Continue Medical Management +/- brace*** Pain significantly affecting day to day functioning (or VAS pain score 6) Cement Augmentation* /Radiotherapy or combination of both (according to MDT review) Balloon Kyphoplasty creation of cavity, injection of cement with potential restoration of VB height * Antibiotic prophylaxis recommended for all patients undergoing cement augmentation (to avoid potential risk of severely debilitating discitis) ** Spinal Instability Neoplastic Score *** Thermoplastic/TLSO brace if available to prevent progressive deformity +/- further vertebral body collapse Δ High risk patient e.g., patient with bilateral facet joint destruction, therefore posing risk of spondylolisthesis See appendix for clinical data pertaining to Balloon Kyphoplasty, Vertebroplasty and Radiotherapy 73

74 Spinal Myeloma Working Group Pathway Patient with Plasmacytoma SOLITARY NOT SOLITARY NO ABNORMAL NEUROLOGY ABNORMAL NEUROLOGY Treat as a patient with Multiple Myeloma according to standard pathway RADICAL DXT Consider cement augmentation If risk of instability or if pain is significantly affecting day to day functioning (VAS pain score 6) URGENT LIAISON WITH MDT (Surgeon, Haematologist, Radiotherapist and Radiologist) Treat according to MDT review decision 74

75 75 Appendix 6 - Spinal Team Referral form