Clinical Haematological Malignancy Guidelines

2015

Peer review measures 13-2H-106-108,110

May 2015

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CONTENTS

Page No.

Lymphoma 4

Myeloma 18

Chronic Lymphocytic Leukaemia 21

Chronic Myeloid Leukaemia 24

Acute Myeloid Leukaemia 25

Acute Lymphoblastic Leukaemia 27

Myelodysplasia 28

Myeloproliferative Disorders 30

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Clinical guidelines for the investigation and management of haematological malignancies 13-2H-106,107, 108

Where ever available national guidelines are used developed by British Society of Haematology. Currently guidelines exist for individual malignancies- see each chapter and the following:

Obtaining consent 2012 Diagnosis and management of acute GvHD 2012 Diagnosis and management of chronic GvHD 2012 Management of organ specific chronic GvHD 2012 Facilities for the treatment of adult haematological malignancies – levels of

care 2009 Haematological malignancies and ITU- in progress Insertion and management of central venous devices- in progress Management of CMV infection in haemopoietic stem cell transplantation -

2013 Management of veno-occlusive disease 2013 Management of tumour lysis in adults and children with haematological

malignancy -2015

These can be accessed at: http://www.bcshguidelines.com/

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LYMPHOMAS

WHO CLASSIFICATION

B-CELL NEOPLASMS

Pre-cursor B-cell neoplasmPrecursor B lymphoblastic lymphoma/leukaemia

Mature B-cell neoplasmsChronic Lymphocytic leukaemia/ Small Lymphocytic lymphomaB-cell prolymphocytic leukaemiaLymphoplasmacytic lymphomaSplenic marginal zone lymphomaHairy cell leukaemiaPlasma cell myelomaSolitary plasmacytoma of boneExtraosseous plasmacytomaExtranodal marginal zone B-cell

lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma)

Marginal zone B-cell lymphomaFollicle centre cell lymphomaMantle cell lymphomaDiffuse large B-cell lymphomaMediastinal (thymic) large B-cell

lymphomaIntravascular large B-cell lymphomaPrimary effusion lymphomaBurkitt lymphoma/leukaemia

B-cell proliferations of uncertain malignant potentialLymphoid granulomatosisPost-transplant lymphoproliferative

disorder, polymorphic

T-CELL AND NK-CELL NEOPLASMS

Precursor T-cell neoplasmsPrecursor T lymphoblastic

leukaemia/lymphomaBlastic NK cell lymphoma

Mature T-cell and NK-cell neoplasmsT-cell prolymphocytic leukaemiaT-cell large granular lymphocytic leukaemiaAggressive NK cell leukaemiaAdult T-cell lymphoma/leukaemiaExtranodal NK/T cell lymphoma, nasal typeEnteropathy-type T-cell lymphomaHepatosplenic T-cell lymphomaSubcutaneous panniculitis-like T-cell

lymphomaMycosis fungoidesSezary syndromePrimary cutaneous anaplastic large cell

lymphomaPeripheral T-cell lymphoma, unspecifiedAngioimmunoblastic lymphomaAnaplastic large cell lymphoma

T-cell proliferation of uncertain malignant potentialLymphoid papulosis

HODGKIN’S LYMPHOMAClassical Hodgkin lymphoma

Nodular sclerosis classical Hodgkin lymphoma

Lymphocyte-rich classical Hodgkin lymphoma

Mixed cellularity classical Hodgkin lymphoma

Lymphocyte depleted classical Hodgkin lymphoma

Nodular lymphocyte predominant lymphoma

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WHO Performance score

0 No symptoms1 Symptoms but ambulatory2 Bedridden less than half the day3 Bedridden half the day or longer4 Chronically bedridden and requiring

Assistance with activities of daily livingInternational Prognostic Index for DLBCL Risk

Risk Factor Score 0 Score 1Age (years) <60 >60Stage (Ann Arbour) I or II III or IV Low 0-1Number of extranodal sites 0 or 1 >1 Intermediate/ low 2Performance Status (ECOG) 0 or 1 >1 Intermediate/ high 3Serum LDH Normal Elevated High 4Hasenclever Score for CHL

Score Risk

Age > 45yrs 1 Low <3Intermediate 3-4

High >4Male gender 1Albumin <40g/l 1Hb <105g/l 1Stage IV disease 1WCC > 15x 109/l 1WCC< 0.6x109/l 1

Early Stage- Favourable v.s. Unfavourable CHL (GHSG criteria)

Favourable Unfavourable (any 1 of below)No bulk in mediastinum (<10cm) Bulk in mediastinumESR<50 with no B Sx ESR≥ 50 with no B SxESR <30 with B Sx ESR ≥ 30 with B SxNo extranodal disease Extranodal disease1-2 lymph node groups ≥3 lymph node groups

FLIPI score for Follicle Centre Cell Lymphoma

Score 0 1 Low 0-1Intermediate 2

high 3-5 Age <60 ≥60Stage <II ≥IIIHb <11.

9³

12.0LDH N >NNo of nodal areas <4 ≥5

MIPI for mantle cell lymphoma

Age PS LDH WCC0 <50 0-1 <319 <6.71 50-59 n/a 320-479 6.7-9.92 60-69 2-4 480-715 10-14.93 ≥70 n/a >716 >15

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Lymphoma Investigational and Clinical Management Guidelines13 2H- 105 and 107

Investigations

FBC, viscosity, DATU+Es, LFTs, Ca2+, LDH, uric acid, b2microglobulinIgs and serum protein electrophoresisHepatitis BsAg and cAb, hepatitis C and HIV

Bone marrow aspirate and trephineMorphology-processed and reported locallyImmunophenotyping- processed Plymouth, reported locallyMolecular genetics- processed and reported Plymouth

Lymph node biopsyMorphology-processed and reported locally, a proportion sent to Plymouth for dual reporting or second opinionImmunophenotyping- processed Plymouth, reported locallyMolecular genetics- processed and reported PlymouthFISH- for double hit lymphomas – Guys and Thomas’ LondonIgH gene rearrangement – Exeter

CT scan -Neck, Thorax, Abdomen and PelvisCT PET scan in selected patients- see indication below.

Lumbar Puncture (only for clinical suspicion or where intrathecal therapy indicated)ECHO only if likely to receive anthracycline and previous cardiac history or other risk factors and/ or over 70)Pulmonary function tests if chest symptoms / disease and planned therapy with BleomycinSemen cryopreservation where appropriate

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Suggested Use of CT PET scanning in Lymphoma Outside a Clinical Trial

All New Patients with Hodgkin’s Lymphoma

CT PET at diagnosis

DLBC NHL

Should consider CT PET upfront to stage Certainly all early stage patients by CT should have upfront CT PET No evidence for use of routine interval CT PET outside context of clinical trial. May be

of value if considering stopping systemic chemotherapy early and considering other treatment options e.g. DXT

CT PET should be performed in all patients at end of planned therapy to see that PET negative CR has been reached

Radiotherapy should be tailored on basis of PET positivity rather than historical bulk criteria i.e. > 10 cm.

FCC NHL

Should consider CT PET up front to stage especially clinical stage 1A where considering involved site DXT

Tailor DXT to sites of residual “disease” on basis of CT PET positivity

Other Haematological Malignancies Where CT PET may be useful:

1. Some cases of peripheral T-cell NHL (NOS)2. Occasional case of multiple extramedullary plasmacytomas or myeloma with

predominantly bony disease 3. Langerhans cell histiocytosis with bony disease

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Early stage limited disease (1A, IIA, non-bulky). Apply GHSG criteria

Early stage favourableABVD x 2 plus involved site DXT (20 Gy)

Early stage unfavourableABVD x 4 plus involved site DXT (30 Gy)

CT PET following DXT

If DXT contraindicatedDo CT PET following ABVD x 2.If PET neg 2 more A(B)VD and stop

Advanced stage disease IIB, III, IV

If PET negative continue to ABVD x6

IF PET positive switch to esc BEACOPP x 4

ABVD X 2Then repeat CT PET at week 3 of cycle 2

CT PET 3 at end of treatment. DXT to any single areas of PET positivity

CT PET 3 at end of treatment. DXT to any single

Management of Hodgkin’s Lymphoma

BCSH Guidelines: Classical Hodgkin’s lymphoma, first line - 2014 Management of Classical Hodgkin’s lymphoma, relapsed and refractory -

2013 Management of nodular lymphocyte predominant Hodgkin’s lymphoma- in

progress

All patients need to have therapy discussed and documented at an appropriately convened MDT. All patients with Hodgkin’s lymphoma should receive irradiated blood products to prevent transfusion-associated graft vs. host disease.Male patients should be offered semen cryopreservation where appropriate.

Induction Treatment Options

All patients should be offered an appropriate clinical study if available.See CT PET use guidance document

Classical Hodgkin’s Lymphoma

Early Stage as defined by GHSG criteria Favourable ABVD x 2 + 20 Gy IF radiotherapy Unfavourable ABVD x 4 + IF 30Gy Elderly consider ChLVPP +/- DXT or DXT alone

Advanced Stage ABVD x 2 the interim CT PET. IF interim CT Pet +ve change chemotherapy to

esc BEACOPP. Consider PET directed DXT to residual single PET positive areas at end of

chemotherapy Elderly consider ChLVPP or Gemcitabine based regimens

Nodular lymphocyte predominant Hodgkin’s lymphoma

Localised Local RT

Advanced Stage R-CVP

Relapsed/ refractory Disease Treatment Options

Suitable for Intensive Treatment GDP x 2 and assess response to chemotherapy. If chemo sensitive disease

or CT PET remission then mobilise PBSC and proceed to BEAM based PBSCT

Late relapse, consider different chemotherapy regimen to original, radiotherapy if relapse in previously untreated field, especially if first remission was very long.

Brentuximab - accessed via CDF. BV x 4 then assess response

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Treatment of relapsed or refractory Hodgkin’s lymphoma in patients who have failed at least two prior multi-agent chemotherapy regimens and are not transplant candidates

As a bridge to allograft transplant for the treatment of Hodgkin’s lymphoma where no other salvage treatment is available

Not suitable for intensive treatment options Localised disease - consider RT Advanced Stage - ChLVPP or Gemcitabine

Long-term Follow-up of Patients with Hodgkin’s Lymphoma

MammographyYoung patients are at a much-increased risk from breast cancer following mantle or other radiotherapy involving breast tissue. DxT should be avoided if at all possible in young women

All women aged <30 who receive mediastinal radiotherapy should receive screening starting 10 years after irradiation.All those >35 years at time of DxT will be enrolled into national breast screening programme at 45 years of age

Thyroid dysfunctionAnnual thyroid function testing is recommended in patients who have received radiotherapy to this area.

Stop smokingPatients should be strongly discouraged from smoking following therapy as there is an Increased incidence of lung cancer if have Hodgkin’s lymphoma and smoke; this risk normalises if they are non-smokers.

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Regimens for Hodgkin’s Lymphoma

ABVD Cycle frequency every 28 days for 3-6 cycles

Day 1 + 15 Doxorubicin 25mg/m2 IV Day 1 + 15 Bleomycin 10,000 units/m2 IV Day 1 + 15 Vinblastine 6mg/m2 IV (max 10mg) Day 1 + 15 Dacarbazine 375mg/m2 IV

Pulmonary function tests may be performed pre-treatment and during treatment at set frequencies e.g. alternate cycles

ChLVPP Cycle frequency every 28 daysDay 1-14 Procarbazine 100mg/m2 PODay 1-14 Chlorambucil 6mg/m2 (max. 10mg) PODay 1-14 Prednisolone 40mg/m2 PODay 1+8 Vinblastine 6mg/m2 (max. 10mg)

Gemcitabine can be given every 14 daysGemcitabine 1000mg/m2 IV

BrentuximabDay1 1.8 mg/kg IVI over 30 minutes every 21 days

GDPDay 1 Gemcitabine 1000mg/m2 IV every 21 days Day 1 Cisplatin 75mg/m2 IVDay 1-4 Dexamethasone 40mg PODay 8 Gemcitabine 1000mg/m2 IV

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Management of Non-Hodgkin’s Lymphoma

BCSH Guidelines: Investigation and management of mantle cell lymphoma 2012 Diagnosis and management of hairy cell leukaemia 2012 Investigation and management of follicular lymphoma 2011 Management of mature T cell and NK cell neoplasms 2013 Management of cutaneous T cell lymphomas- 2013 Waldenstrom’s macroglobulinaemia- 2014 CNS prophylaxis in NHL- 2013 Diffuse large B cell lymphoma- in progress Diagnosis of post-transplant lymphoproliferative disorder in solid organ

transplant recipients – BCSH and BTS Guidelines 2012 Best Practice in Lymphoma Diagnosis and Reporting 2010 Best Practice in Lymphoma Diagnosis and Reporting Specific disease

appendix 2010

Any patients receiving purine analogues (Fludarabine, Cladribine, and Deoxycorfomycin) required irradiated blood products for life.

Aggressive lymphomas- common subtypes

Diffuse Large cell B NHL

First line Treatment Trial REMoDL B, INCA Stage I disease; R-CHOP x 3-4 + IFRT or R-CHOP x 6 depending on site of

disease R-CHOP x 6 and consider IFRT to bulk disease (if no significant disease post

chemotherapy – radiological CR – role of RT not clear cut- guided by CT PET)

Unfit for anthracycline –RGCVP PMBL, high risk double hit Burkitts/ Burkitt like lymphoma DA EPOCH-R

Central Nevous system chemo prophylaxis in Diffuse large B cell NHLRisk of CNS disease is generally considered to be dependent on site of primary disease. However the following sites are considered at particular risk and should receive intrathecal prophylaxis.

Primary testicular DLBCL Primary breast DLBCL DLBCL involving epidural space

In addition the risk of CNS disease is dependent on factors encompassed within the IPI score – particularly the number of extra nodal sites of disease (2 or more), and an elevated LDH. Therefore patients with:

2 or more sites of Extranodal disease and

Elevated LDH are also considered at risk of CNS disease.

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Patients should have:At least 3 intrathecal injections of methotrexate 12.5 mg (normally with cycles 2, 3 and 4 of systemic chemotherapy)Testicular DLBC should have at least 4 intrathecal injectionsIf renal function and performance score allows, consideration should be given to high dose (3.5 g/m2) systemic methotrexate with folinic acid rescue in patients with testicular DLBC and consideration should also be given to primary DLBCL breast that appear to have a higher rate of parenchymal CNS disease. Current Torbay practice would be to give this at the end of first line chemotherapy – for 2 cycles at 15 day intervals.

If DA EPOCHR is considered for high risk DLBCL (cmyc +ve, double hit etc) and high risk Burkitt’s lymphoma intrathecal methotrexate on days 1 and 5 of cycles 3-6 is suggested (Dunleavy ASH 2014)CNS directed therapy is not delivered to patients over the age of 80 years in some centres.

Relapse

Suitable for Intensive Treatment RGDP is more commonly used than RDHAP BEAM based PBSCT Not suitable for Intensive Treatment

No standard treatment e.g. RGCVP

Peripheral T cell lymphoma and anaplastic CD30+ T cell NHL CHOP x 6-8 Trial- chemo T Consider HD Rx for first CR in young/fit Brentuximab anaplastic lymphoma only via national CDF cohort application

Primary Cerebral Lymphoma A regimen containing high dose methotrexate At least 3.5g/m2 MTX ideally given every 2 weeks for 4 cycles If radiological CR post chemotherapy no RT if residual disease or progression

for RT

Lymphoblastic lymphoma

ALL-like protocol Nelarabine refractory T cell disease as bridge to BMT- at present via national

CDf cohort application

Burkitt’s and Burkitt’s-like Lymphoma

First line Treatment optionsDA EPOCH-R, (R-CODOX-M IVAC) or CHOP-R like regimen

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Follow-up

Patients, when in remission, are followed up 3/12ly in year 1, 4/12ly in year 2, 6/12ly in year 3 and then annually. Patients with diffuse large B cell NHL who have remained in remission may be discharged at 5 years with the appropriate letter. Recent evidence has shown that elderly patients who enter and stay in a complete remission after first course of chemotherapy have the same OS as their peer group at 2 years post chemotherapy; this group of patients can be discharged at 3 years unless in a clinical trial. Patients are encouraged to telephone for an earlier appointment if they develop lymphadenopathy or other related symptoms.

Indolent Lymphomas

Early stage diseasePatients with stage I and II diseases have high rates of long-term disease free

survival when treated with radiotherapy alone.

Advanced stage diseaseMany of these patients will not require immediate treatment, as early

treatment has no effect on overall survival.

Patients when in remission are followed up 3-12/12ly depending on duration from treatment. They are encouraged to telephone for an earlier appointment if they develop lymphadenopathy or other related symptoms.

Treatment Options for common subtypes of indolent lymphoma

Follicle centre cell lymphoma

First line treatment Watch and Wait Stage IA/IIA – localised RT Appropriate regimens would include

R –Bendamustine- via CDFR-CVP R-CHOPR-Chlorambucil – elderly/frail

Followed by R maintenance 2 monthly for 2 years

At relapse and subsequent relapses Re-biopsy to exclude transformation and re-stage Watch and wait Young and fit consider an autologous transplant procedure after salvage with

RGDP In young patients with biologically aggressive disease and an available donor

consider an allogeneic BMT. R-Bendamustine – at present via national cohort CDF application RCVP, FCR R-Chlorambucil R maintenance if not received as part of up front treatment Rituximab as a single agent when exhausted chemotherapy

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Lymphoplasmacytic Lymphoma/ Waldenstrom’s macroglobulinaemia/SLVL First line Treatment options

Watch and |Wait R2W trial R-bendamustine (CDF) R-CVP R-chlorambucil

Relapsed/ refractory Disease Watch and wait RCVP R-chemo if not received R as part of first line regimen R-Bendamustine – at present via national cohort CDF application

Hairy cell Leukaemia

First line treatment Watch and wait Cladribine

Relapsed / refractory disease Watch and wait R-Cladribine/ DCF Splenectomy

Marginal zone lymphomas

First line treatment options Watch and wait R chemo R maintenance in those who have responded to first line therapy R bendamustine RCVP R-chlorambucil

Relapsed treatment options Watch and wait R chemo in those who have not previously received chemotherapy Bendamustine

Of the stomach Watch and wait Eradication therapy and re-biopsy at 3 months R-Chlorambucil R- bendamustine R-CVP Repeat endoscopy/ endoscopic ultrasound monitoring 6 monthly for 2 years

and then annually for 5 years.

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For MALT lymphomas which have transformed to a more aggressive grade- as per DLBCL

Mantle Cell Lymphoma

First Line Treatment options Watch and wait particularly for patients presenting with a lymphocytosis and

patients with low volume disease and asymptomatic irrespective of age. R bendamustine RCVP or FCR R-Chlorambucil for elderly patients In young patients (under 40yrs) strong consideration should be given to a low

intensity allograft in first remission (PR or CR) For these patients a more intensive initial therapy would be indicated e.g. Nordic protocol

R maintenance in those who have responded to first line therapy R Bendamustine- at present via national CDF cohort application

Relapsed Disease Watch and wait (same criteria as for first line therapy) ibrutinib Intensive treatments as per DLCB NHL Other Rchemo e.g. FCR Thalidomide CHOP v CHOP + Velcade NCRN trial Bendamustine- at present via national CDF cohort application

Phase II trials available in Plymouth for most relapsed patients. Currently open trials and inclusion/exclusion criteria available via research sisters.

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Examples of Regimens for NHL

R Chlorambucil Day 1-7 Chlorambucil 10mg/m2 PO every 28 daysDay 1 Rituximab 375mg/m2 IV

R bendamustine every 28 days Day 1 Rituximab 375mg/m2 IV

Day 1 +2 Bendamustine 90mg/m2 IV

RCVP every 21 daysDay1 Rituximab 375mg/m2 IVDay1 Cyclophosphamide 750mg/m2 IVDay1 Vincristine 1.4mg/m2 (max 2mg) IVDay 1-5 Prednisolone 100mg PO

FCR usually every 28 days Day1 Rituximab 375mg/m2 IVDay 1-3 Fludarabine 40mg/m2 PODay 1-3 Cyclophosphamide 250mg/m2 PO

RCHOP usually every 21 daysDay 1 Cyclophosphamide 750mg/m2 IVDay 1 Doxorubicin 50mg/m2 IVDay 1 Vincristine 1.4mg/m2 (max 2mg) IVDay 1-5 Prednisolone 100mg PODay 1 Rituximab 375mg/m2 IV

RGCVP every 21 daysDay1 Rituximab 375mg/m2 IVDays 1,8 Gemcitabine 1000mg/m2 IVDay1 Cyclophosphamide 750mg/m2 IVDay1 Vincristine 1.4mg/m2 (max 2mg) IVDay 1-5 Prednisolone 100mg PO

GDPDay 1 Gemcitabine 1000mg/m2 IV every 21 days Day 1 Cisplatin 75mg/m2 IVDay 1-4 Dexamethasone 40mg PODay 8 Gemcitabine 1000mg/m2 IV

Cladribine usually once, but can be given subsequently if patient relapsesDay 1-5 Cladribine 0.14mg/kg/d or can be given weekly

Rituximab usually weekly x 4Rituximab 375mg/m2 IV

Brentuximab Day1 1.8 mg/kg Brentuximab IVI over 30 minutes every 21 days

Ibrutinib560mg od orally

NelarabineDays 1,3,5 nelarabine 1,500 mg/m2 IV every 21 days.

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DA EPOCH-R every 21 daysDay 1 Rituximab 375mg/m2 IV

Day 1-4 Etoposide 50mg/m2/d Day 1-4 Vincristine 0.4mg/m2/d (no cap) all infused in 500ml Nsaline over 24hrs Day 1-4 Doxorubicin 10mg/m2/d Day 5 Cyclophosphamide 750mg/m2 over 2 hrs Day 6 Lenograstim 263mcg sc daily until count recovery

Give on day 1 if N>1.0 and plts >75 for up to 6 cycles, patients are encouraged to administer their own GCSF and attend for FBC M,W F with a formal review on one day

Dose escalations are required for each cycle and drugs individually see chemotherapy script

RDHAP

Day1 Rituximab 375mg/m2 IVDay 1 Cisplatin 100mg/m2 IV as 24 hr infusionDay 1-4 Dexamethasone 40mg PO or IVDay 2 Cytarabine 2g/m2 IV bd as a 3 hr infusion

Patients require 0.5% Prednisolone eye dropsIf collecting peripheral blood stem cells start G-CSF from day 5

RIVEDay1 Rituximab 375mg/m2 IVDay 1 Epirubicin 50mg/m2 IVDay 1-3 Etoposide 200mg/m2 IV as 2 h infusionDay 1 Mesna 1.8g/m2 IV bolusDay 1-3 Ifosfamide 3g/m2 IV as 22 hr infusionDay 1-3 Mesna 3g/m2 IV as 22 hr infusionDay 4 Mesna 5.4g/m2 IV 12 hr infusion

Patients require phenytoin 300mg nocte day-1 to day +5 to protect against the potential toxic effects of Ifosfamide.

If collecting peripheral blood stem cells start G-CSF day 5

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MULTIPLE MYELOMA Investigational and Clinical Management Guidelines

13 2H- 105 and 108

BCSH Guidelines- Diagnosis and management of multiple myeloma 2014 Al amyloidosis- 2014 UK Myeloma Forum (UKMF) and Nordic Myeloma Study

Group(NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS) 2012

Draft national chemotherapy algorithm –multiple myeloma 2015

Suggested Baseline InvestigationsFBC, viscosityU+Es, LFTs, Ca2+

Igs and serum protein electrophoresis, serum free light chains, b2microglobulin

Urine Bence Jones protein. If positive 24 hr quantitationSkeletal survey/ MRI scan if suspect cord compression/ plasmacytomaBone marrow aspirate and trephine

Staging systems

Criteria for Distinguishing MGUS from Myeloma

Myeloma MGUSBone marrow (aspirate) plasma cell % >10% < 10%

Serum paraproteinVariable concentration in

serum; no specific diagnostic levels

IgG usually < 20 g/lIgA usually < 10 g/l

BJP > 50% cases RareImmune paresis > 95% cases RareLytic bone lesions Often present AbsentSymptoms Frequent Absent or otherwise explainedAnaemia Frequent Absent or otherwise explainedHypercalcaemia May be present Absent or otherwise explainedAbnormal renal function May be present Absent or otherwise explained

Factors at Diagnosis of MGUS, Predictive For Risk of Progression

IgA Paraprotein > 10 g/lIgG Paraprotein > 20 g/l

ESR > 40BJP Present

Serum Free Light Chains RaisedNormal globulins Two reduced

ISS score

B2m <3.0mg/l and albumin >35g/l 1

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Neither 2B2m >5.5mg/l 3

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Newly diagnosed and Suitable for Intensive Treatment Options CTD or similar followed by melphalan-based PBSCT Myeloma XI Bortezomib- due to presentation with a) advanced renal failure

contraindicating standard therapy (dialysis either current or imminent) or b) multisystem amyloidosis (on amyloid centre review)

Newly diagnosed and not suitable for intensive treatment Options Watch and wait Myeloma XI CTDa to plateau Bortezomib containing regimens- patients for who transplant is considered

unsuitable

Subsequent chemotherapy treatments Options Bortezomib sc with dexamethasone, bi-weekly or weekly +/-

cyclophosphamide, for 2nd and subsequent relapse needs to be accessed via national cancer CDF cohort application at present

Lenalidomide dexamethasone –third line; second line patients at present, require national CDF cohort application

Bendamustine - at present via national CDF cohort application Re treat with induction chemotherapy if long duration of remission e.g. CTD Second autologous stem cell procedure Allograft

Supportive careConsider PCP prophylaxis for patients treated with dexamethasone-based regimens

Consider anti-thrombotic prophylaxis for patients treated with thalidomide or lenalidomide,

Zoledronate monthly for 2 yearsConsider dental check prior to commencement and stop bisphosphonate (particularly zoledronate prior to dental work) to prevent osteonecrosis of jaw.

Radiotherapy to painful lytic lesions- refer to appropriate oncologistSpinal cord compression refer to on call oncologist, consider discussing patient with spinal team at RDE/Plymouth

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Myeloma Regimens (examples)

CTD Cycle to be repeated every 3/52 for 4-6 cycles

D1, 8, 15 Cyclophosphamide 500mg po dailyD1-21 Thalidomide 50mg D1-4 and 12-15 Dexamethasone 40mg daily

CTDa Repeated every 4/52 to max. response 6-9 cyclesD1, 8, 15, 22 Cyclophosphamide 500mg/dD1-28 Thalidomide 50mg D1-4 & 15-18 Dexamethasone 20mg/d

C Weekly Repeated every week until plateauCyclophosphamide 500mg/m2 po (reduce to 200mg/m2 if creatinine>300)

Bortezomib 1.3mg/m2 of Bortezomib sc Days 1, 4, 8, 11 given every 21 days or weekly on days 1, 8, 15 of 28 day cycleDexamethasone day of and following bortezomib

Bendamustine every 28 days Bendamustine 100-120mg/m2 IV days 1 and 2

Lenalidomide every 28 days on-going until disease progression or intoleranceLenalidomide 25mg D1-21

Dexamethasone D1-4,9-12,17-20 ( cycles 1-4 only) then for all subsequent cycles Dexamethasone D1-4 only

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CHRONIC LYMPHOCYTIC LEUKAEMIA- CLL Investigational and Clinical Management Guidelines 13 2H- 105 and 107

BCSH Guidelines Investigation and management of CLL 2012

Suggested Investigations

FBC, Immunophenotyping- processed at Plymouth, reported locally : DATU+Es, LFTs, IgsHepatitis BsAg, cAb, hep C and HIVBone marrow aspirate and trephine, if cytopenias/ commencing treatmentConsider cytogenetics IgH gene rearrangements and 19p in selected patients, consider re- checking p53 status prior to treatment courses- BristolImaging –CT TAP

Staging

RAI

Stage Clinical features

0 Lymphocytosis onlyBlood > 14.9 x 109/L, Marrow > 39%

1 Lymphocytosis and lymphadenopathy2 Splenomegaly and/or Hepatomegaly3 Anaemia < 11g/100ml (not immune)4 Thrombocytopenia < 100 x 109/L (not immune)

BINET

Stage Clinical features

I No anaemia, thrombocytopenia. < 3 involved lymph nodes

II No anaemia, thrombocytopenia. > 2 involved lymph nodes

III Anaemia < 10 g/100ml and/or thrombocytopenia < 100 x 109/L (not immune)

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First Line Treatment Options

Watch and Wait FCR Trial- RIALTO Bendamustine R Ofatumumab with chlorambucil for patients in patients who are unsuitable for

fludarabine based therapy R-Chlorambucil to maximal response in those unable to tolerate FCR or R

Bendamustine alemtuzumab- first line patients p53 deleted

Subsequent Treatment Options

Risk adjusted depending on age duration of remission etc Watch and Wait Trial- COSMIC R-Chlorambucil if patient achieved adequate response previously FCR R Bendamustine in whom Fludarabine is not an option- at present via national

CDF cohort application Idelalisib or ibrutinib with rituximab(but not both) at relapse –via CDF Alemtuzumab- second line patients p53 deleted if not received previously Allogeneic transplant

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CLL Treatment Regimens (examples)

R Chlorambucil every 28/7 to maximum responseRituximab 375mg/m2 IV for first cycle escalating to 500mg/m2 for subsequent cycles Chlorambucil 10mg/m2 PO daily 7/7

FCR every 28/7 maximum 6 cycles Rituximab 375mg/m2 IV for first cycle escalating to 500mg/m2 for subsequent cycles Fludarabine 24mg/m2 PO daily 5/7 and Cyclophosphamide 150mg/m2 daily 5/7

Bendamustine every 28 days Bendamustine 100mg/m2 IV days 1 and 2 as single agent first line treatment R-Bendamustine 90mg/m2 IV days 1 and 2 (this is reduced to 70mg/m2 for relapsed disease)

Alemtuzumab1st week dose escalation 3mg, 10mg, 30 mg then 30mg three times a week for 12 weeks, given either IV or SC.This regimen require appropriate monitoring for atypical infections esp CMV

Ofatumumab300 mg Ofatumumab IV day1 and 2,000 mg ofatumumab for all subsequent infusions. The infusion schedule is 8 consecutive weekly infusions, followed 4-5 weeks later by 4 consecutive monthly (i.e. every 4 weeks) infusions.

Idelalisib150mg bd orally

Ibrutinib420mg od orally

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CHRONIC MYELOID LEUKAEMIA Investigational and Clinical

Management Guidelines13 2H- 105 and 106

BCSH guidelinesGuidelines for the measurement of BCR-ABL1 transcripts in chronic myeloid leukaemia 2011

Suggested Investigations

FBC, U+Es, LFTsG+SHLA type patient and siblings if may be suitable for transplant optionsBone marrow aspirate and trephine,

Conventional cytogenetics and FISH for BCR-ABL- BristolMolecular genetics quantitative PCR for BCR-ABL-Plymouth.( mutation analysis – Kings, London)

Treatment OptionsTrial – As national trial becomes available, SPIRIT 3 currently awaited.First line – Imatinib 400 mg / day OR Nilotinib 300mg bd

Assess response according to ELN criteriaFailure - Dasatinib 100mg / day or Nilotinib 400mg bd depending on initial treatment and mutation analysis.Sub-optimal response – treat as failure or opt to continue first line therapy for further period.Allogeneic bone marrow transplant may be an option for some treatment failuresBosutinib or Ponatinib may be needed in selected cases (eg Ponatinib in T315I mutated cases)

Monitoring

Bone marrow cytogenetics 6/12ly until achieved CCyR. Annual marrow considered standard although may be inappropriate for some patients with good response.BCR-ABL 3 monthly. If achieve MMR (<0.1) or CMR 6 monthly monitoring can be considered.

ELN response criteria (abbreviated);Treatment failure: No HR at 3 months, no MCyR at 12 months, no CCyR at 18 monthsSuboptimal response: No CHR at 3 months, no CCyR at 12 months, no MMR at 18 months. Failure to achieve <10% MR at 3 months currently under evaluation.

For failure, suboptimal response or loss of response, check mutation analysis to guide further therapy.

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ACUTE MYELOID LEUKAEMIA- AML Investigational and Clinical Management Guidelines 13 2H- 105 and 106

WHO Classification AMLAcute Myeloid Leukaemia with Recurrent Cytogenetic Abnormalities

AML with t(8,21)(q22,q22) (AML1/ETO)AML with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16,16)(p13,q22); (CBFb/MYH11)Acute promyelocytic leukaemia- t(15,17)(q22,q12) (PML/RARa) and variantsAML with 11q23 (MLL) abnormalities

Acute Myeloid Leukaemia with multilineage dysplasiaFollowing a myelodysplastic syndrome (MDS) or MDS/myeloproliferative disorderWithout antecedent MDSAcute Myeloid Leukaemia and Myelodysplastic Syndromes, therapy-related

Alkylating agent-relatedTopoisomerase type II inhibitor-related (some may be lymphoid)Other types

Acute Myeloid Leukaemia not otherwise categorisedAcute Myeloid Leukaemia minimally differentiatedAcute Myeloid Leukaemia without maturationAcute Myeloid Leukaemia with maturationAcute Myelomonocytic LeukaemiaAcute Monocytic and Monoblastic leukaemiaAcute Megaloblastic LeukaemiaAcute Basophilic LeukaemiaAcute panmyelosis with MyelofibrosisMyeloid sarcoma

Suggested Investigations

FBC, coagulation screenU+Es, LFTsG+S

Bone marrow aspirate- reported locallyConventional cytogenetics/ FISH- BristolImmunophenotyping- PlymouthMolecular genetics –Plymouth

Remember to think about study enrolment before marrow if diagnosis certain, as extra samples are required.

HLA typing if transplant procedure possibleSemen cryopreservation- if appropriate

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First Line Treatment- intensive options AML 18 or 19 (when open) DA3+10, DA3+8 followed by 2 cycles high dose Ara-C Gemtuzumab- CBF AML first line who are not in trial –at present via iCDF

application

First Line Treatment- non-intensive options low dose subcutaneous Ara-C Azacitidine Hydroxycarbamide

Blood product supportive care

Relapsed disease Re-induce with FLAG+/- Ida and search for sibling/ unrelated donor. Clofarabine as a bridge to transplant procedure- at present via national CDF

cohort application Arsenic trioxide- relapsed refractory APL- Palliative options e.g.

Hydroxycarbamide Supportive care

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ACUTE LYMPHOID LEUKAEMIA- ALL Investigational and Clinical Management Guidelines 13 2H- 105 and 106

Suggested Investigations

FBC, coagulation screenU+Es, LFTsG+S

Bone marrow aspirate- reported locallyConventional cytogenetics/ FISH- BristolImmunophenotyping- PlymouthMolecular genetics –Plymouth

Remember to think about study enrolment before marrow if diagnosis certain, as extra samples are required.

HLA typing if transplant procedure possibleSemen cryopreservation- if appropriate

First Line Treatment options

<60 UKALL14 or similar with allograft if sibling donorTYA trial Brightlight

>60 UKALL60+ Vincristine and prednisolone

Relapsed Treatment Options

If suitable for intensive treatment FLAG-Ida and consider transplant

If not, consider palliative re-induction with Vincristine and Prednisolone and maintenance methotrexate/ mercaptopurine.

Nelarabine- at present via national CDF cohort application for refractory T-ALL as a bridge to a transplant procedure

Clofarabine- relapsed refractory disease as a brdge to transplant procedure- at present via national CDF cohort application

Dasatinib- Ph+ ALL or lymphoid blast crisis of CML with resistance or intolerance to imatinib, at present via national CDF cohort application

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MYELODYSPLASIA Investigational and Clinical Management Guidelines13 2H- 105 and 106

BCSH Guidelines- diagnosis and management of adult myelodysplasia 2013

Disease Blood findings Marrow findings

RA AnaemiaNo or rare blasts

Erythroid dysplasia only, <5% blasts, <15% ringed sideroblasts

RARS Anaemia, no or rare blasts Erythroid dysplasia only, < 5% blasts, >15% ringed sideroblasts

RCMD-RS >1 cytopenia, no or rare blasts, no Auer rods, <1x109 monocytes

Dysplasia in ³10% marrow cells in two or more myeloid lines, <5% blasts, >15% ringed sideroblasts

RCMD* >1 cytopenia, no or rare blasts, no Auer rods, <1x109 monocytes

Dysplasia in ³10% marrow cells in two or more myeloid lines, <5% blasts, >15% ringed sideroblasts

RAEB-1 Cytopenias, < 5% blasts, no Auer rods, <1x109 monocytes

Unilineage or multilineage dysplasia, 5-9% blasts, no Auer rods

RAEB-2 Cytopenias, 5-9% blasts, Auer rods or none, <1x109 monocytes

Unilineage or multilineage dysplasia, 10-19% blasts, Auer rods or none

**MDS-U Cytopenias, no or rare blasts, no Auer rods

Dysplasia in ³10% marrow cells in one myeloid line, <5% blasts, no Auer rods

MDS with isolated 5q-

Anaemia, Usually normal or increased platelet count, < 5% blasts, no Auer rods

Normal to increased MGK with hypolobate nuclei, <5% blasts, isolated 5q-, no Auer rods

*Refractory cytopenia with multilineage dysplasia, ** MDS-unclassifiable,

Suggested Baseline InvestigationsFBC +filmU+Es, LFTsHaematinicsG+SBone marrow aspirate- reported locally

Conventional cytogenetics/ FISH- BristolImmunophenotyping- Plymouth

Erythropoietin level

International Prognostic Scoring system

0 0.5 1 1.5 2BM blast

percentage <5 5-10 11-20

21-30

Karyotype Good Intermediate Poor

Cytopenias 0/1 2/3

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Treatment Options

Transfusion support to maintain Hb below that causing symptoms Trial of erythropoietin if epo level <200U/l (RA/RAEB) <500U/l (RARS) Routine platelet transfusion not routinely recommended for thrombocytopenia

patients- consider tranexamic acid Azacitidine-( NICE approved for IPSS int 2 or worse; CMML with 20-29% blasts, AML

20-30% with trilineage dysplasia) Consider transplant options for young/ fit patients

CMMLCytoreduction with Hydroxycarbamide as required

5q- SyndromeConsider lenalidomide

Management of infectionProphylacticRoutinely no evidence for prophylaxisConsideration to use of prophylactic low dose GCSF in severely neutropenic patients to maintain N>1x109/lTherapeuticNeutropenic sepsis should be treated as per local policy with intravenous antibiotics

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MYELOPROLIFERATIVE DISORDERS Investigational and Clinical Management Guidelines 13 2H- 105 and 107

BCSH Guidelines Diagnosis and management of myelofibrosis 2012 Amendment to diagnosis and management of polycythaemia 2007 (original guideline

2005) Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the

detection of JAK2 V617F and other relevant mutations 2012 Thrombocytosis and thrombocythaemia 2013

InvestigationsFBC, filmerythropoietinMolecular – thrombocytosis- bcr-abl ,JAK2, CALR, exon 10- Plymouth

- Raised haematocrit- JAK2- Plymouth, exon 12- Kings, LondonBone marrow aspirate and trephine- reported locallyConventional cytogenetics/ FISH- Bristol

Polycythaemia Vera

Diagnostic Criteria

JAK2 positive polycythaemiaA1 High haematocrit (>0.52 in men and >0.48 in women)A2 Mutation in JAK2Diagnosis requires both criteria to be present

JAK2 negative polycythaemiaA1 raised RCM (>25% above predicted) OR Haematocrit >0.60 in men and 0.56 in

women A2 absence of mutation in JAK2A3 no secondary causeA4 palpable splenomegalyA5 presence of an acquired genetic abnormality (excluding bcr-abl)

B1 thrombocytosis (>450x 109/l)B2 neutrophilia (>10x109/l in non-smokers and >12.5x109/l in smokers)B3 radiological evidence of splenomegalyB4 endogenous erythroid colonies or low serum erythropoietinDiagnosis requires A1+A2+A3+ either another A or two B criteria

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Management of PV

Venesect to maintain Hct<0.45 Aspirin 75mg daily Cytoreduction should be considered if

-Poor tolerance to venesection-Symptomatic/ progressive splenomegaly-Other evidence of disease progression e.g. weight loss/ night sweats

Choice of cytoreductive agent < 40 years- 1st line- Interferon

2nd line- Hydroxycarbamide or anagrelide40-75 years- 1st line- Hydroxycarbamide

2nd line- Interferon or anagrelide>75 years 1st line- Hydroxycarbamide

2nd line- 32P or intermittent busulphan

Management of Apparent Erythrocytosis (³2 measurements of Hct³3/12 apart)

Reduce/ eliminate risk factors- smoking/ alcohol/hypertension (avoid thiazide diuretics)Consider venesection in the following

Recent history of thrombosis, or with additional risk factor for thrombosisHct>0.54 (based on risk of thrombosis in idiopathic erythrocytosis)

Untreated patients should be monitored to exclude further in Hct.

There is no data on which to target Hct for those undergoing venesection – (suggests <0.45)

Management of Idiopathic Erythrocytosis- (RCM but no primary or secondary cause found)

Venesect to reduce Hct <0.45 if Hct is >0.54Venesect to reduce Hct <0.45 if <0.54 and there is increased risk for thrombosis

PMH thrombosis, peripheral vascular disease, diabetes, hypertension

Cytoreductive therapy is contra-indicated

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ESSENTIAL THROMBOCYTHAEMIA

WHO Classification Thrombocytosis ³ 460 x 109/l Bone marrow biopsy showing proliferation mainly of megakaryocytic lineage with increased numbers of enlarged mature megakaryocytes + Criteria of exclusion

No Polycythaemia Vera (Normal red cell mass or Hb < 18.5 men, 16.5 women)Stainable iron in marrow, normal Ferritin, normal MCVNo CML (Philadelphia and BCR/Abl negative)No evidence of IMFNo Collagen fibrosis, reticulin fibrosis minimal or absentNo evidence of MDSCytogenetics: no 5q-, t (3; 3) (q21; q26), inv (3) (q21; q26)No significant granulocyte dysplasia, few if any micromegakaryocytesNo evidence that the thrombocytosis is reactive due to:No underlying inflammation, infection or neoplasmPrior splenectomy

MANAGEMENT Risk assessment adapted from PT1 trial

Low RiskALL of the following features

Intermediate RiskALL of the following features

High RiskANY of the following

featuresAge <40 years Age 40-59 years Age 60 years

Platelet count 600 but which has never been consistently

> 1000 x 109/l

Platelet count 600 but which has never been consistently >

1500 x 109/l

Platelet count 1500 x 109/l (current or

previous)

No history of ischaemia, thrombosis or embolic

features or erythromelalgia

No history of ischaemia, thrombosis or embolic features

or erythromelalgia

History of ischaemia, thrombosis or embolic

events (including erythromelalgia)

Absence of haemorrhage considered to be related to

PT

Absence of haemorrhage considered to be related to PT

Haemorrhage considered to be

related to PT

Absence of hypertension needing Rx, non-smoker

Absence of hypertension needing Rx, non smoker

Presence of hypertension needing

Rx or smokingAbsence of diabetes needing

RxAbsence of diabetes needing

RxPresence of diabetes

needing Rx

Low and Intermediate RiskMRC PT1 trial Note changes in risk group definition above (platelets > 1500 define high Aspirin 75 mg

High Risk no trial available. Aspirin 75 mg for all patients once platelet count below 1000 x 109/lHydroxycarbamideAlternatives for those who cannot receive Hydroxycarbamide

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Interferon: “young” if able to tolerate.Pregnancy ® InterferonBusulfan 32PAnagrelide

IDIOPATHIC MYELOFIBROSIS

FBC and film examination, U+E, LFT, Bone profile, Urate, CRP, Ferritin Bone marrow aspirate and trephine- reported locallyConventional cytogenetics/ FISH (if appropriate)- BristolMolecular genetics bcr-abl –Plymouth

Diagnostic criteria for primary myelofibrosis: diagnosis requires A1 + A2 and any two B criteria.

A1 Bone marrow fibrosis _3 (on 0–4 scale).A2 Pathogenetic mutation (e.g. in JAK2 or MPL),or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis

B1 Palpable splenomegalyB2 Unexplained anaemiaB3 Leuco-erthroblastosisB4 Tear-drop red cellsB5 Constitutional symptoms (Drenching night sweats, weight loss >10% over 6 months, unexplained fever (>37·5°C) or diffuse bone pains)B6 Histological evidence of Extramedullary haematopoiesis

.

Management

Hydroxycarbamide Ruxolitinib- for first or 2nd line treatment of symptomatic splenomegaly –at present

via national CDF cohort application Busulfan, Interferon or splenectomy (in carefully selected cases) as alternatives Allogeneic transplantation for young (discuss with transplant centre) Transfusional support or erythropoietin

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