Clinical Haematological Malignancy Guidelines
2015
Peer review measures 13-2H-106-108,110
May 2015
1
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
2
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:
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


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/
3
LYMPHOMAS
WHO CLASSIFICATION
B-CELL NEOPLASMS
T-CELL AND NK-CELL NEOPLASMS
Pre-cursor B-cell neoplasm
Precursor B lymphoblastic
lymphoma/leukaemia
Precursor T-cell neoplasms
Precursor T lymphoblastic
leukaemia/lymphoma
Blastic NK cell lymphoma
Mature B-cell neoplasms
Chronic Lymphocytic leukaemia/
Small Lymphocytic lymphoma
B-cell prolymphocytic leukaemia
Lymphoplasmacytic lymphoma
Splenic marginal zone lymphoma
Hairy cell leukaemia
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell
lymphoma of mucosaassociated lymphoid tissue
(MALT lymphoma)
Marginal zone B-cell lymphoma
Follicle centre cell lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell
lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukaemia
Mature T-cell and NK-cell neoplasms
T-cell prolymphocytic leukaemia
T-cell large granular lymphocytic leukaemia
Aggressive NK cell leukaemia
Adult T-cell lymphoma/leukaemia
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell
lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous anaplastic large cell
lymphoma
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic lymphoma
Anaplastic large cell lymphoma
T-cell proliferation of uncertain malignant
potential
Lymphoid papulosis
B-cell proliferations of uncertain
malignant potential
Lymphoid granulomatosis
Post-transplant lymphoproliferative
disorder, polymorphic
HODGKIN’S LYMPHOMA
Classical 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
4
WHO Performance score
0
1
2
3
4
No symptoms
Symptoms but ambulatory
Bedridden less than half the day
Bedridden half the day or longer
Chronically bedridden and requiring
Assistance with activities of daily living
Risk
International Prognostic Index for DLBCL
Risk Factor
Age (years)
Stage (Ann Arbour)
Number of extranodal sites
Performance Status (ECOG)
Serum LDH
Score 0
<60
I or II
0 or 1
0 or 1
Normal
Hasenclever Score for
CHL
Score
Age > 45yrs
Male gender
Albumin <40g/l
Hb <105g/l
Stage IV disease
WCC > 15x 109/l
WCC< 0.6x109/l
1
1
1
1
1
1
1
Score 1
>60
III or IV
>1
>1
Elevated
Low
Intermediate/ low
Intermediate/ high
High
Risk
Low
Intermediate
High
<3
3-4
>4
Early Stage- Favourable v.s. Unfavourable CHL (GHSG criteria)
Favourable
No bulk in mediastinum (<10cm)
ESR<50 with no B Sx
ESR <30 with B Sx
No extranodal disease
1-2 lymph node groups
Unfavourable (any 1 of below)
Bulk in mediastinum
ESR≥ 50 with no B Sx
ESR ≥ 30 with B Sx
Extranodal disease
≥3 lymph node groups
FLIPI score for Follicle Centre Cell Lymphoma
Score
Age
Stage
Hb
LDH
No of nodal areas
0
1
<60
≥60
<II
≥III
<11.9 12.0
N
>N
<4
≥5
Low
Intermediate
high
MIPI for mantle cell lymphoma
0
1
2
3
Age
<50
50-59
60-69
≥70
PS
0-1
n/a
2-4
n/a
LDH
<319
320-479
480-715
>716
WCC
<6.7
6.7-9.9
10-14.9
>15
5
0-1
2
3-5
0-1
2
3
4
Lymphoma Investigational and Clinical Management Guidelines
13 2H- 105 and 107
Investigations
FBC, viscosity, DAT
U+Es, LFTs, Ca2+, LDH, uric acid, 2microglobulin
Igs and serum protein electrophoresis
Hepatitis BsAg and cAb, hepatitis C and HIV
Bone marrow aspirate and trephine
Morphology-processed and reported locally
Immunophenotyping- processed Plymouth, reported locally
Molecular genetics- processed and reported Plymouth
Lymph node biopsy
Morphology-processed and reported locally, a proportion sent to Plymouth for dual
reporting or second opinion
Immunophenotyping- processed Plymouth, reported locally
Molecular genetics- processed and reported Plymouth
FISH- for double hit lymphomas – Guys and Thomas’ London
IgH gene rearrangement – Exeter
CT scan -Neck, Thorax, Abdomen and Pelvis
CT 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
Bleomycin
Semen cryopreservation where appropriate
6
Suggested Use of CT PET scanning in Lymphoma Outside a Clinical
Trial
All New Patients with Hodgkin’s Lymphoma
CT PET at diagnosis
Advanced stage disease
IIB, III, IV
Early stage limited
disease
(1A, IIA, non-bulky).
Apply GHSG criteria
ABVD X 2
Then repeat CT PET at week 3
of cycle 2
Early stage favourable
ABVD x 2 plus involved
site DXT (20 Gy)
Early stage
unfavourable
ABVD x 4 plus involved
site DXT (30 Gy)
CT PET following DXT
If DXT contraindicated
Do CT PET following
ABVD x 2.
If PET neg 2 more
A(B)VD and stop
If PET negative continue
to ABVD x6
IF PET positive switch to
esc BEACOPP x 4
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
DLBC NHL

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
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
predominantly bony disease
3. Langerhans cell histiocytosis with bony disease
plasmacytomas
or
myeloma
with
areas of PET positivity
7
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
 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
8

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
Mammography
Young 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 dysfunction
Annual thyroid function testing is recommended in patients who have received
radiotherapy to this area.
Stop smoking
Patients 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.
9
Regimens for Hodgkin’s Lymphoma
ABVD
Cycle frequency every 28 days for 3-6 cycles
Day 1 + 15
Day 1 + 15
Day 1 + 15
Day 1 + 15
Doxorubicin 25mg/m2 IV
Bleomycin 10,000 units/m2 IV
Vinblastine 6mg/m2 IV (max 10mg)
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 days
Day 1-14
Procarbazine 100mg/m2 PO
Day 1-14
Chlorambucil 6mg/m2 (max. 10mg) PO
Day 1-14
Prednisolone 40mg/m2 PO
Day 1+8
Vinblastine 6mg/m2 (max. 10mg)
Gemcitabine can be given every 14 days
Gemcitabine 1000mg/m2 IV
Brentuximab
Day1
1.8 mg/kg IVI over 30 minutes every 21 days
Day 1
Day 1
Day 1-4
Day 8
Gemcitabine 1000mg/m2 IV every 21 days
Cisplatin 75mg/m2 IV
Dexamethasone 40mg PO
Gemcitabine 1000mg/m2 IV
GDP
10
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 NHL
Risk 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.
11
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 injections
If 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 options
DA EPOCH-R, (R-CODOX-M IVAC) or CHOP-R like regimen
12
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 disease
Patients with stage I and II diseases have high rates of long-term disease free
survival when treated with radiotherapy alone.
Advanced stage disease
Many 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 CDF
R-CVP
R-CHOP
R-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
13
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.
14

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.
15
Examples of Regimens for NHL
R Chlorambucil
Day 1-7
Day 1
Chlorambucil 10mg/m2 PO every 28 days
Rituximab 375mg/m2 IV
R bendamustine
Day 1
Day 1 +2
every 28 days
Rituximab 375mg/m2 IV
Bendamustine 90mg/m2 IV
RCVP
Day1
Day1
Day1
Day 1-5
every 21 days
Rituximab 375mg/m2 IV
Cyclophosphamide 750mg/m2 IV
Vincristine 1.4mg/m2 (max 2mg) IV
Prednisolone 100mg PO
Day1
Day 1-3
Day 1-3
usually every 28 days
Rituximab 375mg/m2 IV
Fludarabine 40mg/m2 PO
Cyclophosphamide 250mg/m2 PO
RCHOP
Day 1
Day 1
Day 1
Day 1-5
Day 1
usually every 21 days
Cyclophosphamide 750mg/m2 IV
Doxorubicin 50mg/m2 IV
Vincristine 1.4mg/m2 (max 2mg) IV
Prednisolone 100mg PO
Rituximab 375mg/m2 IV
FCR
RGCVP
every 21 days
Day1
Rituximab 375mg/m2 IV
Days 1,8
Gemcitabine 1000mg/m2 IV
Day1
Cyclophosphamide 750mg/m2 IV
Day1
Vincristine 1.4mg/m2 (max 2mg) IV
Day 1-5
Prednisolone 100mg PO
GDP
Day 1
Day 1
Day 1-4
Day 8
Gemcitabine 1000mg/m2 IV every 21 days
Cisplatin 75mg/m2 IV
Dexamethasone 40mg PO
Gemcitabine 1000mg/m2 IV
Cladribine
usually once, but can be given subsequently if patient relapses
Day 1-5
Cladribine 0.14mg/kg/d or can be given weekly
Rituximab
usually weekly x 4
Rituximab 375mg/m2 IV
Brentuximab
Day1
1.8 mg/kg Brentuximab IVI over 30 minutes every 21 days
Ibrutinib
560mg od orally
Nelarabine
Days 1,3,5
nelarabine 1,500 mg/m2 IV every 21 days.
16
DA EPOCH-R every 21 days
Day 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
Day 1
Day 1-4
Day 2
Rituximab 375mg/m2 IV
Cisplatin 100mg/m2 IV as 24 hr infusion
Dexamethasone 40mg PO or IV
Cytarabine 2g/m2 IV bd as a 3 hr infusion
Patients require 0.5% Prednisolone eye drops
If collecting peripheral blood stem cells start G-CSF from day 5
RIVE
Day1
Day 1
Day 1-3
Day 1
Day 1-3
Day 1-3
Day 4
Rituximab 375mg/m2 IV
Epirubicin 50mg/m2 IV
Etoposide 200mg/m2 IV as 2 h infusion
Mesna 1.8g/m2 IV bolus
Ifosfamide 3g/m2 IV as 22 hr infusion
Mesna 3g/m2 IV as 22 hr infusion
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
17
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 Investigations
FBC, viscosity
U+Es, LFTs, Ca2+
Igs and serum protein electrophoresis, serum free light chains, 2microglobulin
Urine Bence Jones protein. If positive 24 hr quantitation
Skeletal survey/ MRI scan if suspect cord compression/ plasmacytoma
Bone marrow aspirate and trephine
Staging systems
Criteria for Distinguishing MGUS from Myeloma
Bone marrow (aspirate)
plasma cell %
Serum paraprotein
BJP
Immune paresis
Lytic bone lesions
Symptoms
Anaemia
Hypercalcaemia
Abnormal renal function
Myeloma
MGUS
>10%
< 10%
Variable concentration in
serum; no specific
diagnostic levels
> 50% cases
> 95% cases
Often present
Frequent
Frequent
May be present
May be present
IgG usually < 20 g/l
IgA usually < 10 g/l
Rare
Rare
Absent
Absent or otherwise explained
Absent or otherwise explained
Absent or otherwise explained
Absent or otherwise explained
Factors at Diagnosis of MGUS, Predictive For Risk of Progression
IgA Paraprotein
IgG Paraprotein
ESR
BJP
Serum Free Light Chains
Normal globulins
ISS score
B2m <3.0mg/l and albumin >35g/l
Neither
B2m >5.5mg/l
1
2
3
18
> 10 g/l
> 20 g/l
> 40
Present
Raised
Two reduced
Newly diagnosed and Suitable for Intensive Treatment Options
 CTD or similar followed by melphalan-based PBSCT
 Myeloma XI
 Bortezomibdue 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 care
Consider PCP prophylaxis for patients treated with dexamethasone-based
regimens
Consider anti-thrombotic prophylaxis for patients treated with thalidomide or
lenalidomide,
Zoledronate monthly for 2 years
Consider 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 oncologist
Spinal cord compression refer to on call oncologist, consider discussing patient
with spinal team at RDE/Plymouth
19
Myeloma Regimens (examples)
CTD
Cycle to be repeated every 3/52 for 4-6 cycles
D1, 8, 15
D1-21
D1-4 and 12-15
Cyclophosphamide 500mg po daily
Thalidomide 50mg
Dexamethasone 40mg daily
CTDa
Repeated every 4/52 to max. response 6-9 cycles
D1, 8, 15, 22
Cyclophosphamide 500mg/d
D1-28
Thalidomide 50mg
D1-4 & 15-18
Dexamethasone 20mg/d
C Weekly
Repeated every week until plateau
Cyclophosphamide 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 cycle
Dexamethasone 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 intolerance
Lenalidomide 25mg D1-21
Dexamethasone D1-4,9-12,17-20 ( cycles 1-4 only) then for all
subsequent cycles Dexamethasone D1-4 only
20
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 :
DAT
U+Es, LFTs, Igs
Hepatitis BsAg, cAb, hep C and HIV
Bone marrow aspirate and trephine, if cytopenias/ commencing treatment
Consider cytogenetics IgH gene rearrangements and 19p in selected patients,
consider re- checking p53 status prior to treatment courses- Bristol
Imaging –CT TAP
Staging
RAI
Stage
0
1
2
3
4
Clinical features
Lymphocytosis only
Blood > 14.9 x 109/L, Marrow > 39%
Lymphocytosis and lymphadenopathy
Splenomegaly and/or Hepatomegaly
Anaemia < 11g/100ml (not immune)
Thrombocytopenia < 100 x 109/L (not immune)
BINET
Stage
I
II
III
Clinical features
No anaemia, thrombocytopenia. < 3 involved lymph
nodes
No anaemia, thrombocytopenia. > 2 involved lymph
nodes
Anaemia < 10 g/100ml and/or thrombocytopenia <
100 x 109/L (not immune)
21
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
22
CLL Treatment Regimens (examples)
R Chlorambucil every 28/7 to maximum response
Rituximab 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)
Alemtuzumab
1st 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
Ofatumumab
300 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.
Idelalisib
150mg bd orally
Ibrutinib
420mg od orally
23
CHRONIC MYELOID LEUKAEMIA Investigational and Clinical Management
Guidelines13 2H- 105 and 106
BCSH guidelines
Guidelines for the measurement of BCR-ABL1 transcripts in chronic myeloid
leukaemia 2011
Suggested Investigations
FBC,
U+Es, LFTs
G+S
HLA type patient and siblings if may be suitable for transplant options
Bone marrow aspirate and trephine,
Conventional cytogenetics and FISH for BCR-ABL- Bristol
Molecular genetics quantitative PCR for BCR-ABL-Plymouth.
( mutation analysis – Kings, London)
Treatment Options
Trial – As national trial becomes available, SPIRIT 3 currently awaited.
First line – Imatinib 400 mg / day OR Nilotinib 300mg bd
Assess response according to ELN criteria
Failure - 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 failures
Bosutinib 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
months
Suboptimal 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.
24
ACUTE MYELOID LEUKAEMIA- AML Investigational and Clinical
Management Guidelines 13 2H- 105 and 106
WHO Classification AML
Acute 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);
(CBF/MYH11)
Acute promyelocytic leukaemia- t(15,17)(q22,q12) (PML/RAR) and variants
AML with 11q23 (MLL) abnormalities
Acute Myeloid Leukaemia with multilineage dysplasia
Following a myelodysplastic syndrome (MDS) or MDS/myeloproliferative disorder
Without antecedent MDS
Acute Myeloid Leukaemia and Myelodysplastic Syndromes, therapy-related
Alkylating agent-related
Topoisomerase type II inhibitor-related (some may be lymphoid)
Other types
Acute Myeloid Leukaemia not otherwise categorised
Acute Myeloid Leukaemia minimally differentiated
Acute Myeloid Leukaemia without maturation
Acute Myeloid Leukaemia with maturation
Acute Myelomonocytic Leukaemia
Acute Monocytic and Monoblastic leukaemia
Acute Megaloblastic Leukaemia
Acute Basophilic Leukaemia
Acute panmyelosis with Myelofibrosis
Myeloid sarcoma
Suggested Investigations
FBC, coagulation screen
U+Es, LFTs
G+S
Bone marrow aspirate- reported locally
Conventional cytogenetics/ FISH- Bristol
Immunophenotyping- Plymouth
Molecular genetics –Plymouth
Remember to think about study enrolment before marrow if diagnosis
certain, as extra samples are required.
HLA typing if transplant procedure possible
Semen cryopreservation- if appropriate
25
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
26
ACUTE LYMPHOID LEUKAEMIA- ALL Investigational and Clinical Management
Guidelines 13 2H- 105 and 106
Suggested Investigations
FBC, coagulation screen
U+Es, LFTs
G+S
Bone marrow aspirate- reported locally
Conventional cytogenetics/ FISH- Bristol
Immunophenotyping- Plymouth
Molecular genetics –Plymouth
Remember to think about study enrolment before marrow if diagnosis certain, as
extra samples are required.
HLA typing if transplant procedure possible
Semen cryopreservation- if appropriate
First Line Treatment options
<60
UKALL14 or similar with allograft if sibling donor
TYA 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



27
MYELODYSPLASIA Investigational and Clinical Management Guidelines
13 2H- 105 and 106
BCSH Guidelines- diagnosis and management of adult myelodysplasia 2013
Disease
RA
RARS
RCMD-RS
RCMD*
RAEB-1
RAEB-2
**MDS-U
MDS with
isolated
5q-
Blood findings
Marrow findings
Anaemia
No or rare blasts
Erythroid dysplasia only, <5% blasts,
<15% ringed sideroblasts
Erythroid dysplasia only, < 5%
Anaemia, no or rare blasts
blasts, >15% ringed sideroblasts
Dysplasia in 10% marrow cells in
>1 cytopenia, no or rare blasts, no
two or more myeloid lines, <5%
Auer rods, <1x109 monocytes
blasts, >15% ringed sideroblasts
Dysplasia in 10% marrow cells in
>1 cytopenia, no or rare blasts, no
two or more myeloid lines, <5%
Auer rods, <1x109 monocytes
blasts, >15% ringed sideroblasts
Cytopenias, < 5% blasts, no Auer Unilineage or multilineage dysplasia,
rods, <1x109 monocytes
5-9% blasts, no Auer rods
Cytopenias, 5-9% blasts, Auer rods Unilineage or multilineage dysplasia,
or none, <1x109 monocytes
10-19% blasts, Auer rods or none
Dysplasia in 10% marrow cells in
Cytopenias, no or rare blasts, no
one myeloid line, <5% blasts, no
Auer rods
Auer rods
Anaemia, Usually normal or
Normal to increased MGK with
increased platelet count, < 5%
hypolobate nuclei, <5% blasts,
blasts, no Auer rods
isolated 5q-, no Auer rods
*Refractory cytopenia with multilineage dysplasia, ** MDS-unclassifiable,
Suggested Baseline Investigations
FBC +film
U+Es, LFTs
Haematinics
G+S
Bone marrow aspirate- reported locally
Conventional cytogenetics/ FISH- Bristol
Immunophenotyping- Plymouth
Erythropoietin level
International Prognostic Scoring system
BM blast
percentage
Karyotype
Cytopenias
0
0.5
<5
5-10
Good
0/1
Intermediate
2/3
1
1.5
1120
Poor
28
2
2130
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
CMML
Cytoreduction with Hydroxycarbamide as required
5q- Syndrome
Consider lenalidomide
Management of infection
Prophylactic
Routinely no evidence for prophylaxis
Consideration to use of prophylactic low dose GCSF in severely neutropenic patients
to maintain N>1x109/l
Therapeutic
Neutropenic sepsis should be treated as per local policy with intravenous antibiotics
29
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
Investigations
FBC, film
erythropoietin
Molecular – thrombocytosis- bcr-abl ,JAK2, CALR, exon 10- Plymouth
- Raised haematocrit- JAK2- Plymouth, exon 12- Kings, London
Bone marrow aspirate and trephine- reported locally
Conventional cytogenetics/ FISH- Bristol
Polycythaemia Vera
Diagnostic Criteria
JAK2 positive polycythaemia
A1
High haematocrit (>0.52 in men and >0.48 in women)
A2
Mutation in JAK2
Diagnosis requires both criteria to be present
JAK2 negative polycythaemia
A1
raised RCM (>25% above predicted) OR Haematocrit >0.60 in men and 0.56 in
women
A2
absence of mutation in JAK2
A3
no secondary cause
A4
palpable splenomegaly
A5
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 splenomegaly
B4
endogenous erythroid colonies or low serum erythropoietin
Diagnosis requires
A1+A2+A3+ either another A or two B criteria
30
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 years1st line- Interferon
2nd line- Hydroxycarbamide or anagrelide
40-75 years- 1st line- Hydroxycarbamide
2nd line- Interferon or anagrelide
>75 years
1st line- Hydroxycarbamide
2nd line- 32P or intermittent busulphan
Management of Apparent Erythrocytosis (2 measurements of Hct3/12 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 thrombosis
Hct>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 >0.54
Venesect 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
31
ESSENTIAL THROMBOCYTHAEMIA
WHO Classification
Thrombocytosis  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 MCV
No CML (Philadelphia and BCR/Abl negative)
No evidence of IMF
No Collagen fibrosis, reticulin fibrosis minimal or absent
No evidence of MDS
Cytogenetics: no 5q-, t (3; 3) (q21; q26), inv (3) (q21; q26)
No significant granulocyte dysplasia, few if any micromegakaryocytes
No evidence that the thrombocytosis is reactive due to:
No underlying inflammation, infection or neoplasm
Prior splenectomy
MANAGEMENT Risk assessment adapted from PT1 trial
Low Risk
ALL of the following features
Intermediate Risk
ALL of the following features
Age <40 years
Platelet count 600 but which
has never been consistently
> 1000 x 109/l
Age 40-59 years
Platelet count 600 but which
has never been consistently >
1500 x 109/l
No history of ischaemia,
thrombosis or embolic
features or erythromelalgia
No history of ischaemia,
thrombosis or embolic features
or erythromelalgia
Absence of haemorrhage
considered to be related to
PT
Absence of haemorrhage
considered to be related to PT
Absence of hypertension
needing Rx, non-smoker
Absence of hypertension
needing Rx, non smoker
Absence of diabetes needing
Rx
Absence of diabetes needing
Rx
High Risk
ANY of the following
features
Age 60 years
Platelet count 1500 x
109/l (current or
previous)
History of ischaemia,
thrombosis or embolic
events (including
erythromelalgia)
Haemorrhage
considered to be
related to PT
Presence of
hypertension needing
Rx or smoking
Presence of diabetes
needing Rx
Low and Intermediate Risk
MRC 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/l
Hydroxycarbamide
Alternatives for those who cannot receive Hydroxycarbamide
32
Interferon: “young” if able to tolerate.
Pregnancy  Interferon
Busulfan
32
P
Anagrelide
IDIOPATHIC MYELOFIBROSIS
FBC and film examination, U+E, LFT, Bone profile, Urate, CRP, Ferritin
Bone marrow aspirate and trephine- reported locally
Conventional cytogenetics/ FISH (if appropriate)- Bristol
Molecular 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 splenomegaly
B2 Unexplained anaemia
B3 Leuco-erthroblastosis
B4 Tear-drop red cells
B5 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
33