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Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 1 of 54
Title: Clinical management guidelines for Acute Leukaemia and Myelodysplastic/Myeloproliferative disorders
Author(s)
Professor MF McMullin
Ownership:
Approval by: Haematology CRG & NICaN Drugs & therapeutics Committee
Approval date:
May 2016
Operational Date:
May 2016 Next Review:
May 2017
Version No. 1.1 Supercedes 1.0
Links to other policies
Version control for drafts:
Date Version Author Comments
February 2016
1.0 Prof MF Mullan
Amended to reflect comments from D&T Committee
May 2016 1.1 Prof MF Mullan
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 2 of 54
Good medical practice and the Manual of Cancer Services Chemotherapy Measures mandate the use of agreed guidelines on use of SACT within each disease site. For each disease site these guidelines should specify the acceptable ranges of regimen options for named steps on the patient pathway to include adjuvant/neo-adjuvant, first/second etc. line palliative regimens and ideally should include decision trees. References must be included for each regimen. They should be updated every 2 years. The guideline should specify if a treatment is not recurrently funded. Only those regimens listed in the guideline will be available for use in the particular disease site. The SACT regimen protocols will be produced using the guidelines for every regimen listed in the disease site SACT guideline and will contain additional detail on route of administration, tests required prior to starting a course, dose modifications etc. The minimum acceptable dataset is completion of
Page 1
For each step on the patient pathway (neo-adjuvant/adjuvant/etc each line of palliative treatment) – as a minimum an algorithm containing the detail below is sufficient for now with the understanding that the full guideline will be completed in the near future
o Drug name and dose o If there is more than one choice the guideline should specify why one
regimen would be chosen as opposed to another o References
Completed signature page
Each guideline should be in the Regional format and be signed up to by each consultant working within the disease. The hard copy with signatures and electronic version should be sent to Bridget Tourish. It will then be uploaded onto RISOH.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 3 of 54
Authorisation of Systemic Anti-Cancer Therapy (SACT) Guidelines for acute
leukaemia and Myelodysplastic/Myeloproliferative disorders These SACT guidelines are accepted for the treatment of acute leukaemia and myelodysplastic/myeloproliferative disorders
Consultant Haematologist Signature Print Name/Title
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr
Signature Print name/Title Date
Written by Systemic Guidelines Author
Professor McMullin, Consultant Haematologist
Approved by Site Clinical Lead
Dr Consultant Haematologist
Approved by SACT Clinical Lead/Clinical Director
Dr Clinical Director/SACT CL
Review Date
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 4 of 54
Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Dr Consultant Haematologist
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 5 of 54
1.0 INTRODUCTION / PURPOSE OF POLICY
1.1 Background
Systemic anti-cancer therapy (SACT) is a key treatment in acute leukaemia. These
guidelines describe the agreed management for patients with acute leukaemia, and
myelodysplastic/myeloproliferative disorders. These guidelines should be read in
conjunction with the latest and applicable national /international guidance.
1.2 Purpose
To ensure consistent use of SACT for patients with acute leukaemia, and
myelodysplastic/myeloproliferative disorders.
2.0 SCOPE OF THE POLICY
This document is aimed at all clinical staff involved in the management of patients
with acute leukaemia, and myelodysplastic/myeloproliferative disorders . They are
designed to supplement current national and international guidelines and NICE/
SMC advice relating to these disorders. It should be noted that these CMG
guidelines are written to reflect current advice and practices but regular updating will
be required as new evidence emerges.
3.0 ROLES/RESPONSIBILITIES
It is the responsibility of all clinical staff involved in the management of patients with
acute leukaemia, myelodysplastic/myeloproliferative disorders to familiarise
themselves with these guidelines.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 6 of 54
4.0 Key policy principles 4.1 Acute Myeloid Leukaemia 4.1.1 Diagnostic criteria 4.1.2 Primary treatment 4.1.3 Acute promyelocytic leukaemia (APL) 4.1.4 Poor risk, refractory or relapsed patients 4.1.5 Relapsed APL 4.2 Indications for allogeneic transplant in AML 4.3 Precursor Cell Lymphoblastic leukaemia in
adults
4.3.1 Diagnostic criteria 4.3.2 Risk factors, Remission status and
investigations
4.3.3 Primary treatment 4.3.4 Adults not suitable for UKALL 14 entry 4.3.5 Treatment of primary refractory disease 4.3.6 Treatment of ALL relapsing after CR 4.3.7 CNS Leukaemia at diagnosis 4.4 Myelodysplastic Syndromes 4.5 Myelodysplastic/Myeloproliferative Neoplasms 4.5.1 CML 4.5.2 Primary therapy in CML 4.5.3 Management of CML patients who are resistant
or intolerant to imatinib
4.5.4 Management of CML in Pregancy 4.5.5 Bone marrow transplantation 4.6 Chronic Myeloproliferative disorders
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 7 of 54
4.1 Acute myeloid leukaemia 4.1.1 Diagnostic Criteria Core Criteria • More than 20% blast cells by flow cytometry, or morphology when the quality of the EDTA sample is sub-optimal (use higher figure), or more than 5% blasts in the presence of a balanced translocation Peripheral blood (PB) with high white count in older patients is acceptable. However, cytogenetics not valid on PB samples. • Myeloid lineage demonstrated by immunophenotype • The immunophenotype can be one of two patterns: Type A: CD34+, CD117+, CD13+, CD33+, HLA-DR+, cCD3-, cCD79- Type B: CD34-, CD117+, CD13+, CD33+, CD15var+, cCD3-, cCD79-, MPO+ (by flow) Intermediate phenotypes occur and are acceptable to define myeloid lineage. • Cytogenetics allows risk stratification. Cytogenetic analysis should be mandatory in the initial/diagnostic evaluation of all patients and at suspected or confirmed relapse. • Molecular analysis
FLT3 ITD: 40% CN (cytogenetically normal) AML
NPM1 mutation: ~50% CN AML, CEBPmutation: ~15% CN AML All cases of acute promyelocytic leukaemia (APML) must have: • CD34+/-, CD13-hetero+, CD33-homo+++, CD117+, CD15-, HLA-DR-, MPO+++ (by flow)
• Microparticulate pattern with anti-PML
• Confirmation of t(15;17) by cytogenetics and PML/RARA pcr
Essential Investigations
• Coagulation screen
• Renal and liver function tests
• CXR
• ECG +/- echocardiogram
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 8 of 54
Definitions;
Induction chemotherapy is given to induce a complete remission – in NCRI (MRC) trials
this is defined as a normocellular marrow with less than 5% blasts.
Consolidation or post-remission chemotherapy is necessary to prevent early relapse
and increase the chance of cure, and may include stem cell transplantation.
Risk stratification is used to determine consolidation therapy. From the results of AML 10
and 11 the MRC have defined the following risk groups:
Good risk: Any patient with favourable genetic abnormalities – t(8;21), inv(16),
t(16;16), irrespective of other genetic abnormalities or marrow status after Course 1.
Standard: Any patient not in either good or poor risk groups.
Poor risk: Any patient with more than 15% blasts in the bone marrow after Course
1, or with adverse genetic abnormalities: -5, -7, del(5q), abnormal (3q) or complex
(5 or more abnormalities) – and without favourable genetic abnormalities or with
Flt3 ITD
(Grimwade, et al 2001, Kottaridis, et al 2001, Wheatley, et al 1999)
AML17 uses a new risk index derived from outcome data from previous AML trials.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 9 of 54
4.1.2 Primary Treatment in Acute leukaemia
All cases of acute myeloid leukaemia, except acute promyelocytic leukaemia
• All eligible patients up to age 60, or above this and suitable for intensive therapy, with de
novo or secondary AML should be considered for entry to NCRI AML AML17 trial and
subsequent trials.
• Non-trial standard and favourable risk patients (except APML) fit for intensive
chemotherapy should receive standard DA induction chemotherapy .
Da 60 3+10
Daunorubicin 60mg/m2 Days 1,3,5 Ref: AML17 trial protocol
Cytarabine 100mg/m2 twice daily
Days 1-10
followed by:
Da 3+8
Daunorubicin 50mg/m2 Days 1,3,5 Ref: AML17 trial protocol
Cytarabine 100mg/m2
twice daily Days 1-8
Options for non-trial consolidation chemotherapy includes HD AraC or MIDAC and/or stem
cell transplantation. Consider MiDAC in adverse-risk cytogenetics (Burnett et al. 2013; J Clin
Oncol).
Midac
Mitoxantrone 8mg/m2 Days 1 to 3 Ref: AML 14 trial
Cytarabine 500mg/m2 twice daily
Days 1 to 3
High dose Cytarabine
Cytarabine 3000mg/m2 twice daily
Days 1,3,5 Ref: AML 15 trial
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 10 of 54
Stem cell transplantation for non-trial standard risk patients is not routinely recommended
but should be considered and discussed on a case by case basis. Stem cell
transplantation in CR1 should be considered as course 3 or 4 for non-trial patients with
adverse risk.
• All patients over the age of 60 with acute myeloid leukaemia (except Acute Promyelocytic
Leukaemia) de novo or secondary AML who are fit for intensive treatment should be
entered into AML 18 trial when available. They should normally be over the age of 60, but
patients under this age are eligible if they are not considered fit for the MRC AML17 trial.
Conversely fit patients in their early 60s may be considered for AML17. If a clinician is not
willing to randomise between the chemotherapy options, then DA should be given.
• Patients >60 unable to tolerate induction should be entered into the non-intensive arm of
AMLL1 or the TAP Trial RaVVa as available. Non-trial patients lacking an adverse risk
karyotype are candidates for low-dose Ara-C. AML with 20-30% blasts should be
considered for 5-azacitidine therapy.
Low Dose Cytarabine (Ara-C)
Cytarabine 20mg twice daily
Days 1-10 Ref: AML 14 trial
Azacitidine
Azacitidine 75mg/m2 Days 1-7 Ref: Itzykson et al. Blood 2011
• All induction remission chemotherapy should be delivered in level II/III trusts. Non-
intensive arm can be delivered in level 1 after discussion in MDT.
• Patients not able to tolerate induction chemotherapy should be treated palliatively or
offered experimental therapy where available.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 11 of 54
4.1.3 Treatment Acute promyelocytic leukaemia (APL)
• All eligible patients up to age 60 with APL should be asked to participate in the NCRI
AML 18 trial when available.
• APL patients in complete remission (CR) should have molecular monitoring by bone
marrow and blood examination every 3 months for 2-3 years to look for signs of early
relapse.
• Non-trial patients should be treated per AML15 Spanish arm protocol with molecular
monitoring
AML15 Spanish Arm
Spanish Arm Course 1
Idarubicin 12 mg/m2 Days 2, 4, 6 and 8 Ref: AML15
ATRA 45mg/m2/day On day 1 of induction therapy until first CR is achieved or until completion of 2 courses of chemotherapy
Spanish Arm Course 2
Idarubicin 7 mg/m2 Days 1, 2, 3, 4 Ref: AML15
ATRA 45 mg/m2 /day On days 1-15 (15 doses) if patient is in CR after Course 1, otherwise ATRA until morphological CR.
Spanish Arm Course 3
Mitoxantrone 10 mg/m2 Days 1-5 Ref: AML15
ATRA 45 mg/m2 /day Days 1-15
Spanish Arm Course 4
Idarubicin 12 mg/m2 Day 1 Ref: AML15
ATRA 45 mg/m2 /day Days 1-15
Spanish Arm maintenance x 2 years
6-Mercaptopurine 50mg/m2 PO Daily Ref: AML15
Methotrexate 15/mgm2 PO Once weekly
ATRA 45 mg/m2 /day Days 1-15 every 3 months
Note hold 6-mercaptopurine and Mtx when taking ATRA
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 12 of 54
• Consider ATO+ATRA as 1st line treatment - Induction and consolidation of patients not
eligible for the AML17 trial, specifically those > 60 years for whom anthracyclines are
contraindicated or where myelosuppression is to be avoided (Slack, JL et al 2002, Estey E
et al Blood 2006, Sanz MA et al 2009).
Arsenic Trioxide + ATRA induction for patients not suitable for anthracycline/standard therapy
Arsenic Trioxide 0.3mg/kg D1-5 (wk 1) Ref: AML 17
Arsenic Trioxide 0.25mg/kg Twice weekly (wk 2-8)
ATRA 45mg/m2 D-1 – continued until remission is achieved
Arsenic Trioxide + ATRA consolidation for patients not suitable for anthracycline/standard therapy
Arsenic Trioxide 0.3 mg/kg D1-5 Wk 1 Ref: AML 17
Arsenic Trioxide 0.25 mg/kg Twice weekly Wk 2-4 Then 4 weeks off then repeat for total of 4 cycles
ATRA 45mg/m2 Wk 1-2, wk 5-6, 9-10 13-14, 17-18, 21-22, 25-26
4.1.4 Poor risk, refractory or relapsed patients
(Craddock, et al 2005, Kantarjian, et al 2003).
• For patients aged <60 yrs, consider use of prognostic index, (Breems et al 2005) which
considers duration of first complete remission, cytogenetics at diagnosis, age at relapse,
and whether previous stem-cell transplantation was performed. The index divides patients
into 3 groups: group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an
intermediate risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk
group C (OS of 16% at 1 year and 4% at 5 years).
Options are DA, Flag-Ida or MEC depending on what treatment the patient has
previously received for treating poor-risk, relapsed or refractory AML outside a clinical trial.
Mylotarg 3mg/m2 may be added if patient has an allogeneic transplant option. (Mylotarg is
not recommended if patient has previously received the same). NOTE currently Mylotarg is
not available for use in routine management of AML.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 13 of 54
Flag-IDA
Filgrastim 30MIU Days 1-7 Ref: AML17 – MRC protocol. Idarubicin 8mg/m² Days 4, 5, 6
Fludarabine 30mg/m² Days 2-6
Cytarabine 2000mg/m² Days 2-6
MEC
Mitoxantrone 8mg/m2 Days 1-5 Ref: Kohrt, H.E. et al Am. J. Hematol 2010; 85:877-881 Waddell J.A. et al Hospital Pharmacy 2003. 218-221
Etoposide 100mg/m2 Days 1-5
Cytarabine 1000mg/m2 Days 1-5
Gemtuzumab Ozagamicin (Mylotarg) in conjunction with AML chemotherapy regimens
Gemtuzumab 3mg/m2 Days 1 Ref: AML15 – MRC protocol. Sievers EL et al JCO, 2001
• All suitable patients should be discussed with a transplant specialist to consider stem cell
transplantation in CR2. (Level 4). Patients refractory to second line therapy or with short
CR1 and refractory to re-induction should be discussed with the transplant team for
consideration of combined chemotherapy-reduced intensity transplants.
4.1.5 Relapsed Acute Promyelocytic Leukaemia
Follow AML15 algorithm namely ATO (Arsenic Trioxide) followed by stem cell transplantation (auto if PCR negative, allo if positive).
Induction Treatment
One of two treatment schedules can be followed for induction:
A) ATO 0.15mg/kg daily by a slow (1-2 hour) infusion for a maximum of 50 days.
B) ATO 0.30mg/kg daily for 5 days followed by 0.25mg/kg twice weekly for up to 7 weeks
Patients should have a marrow re-assessment at 28 days which should include
molecular assessment. If the patient is in morphological and molecular remission
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 14 of 54
they should enter consolidation treatment. If the patient is not in haematological
remission or is in haematological but not molecular remission two doses of
Idarubicin (10mg/m2) should be added on 2 consecutive days and the
morphological and molecular status re-checked 2 weeks later. The ATO treatment
should be continued at the induction dose. When the patient is confirmed to be in
haematological remission they should enter the consolidation phase.
Aresnic Trioxide – induction therapy in relapsed setting
Arsenic Trioxide 0.30mg/kg Days D1-5 (wk 1) Ref: MRC AML15
Arsenic Trioxide 0.30mg/kg Twicwe weekly (wk 2-7)
• Older patients, if initially fit for induction chemotherapy and CR duration > 1 year,
consider offering re-induction. If not fit for re-induction or short CR, experimental therapy or
supportive care.
4.2 Current indications for referral for consideration for allogeneic stem
cell transplant in AML
All patients must be considered fit for allogeneic stem cell transplant
Clear indications
Adverse risk by karyotypic risk group or AML17 index high-risk
Relapsed AML in CR2 (relapsed APL only if not in molecular CR after re-
induction).
Should be considered
FLT3 ITD mutated (+/- NPM1 mutation): although poorer prognosis, the evidence
for a benefit from allo SCT remains inconsistent.
Minimal residual disease detected after course 1 or 2 induction therapy: again
almost certainly poorer prognosis but no benefit for allo SCT yet demonstrated (lack
of randomised controlled trials or large cohort studies to date).
Standard risk patients lacking a molecular abnormality: inconsistent trial data
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 15 of 54
Core-binding factor with either persistent high-level minimal residual disease
and/or c-kit mutation
Not currently recommended
Favourable risk AML, traditionally defined as APL or core-binding factor leukaemia
Normal karyotype with either NPM1 mutation or biallellic CEBPmutation as a sole
molecular abnormality: these AML subtypes have a good prognosis with
chemotherapy alone and should not receive an allograft in CR1.
Please consider all patients with limited co-morbidity for suitability for allogeneic stem cell
transplantation and discuss with the BCH transplant team. Novel approaches to allo SCT
are also emerging including combined chemotherapy – RIC SCT for previously ineligible
patients.
Transplant protocols –
Cyclophosphamide ATG – aplastic anaemia -sibling allograft
Cyclophosphamide IV 50mg/kg D-5 to D-1 Storb R et al. Biol Blood Marrow Transplant. 2001; 7(1): 39-44. Storb R et al
Blood 1994; 84(3): 941-49
Rb-ATG test dose 2.75mg only D-6
Rb-ATG 3.75/kg D-4 to D-2
Cyclophosphamide TBI – AML/ALL- sibling allograft
TBI D-7 to -4
Cyclophopshamide IV 60mg/kg D-3 to D-2 Deeg H J et al. Bone Marrow Transplantation 1986 Dec; 151-7 Clift R A et al Blood 1990 Nov 1;76 (9): 1867-71
Rest D-1
Stem cell return D 0
Busulphan cyclophosphamide –AML/ALL- sibling allograft
Busulphan IV 3.2mg/kg D-8 to D-5 Kashyap A et al. Biology of Blood and Marrow Tranplantation 2002; 8: 493-500
Cyclophosphamide IV 60mg/kg D-3 to D-2
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 16 of 54
Flu Mel Campath AML – RIC
Fludarabine 30 mg/m2/day D–7 to D–3 AML 15
Melphalan 140 mg/m2 D-2
Campath 1H IV 20mg/day D-8 to D-4
FBC- (FLU BU Campath)* RIC
Fludarabine 30mg/m2 D-9 to D-5 AML 15
Busulphan 4mg/kg/day D-3 to d-2
Campath 1H 20mg/day IV D-5 to D-1
* use of phenytoin and low molecular weight heparin for VOD
prophylaxis is optional)
Flamsa-BU for patients up to 60 years old with high risk disease
Fludarabine 30mg/m2 D-12 to D-9 AML 17 trial protocol
Cytarabine 2000mg/m2 D-12 to D-9
Amsacrine 100mg/m2/d D-12 to D-9
REST day D-8to D-6
Busulphan IV 3.2mg/kg x 3 hrs D-5 to D-3
Busulphan IV 1.6mg/kg x 3 hrs D-2
FludarabineIV 30mg/m2 x 1hr D-3 to D-2
ATG 10mg/kg – sibling donors 20mg/kg for unrelated donors
Initiation GVHD propylaxis Ciclosporin D-1
Initiation GVHD propylaxis MMF D0
Infusion of HPC-A/ HPC-BM D0
GVHD prophylaxis- this will be regimen specific and will include ciclosporin and
Methotrexate.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 17 of 54
4.3 PRECURSOR CELL LYMPHOBLASTIC LEUKAEMIA IN ADULTS
4.3.1 Diagnostic Criteria
Precursor B-cell Lymphoblastic Leukaemia
Typical Cases
• Bone marrow or solid tissue infiltration with blast cells
• Immunophenotype: CD19+, CD22+, TdT+, CD117-, CD34var, CD45 wk
Variants
• BCR-ABL associated phenotype: CD34-homo+++, CD10-homo+, CD13+ and/or CD33+,
CD38wk/-.
• t(12;21) associated: common ALL phenotype with CD10-hetero+, CD13+ and/or CD33+.
Precursor T-lymphoblastic Leukaemia
Typical Cases
• Bone marrow or solid tissue infiltration with blast cells
• Immunophenotype: CD19-, TdT+, cCD3+, CD2+, CD7+, CD22-, MPO- (by flow)
Immunologic classification of ALL (Ludwig, et al 1994)
B –lineage
Pro B-ALL HLA-DR+, TdT+, and /or CD79+ and /or CD22+, CD10 -, cy IgM-/surface Ig-
Cytogenetics t(4;11), Molecular genetics:ALL1(MLL)-AF4
Common-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+, cy IgM-/surface Ig-
Cytogenetics: t(9;22), Molecular genetics: BCR-ABL
Pre B-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+/-, cytoplasmic
immunoglobulin (cyIgM) + Cytogenetics: t(9;22), t(1;19), Molecular genetics: BCR-ABL;
E2A-PBX1 B-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+/-, surface
immunoglobulin (sIgM+)
Cytogenetics: t(8;14), Molecular genetics: CMYC-IgH
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 18 of 54
T-lineage
Early T-ALL TdT+, cytoplasmic CD3(cyCD3)+,CD7+,CD5+/-,CD2+/-
Cytogenetics: t(11;14), Molecular genetics: LMO1/–TCRa/d
Cortical T-ALL TdT+, cyCD3+, CD7+, CD1a+, Surface CD3(sCD3)+/–
(ThyALL) Cytogenetics: t(10;14), Molecular genetics: HOX-11-TCRa/d
Mature T-ALL TdT+, sCD3+,CD1a***
4.3.2 Risk factors, remission, essential investigations
Risk factors: any of the following
Age >35 years
WBC at Diagnosis: B ALL >30 x109/L, T ALL>100 x109/L
Cytogenetics: (Moorman, et al 2007) Ph chromosome, t(4;11)(q21;q23),
t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low
hypodiploidy/near triploidy (Ho-Tr)
Definition of Remission Status
When a blast cell population with a leukaemia-associated phenotype is detected
unequivocally by flow cytometry or PCR and not by morphological assessment it will be
reported as morphological remission but not in remission by flow or PCR with the extent of
infiltration stated.
Essential Investigations
• Coagulation screen and fibrinogen
• Renal and liver function tests
• CXR
• ECG +/- echocardiogram
• Consideration of options for transplantation
• Lumbar puncture as part of treatment protocol
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 19 of 54
4.3.3 Primary Treatment
(Annino, et al 2002, Manera, et al 2000, Pui, et al 2003, Vilmer, et al 2000)
Patients aged 25 years or over with Philadelphia negative ALL:
UKALLXIV trial is open and patients should enter trial if consent or follow protocol (N.B.
patients should still be registered with CTSU at diagnosis for MRD study) All new patients
should be discussed with the transplant service, as there are a number of issues that will
be helped by prior warning/ consideration.
Patients aged 25 years or older with Philadelphia positive ALL (up to age 60):
UKALLXIV Ph positive arm is open and should be encouraged to enter into trial.
Patients aged 15-24 (up to 25th birthday) with Ph neg ALL:
Patients aged 15-24 (up to 25th birthday) with Ph pos ALL:
Should follow UKALL2003 and if found to be Ph positive, such patients should transfer
back to UKALLXIV Ph pos arm . NOTE it is anticipated that UKALL 2011 will be opened in
2016 . However if found to be Ph positive, such patients should transfer back to UKALLXIV
Ph positive arm.
Adults (Ph+ve) eligible but not in trial
Should be treated with the current NCRI UKALL XIV trial protocol. Early notification to the
transplant team is essential for these patients.
ALL Phase 1 Induction
Daunorubicin 30mg/m2 Days 1,8,15,22 Ref: UKALL 14 trial
Vincristine 1.4mg/m2 (max dose 2mg)
Days 1,8,15,22
Dexamethasone 10mg/m2 Days 1-4, 8-11, 15-18
PEG Asparaginase** 1000iu/m2 IV Day4, 18
Imatinib 400mg (escalating to 600mg after 2 weeks depending on tolerance)
Day 1-28
Methotrexate 12.5mg Intrathecal Day 14
**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol – patients >40 years should omit Day 4. PH+ve patients should not receive PEG asparaginase**
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 20 of 54
ALL Phase 2 Induction
Cyclophosphamide 1000mg/m2 IV Days 1,15 Ref: UKALL 14 trial
Cytarabine 75mg/m2 IV Days 2-5, 9-12, 16-19,23-26
Mercaptopurine 60mg/m2 PO Days 1-28
Imatinib 600mg as tolerated and continued until transplant if possible.
Methotrexate 12.5mg Intrathecal Days 1,8,15,22
ALL Intensification therapy
Methotrexate 300mg/m2 Day 1,15 Ref: UKALL 14 trial
Methotrexate* 2700mg/m2 Day 1,15
PEG Asparaginase** 1000iu/m2 IV Day 2, 16
Imatinib 600mg as tolerated and continued until transplant if possible.
*NOTE folinic acid resuce must be given – consult with protocol for details. **PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**
ALL Consolidation Cycle 1
Cytarabine 75mg/m2 Days 1,2,3,4,5 Ref: UKALL 14 trial
Etoposide 100mg/m2 Days 1,2,3,4,5
PEG Asparaginase** 1000iu/m2 IV Day 5
Methotrexate 12.5mg Intrathecal Day 1
Imatinib 600mg as tolerated and continued until transplant if possible.
**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**
ALL Consolidation Cycle 2
Cytarabine 75mg/m2 Days 1,2,3,4,5 Ref: UKALL 14 trial
Etoposide 100mg/m2 Days 1,2,3,4,5
Methotrexate 12.5mg Intrathecal Day 1
Imatinib 600mg as tolerated and continued until transplant if possible.
**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 21 of 54
ALL Consolidation Cycle 3 days (1-28)
Daunorubicin 25mg/m2 Days 1,8,15,22 Ref: UKALL 14 trial
Vincristine 1.4mg/m2 Days 1,8,15,22
PEG Asparaginase** 1000iu/m2 IV Day4
Dexamethasone 10mg/m2 (cap at 20mg)
Day 1-4, D8-11,D15-18, D22-25
Methotrexate 12.5mg Intrathecal Day 2, 17
Imatinib 600mg as tolerated and continued until transplant if possible.
Day 1-28
**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**
ALL Consolidation Cycle 3 (days 29-42)
Cyclophosphamide 1000mg/m2 Day 29 Ref: UKALL 14 trial
Cytarabine 75mg/m2 Days 30-33, 37-40
Mercaptopurine 60mg/m2 Day29-42
Dexamethasone 10mg/m2 (Cap at 20mg)
Day 1-4, D8-11, D15-18, D22-25
Imatinib 600mg as tolerated and continued until transplant if possible.
Day 29-42
ALL Consolidation Cycle 4
Cytarabine 75mg/m2 Days 1,2,3,4,5 Ref: UKALL 14 trial
Etoposide 100mg/m2 Days 1,2,3,4,5
Methotrexate 12.5mg Intrathecal Day 1
Imatinib 600mg as tolerated and continued until transplant if possible.
ALL Maintenance therapy (Non transplant ) continue for 2 years
Vincristine 1.4mg/m2 IV Every 3 months Ref: UKALL 14 trial Prednisolone 60mg/m2 PO 5/7 every 3 months
Mercaptopurine 75mg/m2 PO Daily
Methotrexate 20mg/m2 PO or IV Once per week – avoid same day as cotrimoxazole
Imatinib dose depending on tolerance To continue with this throughout maintenance
Methotrexate 12.5mg Intrathecal Once every 3 months
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 22 of 54
4.3.4 Adults too old for UKALL 14 trial entry
When open should be offered UKALL 60+. Fit patients who are only a few years older than
the cut-off could be discussed with the trial coordinators.
It should be remembered that the prognosis for patients 50-60 years and older is poor,
particularly if there are other poor prognostic features (e.g. Ph+ve/ t(4;11))
1. Fit and informed and willing : consider a UKALLXIV like schedule but may need
reduced dosage or early termination depending on response and tolerance.
2. Less fit, older or uncertain: a less intensive schedule is appropriate.
Outlined below is
Pathway for ALL Philadelphia positive patients
Intensive pathway for ALL Philadelphia negative patients
Intensive + pathway for ALL Philadelphia negative patients
Nonintensive pathway in ALL Philadelphia –ve patient
Pathway for ALL Philadelphia positive patients
Regimen Phase 1 induction elderly ALL (Ph +ve)* 28days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 ( cap at 2mg) IV Day 1
Imatinib 400mg/day PO– escalate to 600mg within 2 weeks as tolerated
Days 1-28
Intrathecal Methotrexate 12.5mg IT Days 8,15,22 *Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are
reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to phase
2 when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further details.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 23 of 54
Regimen Phase 2 induction elderly ALL (Ph +ve)* 28 days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 ( cap at 2mg) PO Day 1
Imatinib PO-continue with previously tolerated dose
Days 1-28
Intrathecal Methotrexate 12.5mg IT Days 8,15,22
*Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are
reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to
consolidation when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further details.
Regimen Consolidation elderly ALL (Ph +ve)* 28 days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 ( cap at 2mg) IV Day 1
Imatinib PO-continue with previously tolerated dose
Days 1-28
Intrathecal Methotrexate 12.5mg IT Day 2 only *Bone marrow aspirate should be performed after day 28 as soon as maximum counts are
reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to
consolidation when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further details.
Regimen: Maintenance elderly ALL (Ph +ve)* 24 months
6-Mercaptopurine* PO 25mg/m2 – 75mg/m2 starting dose – titrate for counts as per protocol
Daily Ref: UKALL60+
Imatinib PO continue with previously tolerated dose Daily
Prednisolone PO 60mg/m2 5 days every 3 months
Vincristine 1.4mg/m2 IV (max dose 2mg) Days 1-28
Intrathecal Methotrexate 12.5mg IT Every 3 months
*6-mercaptopurine should be started at 25mg/m2/day and then should be increased upwards in 25% increments to tolerance.- see protocol for details
Intensive pathway for ALL Philadelphia negative patients
Regimen Intensive pathway Phase 1 induction elderly ALL (Ph -ve)* 28days
Dexamethasone 6mg/m2 PO Days 1-3, 7-9 Ref: UKALL60+ Idarubicin 14mg/m2 PO Day 1
Vincristine 1mg/m2 (cap at 2mg) IV Day 1,15,22
Intrathecal Methotrexate 12.5mg IT Days 7,14,21 *Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are
reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to Phase
2 when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further details.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 24 of 54
.
Regimen Intensive pathway Phase 2 induction elderly ALL (Ph -ve)* 17days
Vincristine 1mg/m2 (cap at 2mg) IV Day 1,15 Ref: UKALL60+ Cytarabine 75mg/m2 IV Day 1-3, 15-17
Cyclophosphamide 300mg/m2 Day 1,15
Intrathecal Methotrexate 12.5mg IT Days 7,14 *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are
reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to
intensification when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further
details.
Regimen Intensive pathway Intensification elderly ALL (Ph -ve)* 28days
Methotrexate** 1g/m2 IV (infusion as local policy)
Days 1,15
** Local policies may be followed for folinic acid resuce after IV methotrexate
admisnistraion during induction2. REVIEW PROTOCOL FOR SPECIFIC DETAILS.
*Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are
reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to
consolidation1 when neuts >0.75x 109/L and plts >75x10
9/L. See protocol for further
details.
Regimen ConsolidationCycle 1,2,3 (28 day cycle to be repeated 3 times) Elderly ALL (Ph -ve)* 28days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 (cap at 2mg) IV Day 1
Methotrexate 5mg/m2 PO Days 1,8,15,22
6-mercaptopurine 50mg/m2 PO Day 1-28
Regimen: Maintenance elderly ALL (Ph -ve)* 24 months
6-Mercaptopurine* PO 25mg/m2 – 75mg/m2
starting dose – titrate for counts as per protocol Daily Ref:
UKALL60+
Methotrexate 5mg/m2 PO weekly Daily
Prednisolone PO 60mg/m2 5 days every 3 months
Vincristine 1.4mg/m2 IV (max dose 2mg) Days 1-28
Intrathecal Methotrexate 12.5mg IT Every 3 months *6-mercaptopurine should be started at 25mg/m
2/day and then should be increased upwards in 25%
increments to tolerance.- see protocol for details
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 25 of 54
Intensive + pathway for ALL Philadelphia negative patients
Regimen: Intensive + Phase 1 in elderly ALL (Ph -ve)* 28 days cycle
Methotrexate 12.5 mg+Dexamethasone** 4mg IT 2,9,16 Ref: UKALL60+ Vincristine 1mg/m2 IV (max dose 2mg) Day 1,8,15
Doxorubicin 40mg/m2 IV Day 1,8,15
Prednisolone 40mg/m2 divided in 2 daily doses Days 1-21 and taper dose to 0mg D22-28
Intrathecal Methotrexate 12.5mg IT Every 3 months *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to intensification when neuts >1.0x 10
9/L and plts >100x10
9/L. See protocol for further details.
**Dexamthasone 4mg IT may be substituted with hydrocoertisone suspended in 3- 6ml sterile saline.
Regimen: Intensvie + Phase 2 in elderly ALL (Ph -ve)* 22 days cycle
Cytarabine 200mg/m2 IV over 1 hour Day 1,8 Ref: UKALL60+ Etoposide 120mg/m2 IV over 1 hour Day 1,8
Methotrexate** 500mg/m2 IV over 2 hours Day 4,11
Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 1 *Bone marrow aspirate should be performed after day 22 as asoon as maximum counts are reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to consolidation when neuts >1.0x 10
9/L and plts >100x10
9/L. See protocol for further details.
**Local policies may be followed for folinic acid resuce-
Regimen: Intensive + Consolidation in elderly ALL (Ph -ve)* 21 days cycle
Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day14 Ref: UKALL60+ Vincristine 1mg/m2 IV (max dose 2mg) Day 1,8,15
Doxorubicin 40mg/m2 IV Day 1,8,15
Prednisolone 40mg/m2 divided in 2 daily doses Days 1-21 *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to consolidation 2 when neuts >1.0x 10
9/L and plts >100x10
9/L but no sooner than “day 22” of consolidation1. See protocol
for further details. **Dexamthasone 4mg IT may be substituted with hydrocoertisone suspended in 3- 6ml sterile saline.
Regimen: Intensive + Consolidation 2 in elderly ALL (Ph -ve)* 22 days cycle
Cytarabine 1000mg/m2 IV Day1,2 Ref: UKALL60+ Pegylated-asparaginase 1000iu/m2 Day 3,18
OR
E.coli Asparaginase 6000iu/m2 Day3-12
Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 1
*Proceed to maintenance year 1 when neuts >1.0x 109/L and plts >100x109/L.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 26 of 54
Regimen: Intensive + Maintenance year 1 in elderly ALL (Ph -ve)* 13x28 day cycles
Prednisolone 1mg/kg/d PO Day1-7 Ref: UKALL60+ Vincristine 1.4mg/m2 IV (max dose 2mg) Day 1
6-mercaptopurine 75mg/m2 PO Day 1-28
Methotrexate 15mg/m2 PO Days 8,15,22
Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 2 **NOTE Methotrexate 12.5 mg+Dexamethasone 4mg IT is to given at day 2 ONLY during the first 4 cycles of maintenance treatment Patients may only proceed to maintenance year 2 after year 1 when neuts >0.75x 10
9/L and plts >75x10
9/L.
Regimen: Intensive + Maintenance year 2 in elderly ALL (Ph -ve)* 13x28 day cycles
6-mercaptopurine 75mg/m2 PO Day 1-28
Methotrexate 15mg/m2 PO Days Day1,8,15
Nonintensive pathway in ALL Philadelphia –ve patients
Regimen Induction Phase 1 Elderly ALL (Ph -ve)* 28days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 (cap at 2mg) IV Day 1
Methotrexate 5mg/m2 PO Days 1,8,15,22
6-mercaptopurine 25mg/m2 PO Day 1-28
Methotrexate 12.5mg IT Once during cycle
Patients may only proceed to phase 2 when neuts >0.75x 109/L and plts >75x109/L.
Regimen Induction Phase 2 Elderly ALL (Ph -ve)* 28days
Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1
Vincristine 1mg/m2 (cap at 2mg) IV Day 1
Methotrexate 5mg/m2 PO Days 1,8,15,22
6-mercaptopurine 25mg/m2 PO Day 1-28
Methotrexate 12.5mg IT Once during cycle
Patients may only proceed to consolidation 1 when neuts >0.75x 109/L and plts >75x109/L.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 27 of 54
Regimen Induction Consolidation Elderly ALL (Ph -ve)* 28days
6-mercaptopurine 25mg/m2 -75mg/m2 PO Daily Ref: UKALL60+ Methotrexate 5mg/m2 PO weekly
Prednisolone 60mg/m2 5 days every 3 months
Methotrexate 12.5mg IT Every 3 months but may be omitted at discretion of treating clinician
Vincristine 1.4mg/m2 (max 2mg/dose) IV Every 3 months
Patients may only proceed to maintenance after consolidation 1 when neuts >0.75x 109/L and plts >75x109/L.
3. Elderly or frail: Vincristine x4 (1mg) and prednisolone followed by standard maintenance
is simple. CNS prophylaxis may be considered on a case-by-case basis, and would be
with serial lumbar punctures following the completion of the vincristine phase.
ALL non intensive
Vincristine 1mg IV Days 1,8,15,22 Ref:
Prednisilone PO 40 mg/m2 Days 1-28 followed by taper
4.3.5 Treatment of primary refractory disease
This will be defined post 2nd phase induction in UKALL XIV regime or equivalent time
point in other treatments.
• See below for a discussion of the use of Imatinib in Ph+ve cases.
Refractory disease has a dismal outlook with no schedule being clearly optimal.
• We suggest HyperCVAD (Kantarjian, et al 2000) for B cell ALL and hyper-CVAD with a
Nelarabine containing regimen for T cell ALL. Other alternatives including FLAG-Ida or
High dose Ara-C schedules or clofarabine alone can be considered as 3nd line treatment.
Nice has not reviewed Nelarabine but SMC has “accepted nelarabine for the treatment of
patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic
lymphoma (T-LBL) whose disease has not been improved or has returned following
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 28 of 54
treatment with at least two chemotherapy regimens. It should only be used by specialists
as a treatment to bridge to stem cell transplant”. Therefore Nelarabine would be subject to
a CPC until routinely commissioned.
Hyper CVAD Course A
Cyclophosphamide 300mg/m2 Days 1,2,3 Ref: J Clin Oncol. Feb; 18(3) Doxorubicin 50mg/m2 Day 4
Vincristine 2mg Days 4, 11
Dexamethasone 40mg Days 1-4, 11-14
Hyper CVAD Course B
Methotrexate 200mg/m2 Days 1 Ref: J Clin Oncol. Feb; 18(3) Methotrexate 800mg/m2 Days 1
Cytarabine 3000mg/m2 Days 2,3
Nelarabine
Nelarabine 1500mg/m2 Days 1,3,5 Ref: Blood 2007; 109
Nelarabine/Cyclophosphamide/Etoposide
Nelarabine 650mg/m2 Days 1,2,3,4,5 Ref: Br J Haem 2010, 150
Cyclophosphamide 440mg/m2 Days 1,2,3,4,5
Etoposide 100mg/m2 Days 1,2,3,4,5
Clofarabine
Clofarabine 40mg/m² Days 1,2,3,4,5 Ref: Blood (2005) 105 NO3. P940-947 AML 16
It may be worth discussing these patients with the trial co-ordinators and they should all be
reviewed at the MDT.
4.3.6 Treatment of ALL relapsing after CR (Fielding, et al 2007)
• There is no current trial within the network. UKALL XIV patients should be discussed with
the trial co-ordinators.
• If there is still curative intent then transplant options will be considered if possible and the
patient should be discussed with the transplant centre prior to a decision to give further
treatment as this may influence the choice of therapy.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 29 of 54
• Outcome after relapse (Fielding, et al 2007). Survival at 1 year was 22% and 7% at 5
years.
• Factors predicting a good outcome after salvage therapy were:
1. Young age (OS of 12% in patients younger than 20 years vs. OS of 3% in
patients older than 50 years; P < .001)
2. Duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2
years versus OS of 5% in those with a CR1 of less than 2 years; P < .001)
• HyperCVAD (Koller, et al 1997) for B cell ALL and hyper-CVAD/CLAEG for T cell ALL
followed by transplant is the recommended option. Nelarabine may be used as 2nd line
agent (licensed for 3rd line use). CNS prophylaxis in the form of intrathaecal therapy with
12 mg MTX on day 2 and 8 with each course of Hyper CVAD.
• See below for a discussion of the use of Imatinib in this setting for Ph+ve cases.
• These cases need discussion at an MDT incorporating transplant advice (see above).
Relapse has a very poor prognosis, particularly if it occurs less than a year from treatment
end. If there is no transplant option then further chemotherapy can be considered as for
refractory cases (see above).
Monotherapy in relapsed/refractory cases can achieve CRs in up to a third of patients
although these are not durable. Imatinib can be a useful agent in re-establishing short term
remission prior to transplant. Post transplant relapses can also be managed in this way.
The place of Imatinib in these circumstances should be discussed at an appropriate MDT
(see above). Dasatinib or Nilotinib can be used for refractory relapse on Imatinib. CNS
prophylaxis must be considered in the context of the treatment schedule agreed at the
MDT. (Level 1). NOTE : Dasatinib and Nilotinib are not routinely commissioned for use in
Ph+ve ALL and would be subject to approval through an IFR.
Imatinib
Imatinib 400mg (up to 600mg as tolerated)
Days 1-28 Ref: MRC UKALL 12
Dasatinib
Dasatinib 140mg once daily
Days 1-28 Ref: Blood 2008; 112
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 30 of 54
Nilotinib
Nilotinib 400mg twice daily Days 1-28 Ref: Blood 2007; 110 (10)
4.3.7 CNS leukaemia at diagnosis
• The UKALLXIV protocol can be followed for all patients. This consists of weekly IT MTX
until clear then radiotherapy, depending on whether they are proceeding to transplant.
• As an alternative to IT MTX, IT Depocyte should be considered. (note Depocyte is not
routinely commissioned and would be subject to approval through an IFR).
• For CNS and BM relapse consider* IT + Salvage therapy (hyper-CVAD)
• For Solitary CNS relapse consider* IT + Salvage therapy (as above)
All above salvage treatments should be consolidated with a transplant modality
(*Consider radiotherapy for CNS disease if no transplant option)
Special issues in prophylaxis
Fungal infection – continues to be a particular hazard. Prophylaxis must be with a
minimum of oral fluconazole (itraconazole may be better but is not proven). Serious
consideration should be given to prophylactic amphotericin B i.v. at a dose of 0.25-
0.5mg/kg on alternate days (no standard dose has been established).
Please note that there is a drug-drug interaction between itraconazole and
vincristine which lead to increased vincristine neurotoxicity. Posaconazole could be
considered as antifungal prophylaxis for first induction when vincristine is used.
PCP – Prophylaxis is required and is standard (example: septrin 960mg bd orally 3x a
week or atorvacone or dapsone.).
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 31 of 54
4.3.8 Transplant
MRC UKALL XII/ECOG E2993, sibling donor versus no-donor analysis, showed that
Philadelphia chromosome–negative patients with a donor had a 5-year improved overall
survival (OS), 53% versus 45% (P= .01), and the relapse rate was significantly lower (P
.001).
The survival difference was significant in standard-risk patients, but not in high-risk
patients with a high non relapse mortality rate in the high risk donor group.
Patients randomized to chemotherapy had a higher 5-year OS (46%) than those
randomized to autologous transplantation (37%; P =.03).There is no evidence that a single
autologous transplantation can replace consolidation/maintenance in any risk group
(Goldstone, et al 2008)
4.4 MYELODYSPLASTIC SYNDROMES
Diagnostic Criteria
Typical Cases
• Hypercellular marrow in the presence of cytopenia
• Erythroid series shows nuclear budding or bridging, vacuolation of late erythroblasts,
multinuclear cells, asynchronous haemoglobinisation.
• Myeloid series shows abnormal granulation, pseudo-Pelger change, maturation
asynchrony, increased numbers of CD34+ myeloblasts, usually >3.5% by flow cytometry.
The blasts should have the phenotype CD34+, CD45+, CD117+, CD15-.
• Megakaryocytes are cytologically abnormal with micro forms and nuclear lobe
separation.
• Single lineage dysplasia in the appropriate clinical context is sufficient for a diagnosis of
MDS (WHO classification)
Variants
• Any of the above features in a hypocellular marrow. Increased bone marrow fibrosis and
an excess of blasts are most useful to differentiate from aplastic anaemia.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 32 of 54
• 5q- as sole cytogenetic abnormality often with increased abnormal megakaryocytes +/-
increased platelets and anaemia.
Prognostic Factors
The International Prognostic Scoring System (IPSS) is superior to earlier systems and will
increasingly inform therapeutic decision making (viz. 5q- and Lenalidomide) (Greenberg, et
al 1997).The IPSS requires cytogenetic analysis in all patients, and cytogenetic analysis is
therefore recommended for all patients at diagnosis. If cytogenetics is not available, the
Sanz score can be used (Sanz, et al 1989).
Management
The following recommendations are based on a very limited evidence base with little
standardisation between studies. Supportive treatment with blood and platelet
transfusions, and antibiotics is the mainstay of treatment, but selected groups may benefit
from chemotherapy and other specific treatment. (Bowen, et al 2003)
Anaemia
• RBC transfusion should be considered in any patient with symptomatic anaemia.
• Iron chelation with s/c desferrioxamine should be considered principally in stable
transfusion dependent patients with low/INT-1 IPSS score (predicted survival > 4 yrs)
(especially pure sideroblastic anaemia [WHO RARS], pure refractory anaemia [WHO RA]
and 5q- syndrome).
Initiate iron chelation at serum ferritin >1000 mcg/l, with annual eye and ear assessment.
There is no evidence for benefit from IV desferal given at the same time as blood
transfusion. Desferrioxamine remains chelator of choice if tolerant and effective.
Alternatives are Deferiprone (This is not licensed for these indications, requires a weekly
full blood count and should be initiated only if the baseline neutrophils > 1.5 x 109/l),
Deferasirox (not supported by SMC for use in MDS but licensed for this indication) and a
combination of Deferiprone daily plus Desferrioxamine 3 x /week.
Erythropoietin (EPO) +/- G-CSF can reduce transfusion requirements in selected patients.
This will become increasingly important as blood supplies fall. This should be restricted to
patients with Serum EPO < 500 IU/l and Low transfusion requirement (≤ 2 units / month).
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 33 of 54
Immunosuppression with ALG or cyclosporin can be beneficial in hypoplastic MDS. ALG
should only be used in patients <65 years and only in centres with experience of its use in
aplastic anaemia. (Level 2). Prednisolone is started on the day after ATG is completed at
dose of 1 mg/kg/day for two weeks, followed by rapid tapering over the following two
weeks. CSA should be commenced as the prednisolone dose is tapered, at a dose of 5
mg/kg/day to achieve trough blood levels of 100 to 200 μg/l. CSA should be continued
whilst the blood count continues to rise.
A slow tapering of the drug (25 mg every 2‒3 months) can be started after a minimum of a
further 6 months of therapy, to reduce the risk of later relapse. (Guidelines for the
Diagnosis and Management of Adult Aplastic Anaemia- BCSHguidelines 2015)
ATG Rabbit
Methylprednisilone 2mg/kg Days 1-5 Ref: B. J. Haem 2009; 147
ATG Rabbit 2.5mg/kg Days 1-5
ATG Horse*
Methylprednisilone 2mg/kg Days 1-4 Ref: N Eng J Med 2011; 365 ATG Horse 40mg/kg Days 1-4
*ATG Horse – is available through request via CPC
Lenalidomide (Revlimid) is an effective agent in MDS with del 5q and has been approved
by NICE for use in this condition TA 322.
Consider trial of EPO plus low/ absent transfusion * G-CSF for 6-12 weeks
Marrow not hypo-cellular, or RA/RAEB plus EPO<200U/l Consider trial of EPO for 6
Hypo-cellular but pt unfit for low/ absent transfusion * weeks, then add G-CSF for
immunosuppression 6 weeks +/- EPO escalation
Other: high EPO +/- Supportive care
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 34 of 54
ANAEMIA
(symptomatic) *<2units/month Hypocellular marrow Consider ALG if suitable
Neutropenia
• Neutropenic sepsis should be managed as for patients undergoing chemotherapy
according to the hospital antibiotic policy.
There is no indication for routine antibiotic or antifungal prophylaxis, or for prophylactic
growth factor support. Anecdotally regular granulocyte colony-stimulating factor by sc.
route can be helpful in patients with severe neutropenia and recurrent life threatening
infections.
Thrombocytopenia
• Both the degree of thrombocytopenia and platelet dysfunction can contribute to bleeding
problems. In the absence of bleeding or fever, the threshold for platelet transfusion is 10 x
109/l.
• Antifibrinolytics and danazol may be useful in some patients.
Consider if any trials open for eligibility
Chemotherapy and Stem Cell transplantation
• All MDS patients, with the possible exception of IPSS Low plus limited symptomatic
cytopenias should be considered at diagnosis for suitability for allogeneic stem cell
transplant and should be discussed with the transplant team as appropriate.
• Non-intensive: patients aged >60 years with >10% blasts should be offered therapy
within the AMLL1 non-intensive trial if appropriate.
5-azacytidine (Vidaza) improves overall survival in MDS patients with IPSS/INT-2 and
CMML-2 (non-proliferative with WCC< 15 x 109/L by 9 months) (24 months) compared with
conventional care regimens (15 months)(supportive care, low dose cytarabine, or intensive
chemotherapy) achieving haematological responses in up to 45% of patients with MDS,
and complete remissions in up to 20%.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 35 of 54
Azacitidine
Azacitidine 75mg/m2 Days 1-7 Ref: Itzykson et al. Blood 2011
Responses are similar with 5-aza-2- deoxycytidine(Decitabine/Dacogen) but a survival
advantage has yet to be demonstrated.
5- azacitidine is licensed in Europe and is the worldwide standard of care for the above
MDS categories.
Intensive: patients aged >60 years with >10% blasts should be offered therapy within the
AML18 intensive trial. Patients <60 years with >10% blasts and/or INT-2/ High risk disease
should be considered for the NCRI AML17 study.
All patients < 70 years should be considered for fitness for stem cell transplantation. In
patients <55 years, if a donor (sibling or unrelated) is available, allogeneic stem cell
transplantation should be discussed. In fit patients >55 years reduced intensity allogeneic
stem cell transplantation should be considered.
• Selected patients with INT-1 or even Low risk MDS should be considered for allogeneic
SCT on individual grounds. (Level 4) Examples include young patients with platelet
refractory thrombocytopenia, or heavy red cell transfusion requirement in the absence of
an alternative cause for anaemia. Chemotherapy prior to transplant will be necessary in
this group only in the rare patient with blasts 5-10%.
• Reduced intensity SCT (Level 4) should be offered in the context of clinical trials, where
available. Data for RIC SCT outcome are encouraging, particularly in the INT-1 / INT-2
patients.
• Note that a raised serum ferritin >2500 mcg/l is an adverse prognostic factor for
transplant related mortality and overall survival in MDS patients treated with allografts. As
yet there is no evidence that this adverse outcome can be modified by pre-transplant iron
chelation therapy.
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4.5 Myelodysplastic / Myeloproliferative Neoplasms
Typical Cases
• Bone marrow examination with cytogenetics is required for diagnosis. FBC should be
supplied to HMDS on request.
• Persistent peripheral blood (1 x 109/l) monocytosis (>3 months)
• <20% bone marrow blasts.
• Normal or MDS type cytogenetics.
Variant
CMML with eosinophilia and translocations involving the PDGFRgene is rare but
important, as this variant is sensitive to imatinib therapy.
Refractory Anaemia with Ring Sideroblasts and thrombocytosis (RARS-t) is JAK2
mutated in 50% cases.
A very rare variant is described without monocytosis but with increased neutrophil and
immature myeloid cells in peripheral blood. This is termed atypical CML. Absence of BCR-
ABL is essential and the report must describe this as an MDS variant to avoid confusion
with CML.
Management
• CMML patients should be managed with supportive care for cytopenias and
cytoreductive therapy with hydroxycarbamide for symptomatic myeloproliferation.
Although chemotherapy alone is rarely effective for CMML, younger and / or fitter
patients should be discussed with the transplant team for consideration of allograft
4.5.1 CHRONIC MYELOID LEUKAEMIA
Diagnostic Criteria
Chronic phase CML
• t(9;22) as part of a single or complex translocation, or BCR-ABL transcripts must be
present in every case
• Maximally cellular marrow with left shifted, myeloid series, monolobated megakaryocytes
and suppressed erythroid series
• <5% blasts in bone marrow
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 37 of 54
Prognostic Groups
• 5-10% blasts. The marrow should be repeated in 1 month to establish rate of change of
blast cell population.
• Accelerated phase (AP): 10-19% blasts or >20% basophils in marrow or blood,
associated with clinical progression or refractoriness to treatment (WHO criteria). Other
features may include persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or
persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy; increasing WBC
unresponsive to therapy; cytogenetic evidence of clonal evolution and excessive marrow
fibrosis or dysplastic features.
• Blast crisis (BC): >20% myeloid blasts or >5% lymphoid blasts or solid extramedullary
tumour deposit consisting mainly of blasts.
Essential Investigations
• Full blood count with manual differential.
• Full examination with documentation of liver and spleen size. Ultrasound scanning of the
abdomen to more accurately document spleen size may be considered.
• Routine biochemistry to include U&Es, LFTs, calcium, LDH and urate.
• Bone marrow aspirate and trephine with sample sent for cytogenetics
• Bone marrow and peripheral blood sample for RT-PCR
• All newly diagnosed patients should have either a Sokal or Hasford (Euro) score
calculated.
This can be done using simple web based programmes found at www.roc.se/sokal.asp
and www.pharmacoepi.de. respectively
• A full family history, in particular paying attention to potential sibling donor details, should
be taken. Tissue typing may need to be considered.
4.5.2 Primary Therapy
Patients in Chronic Phase (CP)
• All new patients should be offered entry into the SPIRIT 3 study when open which will
start all patients on imatinib and then change therapy in those who do not have an
adequate response at 3 months.
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• In the absence of published data to support the role of autologous stem cell
transplantation in the treatment of CML, routine collection of autologous stem cells at
diagnosis is not indicated.
In patients with symptoms of leucostasis consideration may be given to therapeutic
leucopheresis.
• All patients should be well hydrated and receive allopurinol 300mg daily.
• In non-trial patients, initial cytoreductive therapy should be with Imatinib 400 mg daily or
Nilotinib 300mg bd.(depending on patient age and comorbidities). NICE TA 251.
Imatinib CML
Imatinib 400mg Days 1-28 Ref:
Nilotinib CML
Nilotinib 300mg bd (may be escalated up to 400mg-600mg bd depending on clinical situation
Days 1-28 Ref: Blood 2007; 110 (10) Nilotinib SPC
• Initial therapy with hydroxycarbamide 0.5g – 2g daily can be considered for patients
contemplating entry into SPIRIT 3 or other drug trials.
Hydroxycarbamide
20mg/kg Days 1-28 Ref: Hydroxycarbamide SPC
Monitoring of therapy
• FBC, U&Es and LFTS weekly for 1st 4 weeks, then reduced frequency depending on
response.
• All patients should have a baseline bone marrow examination with cytogenetic analysis
and peripheral blood sample for quantitative RT-PCR.
• Peripheral blood PCR should be carried out every 3 months. 10ml of EDTA blood is
required.
• Bone marrow (BM) examination with cytogenetics should be carried out in patients with
an inadequate response according to the following criteria:
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 39 of 54
At 3 months:
If 1 log reduction in BCR-ABL not achieved (5.5% according to local reference range)
(BM should be performed at 6 months).
At 12 months:
If <3 log reduction (>0.055%)
Bone marrow cytogenetics should also be performed on patients who have > 2-5 fold rise
in BCR-ABL, confirmed on repeat sample taken at a six week interval. Mutation screening
will also be performed
Response Criteria
• Optimal response according to the revised European leukaemia Net Guidelines
(Baccarani, et al 2013) are:
At 3 months, at least a partial cytogenetic response (PCyR - Ph +ve < 35%) or BCR-
ABL1<10%
After 6 months of therapy: A complete cytogenetic response or BCR-ABL1<1%
After 12 months of therapy BCR-ABL1<0.1%
Patients in Accelerated Phase (AP)
• Patients presenting in the accelerated phase of CML should receive Imatinib 600mg
daily, which is associated with a reported progression-free survival rate of 67% at 12
months, and overall survival of 66% at 36 months.
Patients in Blast Crisis (BC)
• Patients presenting in blast crisis present a difficult management problem. The best
responses have been reported to Imatinib 600-800mg daily, with reported 12 month
survival rates of 32%.Major cytogenetic responses have been reported in 16% of patients,
and complete cytogenetic responses in 7%. Dasatinib is also licensed for this indication, at
a dose of 70mg bd and nilotinib at 400mg bd.
• NICE do not recommend continued use of Imatinib in patients presenting in CP who progress to AP or BC after exposure to the drug. Management of such cases should be discussed with the MDT lead for Leukaemia, but a second generation tyrosine kinase inhibitor (2G – TKIs, Nilotinib should be given while assessing BMT options. For patients in
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 40 of 54
BC, options include acute leukaemia type therapy (as for AML or ALL depending on phenotype) and rarely, autologous stem cell transplantation. NOTE NICE (TA 251) does not recommend Dasatinib for people with chronic myeloid leukaemia in the chronic phase who have not had treatment for chronic myeloid leukaemia before. Therefore its use would be subject to approval through an IFR
Side effects of imatinib and their management
Imatinib is well tolerated by the majority of patients.
• Nausea if it occurs often improved if the drug is taken with food, or split doses. Normal
antiemetics
and in the few patients who experience diarrhoea, anti-diarrhoeal agents can be given
• Side effects include mild allergic type rashes, which may respond to simple anti-
histamines.
• Severe dermatological reactions have been documented which may require steroid
therapy or in some cases the discontinuation of Imatinib.
• Arthralgia is seen in 60% of patients and usually responds to simple treatment with
nonsteroidals, and usually settles after the first few months of treatment
• Fluid retention may be troublesome and occurs in the majority of cases often just as
simple peri-orbital oedema. More severe oedema is often quite refractory to diuretic
therapy and may require dose reduction or discontinuation. Reducing salt intake should be
tried.
• Cytopenias may occur in up to 14% of patients. If thrombocytopenia (plts < 50 x 109/l) or
neutropenia (neuts < 1 x 109/l) develop, imatinib should be stopped. If counts recover in
two weeks, restart at 400mg/day. If not consider introducing at 300mg/day with G-CSF or
platelet support as necessary. Symptomatic anaemia should be managed with blood
transfusions as clinically indicated, but erythropoietin therapy may be effective.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 41 of 54
4.5.3 Management of Chronic Myeloid Leukaemia Patients who are resistant or intolerant to imatinib Intolerance
• Patients who are intolerant of imatinib should be treated with a second generation TKI, ie nilotinib. NOTE NICE does not recommend Dasatinib for people with chronic myeloid leukaemia in the chronic phase who have not had treatment for chronic myeloid leukaemia before and its use would be subject to approval through an IFR. The choice would be influenced by the nature of the intolerance to imatinib, and also other pre-morbid conditions as per resistant patients. Sub-optimal response
The following describes a reasoned approach to the patient with a sub-optimal response:
• Consider compliance (which may require use of plasma level monitoring)
• If the patient has achieved a complete cytogenetic response but not a major molecular
response, consider merely continuing at present dose and monitoring closely. CCyR is the
most important prognostic factor for progression free survival and as long as the patient
achieves a CCyR, OS and PFS are not affected by how long it takes to get there.
• However if CCyR has not been achieved by 18 months of therapy, consider dose
escalation.
Failure
• Patients failing imatinib should receive a 2nd generation tyrosine kinase inhibitor.
Published efficacy data show little difference between the two licensed drugs, Nilotinib
400mg bd and Dasatnib 100mg od in this setting.
NOTE NICE does not recommend Dasatinib for people with chronic myeloid leukaemia in
the chronic phase who have not had treatment for chronic myeloid leukaemia before and
its use would be subject to approval through an IFR.
Factors that may influence choice are:
Presence of a kinase domain mutation:
This information will only be informative in a minority of patients, where the presence of a
so called ‘breakthrough’ mutation will predict the response to one or other of the available
TKIs. These are Y253H, E255K/V and F359C/V which will be resistant to Nilotinib, and
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 42 of 54
F317L and V299L which will be resistant to Dasatinib. T315I is associated with resistance
to both 2G – TKIs as well as imatinib and such patients should not be treated with these
agents, and be assessed for allogeneic SCT.
Pre-morbid conditions
The following table summarises the factors that may influence choice of one or other 2nd
generation TKI (after Laneuville, 2009):
Co-morbidity Dasatinib Nilotinib
Pancreatitis Y N
Cardiovascular disease N Y
Autoimmune disease N Y
Dietary restriction Y N
Post SCT N Y
GI bleeding N Y
Cardiac disease ?Y ?N
(arrhythmia, prolonged QTc)
4.5.4 Management of CML in Pregnancy
• There is little in the way of large published series about the management of chronic
myeloid leukaemia in pregnancy. However, a number of the concerns that are associated
with myeloproliferative disorders (MPD) in pregnancy will also apply to CML.
• There are two scenarios:
1. A patient presenting with CML in pregnancy
2. A patient on Imatinib who becomes pregnant
• As regards the first scenario, there is little evidence that pregnancy itself adversely
affects the natural course and prognosis of CML but any haematological disorder that may
lead to hyperleucocytosis and possibly thrombocytosis is likely to affect fertility, and may
lead to an adverse outcome of the pregnancy itself because of thrombotic or bleeding
complications.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 43 of 54
This is certainly true in primary thrombocythaemia (PT) where first trimester abortion is the
most frequent complication but increased perinatal mortality and premature delivery are
also observed. Placental infarction due to thrombosis is the most consistent event.
As regards management, it is desirable that some attempt to control the white cell count
(and perhaps platelet count) in pregnancy should be attempted. However, Imatinib is
teratogenic with a 25 % incidence of fetal abnormality in the only series collected (Pye, et
al 2008)
Hydroxyurea is teratogenic in animals and one stillbirth and one malformed infant have
been reported after exposure in pregnancy. It should generally be avoided, but there are
several well documented cases of successful outcomes in PT with hydroxyurea given
throughout pregnancy.
• Alternative treatments include -interferon, which has been well documented as being
safe in the management of PT in pregnancy, and leucopheresis. This is the most common
therapeutic manoeuvre cited in the literature with good control of the white cell count and a
successful outcome for mother and baby in all reported cases.
Based on the published evidence, a reasonable recommendation for the management of
CML in first chronic phase diagnosed in pregnancy would be as follows:
• Initial leucopheresis to control the white cell count, together with allopurinol and aspirin
therapy, especially if there is associated thrombocytosis.
• Instigation of -interferon therapy to maximum tolerated dose to control the white cell
count with intermittent leucopheresis to keep the white cell count below 20 x109/l and
platelets below 400 x109/l until delivery.
• No particular precautions need to be taken at delivery, assuming stable peripheral blood
parameters, and normal vaginal delivery should be possible.
• The management of accelerated phase or blast crisis occurring in pregnancy is much
more difficult. Either of these situations should warrant consideration of early termination of
pregnancy and the introduction of Imatinib therapy, but it is possible that hydroxyurea may
control the situation at least until the baby is of a great enough gestational age to deliver
safely. This policy would be associated with a relatively low risk of foetal abnormality. More
specific therapy, including bone marrow transplantation could then be considered following
parturition.
• In the second scenario, management will be influenced by to the patient’s response thus
far to imatinib, and its duration. Recently published data suggests that stopping imatinib in
patients who have achieved a stable complete molecular response (greater than 2 years)
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 44 of 54
can be done with only a small risk of disease progression, with re-establishment of control
if progression occurs (Mahon, et al 2008). Consideration in such a patient could be given
to discontinuing therapy and monitoring closely until delivery. In all other cases, interferon
therapy as described above would be preferable.
4.5.5 Bone Marrow Transplantation
• Bone marrow transplantation remains the only proven curable treatment for patient with
chronic myeloid leukaemia. However, the emergence of Imatinib has led to a reappraisal
of the appropriate timing of BMT. The current consensus is that all patients should have a
trial of imatinib therapy with close monitoring of their haematological, cytogenetic and
molecular responses. BMT remains an option for patients failing IM therapy, but treatment
with a 2G - TKI may be more appropriate in some patients. This should be discussed with
the MDT lead.
4.6 CHRONIC MYELOPROLIFERATIVE DISORDERS
Guidelines
The British Society for haematology has published and updated extensive guidelines
which cover all aspects of management of the myeloproliferative neoplasms.
Polycythaemia Vera
McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey
MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B.Guidelines for the
diagnosis, investigation and management of polycythaemia/erythrocytosis. Br. J.
Haematol. (2005) 130(2), 174-195.
McMullin MF, Reilly JT, Campbell P, Bareford D, Green AR, Harrison CN, Conneally E,
Ryan K. Amendment to the guideline for the diagnosis and investigation of
polycythaemia/erythrocytosis.British Journal for Haematology (2007) 138 (6) 821-2.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 45 of 54
Essential Thrombocythaemia
Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M, Erber W,
Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy C,
Radia DH, Reilly JT, Van der Walt J, Wilkins B, McMullin MF.
Guideline for investigation and management of adults and children
presenting with a thrombocytosis.
British Journal for Haematology (2010) (149) 352-375.
Harrison CN, Butt N, Campbell P, Conneally E, Drummond M, Green AR, Murrin R, Radia
DH, Reilly JT, McMullin MF. Diagnostic pathway for the investigation of
thrombocytosis. British Journal of Haematology ( 2013) May 161(4) 604-6.
Harrison CN, Butt N, Campbell P, Conneally E, Drummond M, Green AR, Murrin R, Radia
DH, Mead A, Reilly JT, Cross NC, McMullin MF. Modification of British Committee for
Standards in Haematology diagnostic criteria for essential thrombocythaemia.
British Journal of Haematology. (2014) Nov;167(3): 421-3.
Myelofibrosis
Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, Michaeel
NG, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison
CN; Writing group: British Committee for Standards in Haematology. Guideline for the
diagnosis and management of myelofibrosis. British Journal of Haematology (2012)
158(4):453-71.
Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe AS, Green AS, Mikhaeel
G, Gilleece MH, Knapper S, Mead AJ, Mesa RA, Sekhar M, Harrison CN. Use of JAK
inhibitors in the management of myelofibrosis: a revision of the British Committee for
Standards in Haematology guidelines for investigation and management of
Myelofibrosis 2012. British Journal of Haematology. (2014) Nov; 167(3): 418-20.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 46 of 54
Diagnostic Guidelines
Diagnostic criteria
Polycythaemia
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 × 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 × 109/l in non-
smokers; >12.5 × 109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 47 of 54
Diagnosis requires A1 + A2 + A3 + either another A or two B criteria
Essential thrombocythaemia
Diagnosis requires A1–A3 or A1 + A3–A5
A1 Sustained platelet count ≥450 × 109/l
A2
Presence of an acquired pathogenetic mutation (e.g. in the JAK2, CALR or MPL
genes)
A3 No other myeloid malignancy, especially PV, PMF, CML or MDS
A4 No reactive cause for thrombocytosis and normal iron stores
A5 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)
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 48 of 54
Myelofibrosis
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 symptomsa
B6 Histological evidence of extramedullary haematopoiesis
Investigation of Suspected Chronic Myeloproliferative Disorder
Raised EPO level – stop investigating for CMPD
JAK 2 /MPL and CALR mutations
Negative
Raised platelets*
No Fe def, no cause
Positive
Suspected
Myelofibrosis
Bone Marrow
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 49 of 54
Diagnosis of CMPD
RCM?? Monitor?
JAK 2 testing outside these indications is not interpretable
Diagnostic Criteria
With the exceptions listed below all cases will be reported using the generic term 'chronic
myeloproliferative disorder'.
The diagnosis can only be made on a trephine biopsy and will not be made where only
aspirate smears are available.
Typical Cases
• Marrow shows normal or increased cellularity
• Trilineage expansion with hyperlobated or clustered megakaryocytes
• If any suspicion of CML this should be excluded by PCR
• Blasts <5%. Blasts >5% require repeat marrow within one month to assess progression
to acute leukaemia
Chronic Idiopathic Myelofibrosis: increased reticulin/ fibrosis, sometimes with new bone
formation with appropriate clinical and peripheral blood features
Essential Investigations
• FBC – Hb is more sensitive than HCT
• Red cell mass (if Hct is normal/ high normal)
• Bone marrow aspirate & trephine biopsy (see diagnostic guidelines)
• Ultrasound abdomen
• CRP, ESR or PV
• U&E, LFT
• EPO
• Ferritin
Mutation analysis for JAK2/MPL/CALR/ASXL1
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 50 of 54
Primary Therapy of Essential Thrombocythaemia
Recommendation: Risk stratification
Patients should be stratified according to their risk of thrombotic complications. The most
widely accepted risk stratification is as follows:
All patients: asses for ET-related thrombotic risk age, prior history, platelet count
Assess and optimize other vascular risk factors,
such as smoking and diabetes
Start aspirin unless contraindicated
High risk patients
ONE of age >60 yrs, platelet count >1500*109/l, disease related thombosis/haemorrhage
The treatment target should be platelet count <400*109/l
MPD-RC 112 Trial: Pegulated Interferon v Hydroxycarbamide
Hydroxycarbamide plus aspirin should be first line therapy
Interferon alpha is a reasonable treatment option for young patients
For patients who become refractory or intolerant of primary therapy – options include:
i) relaxing the platelet target to 600*109/l
ii) switching either partially (combination therapy) or completely to second line
therapy that is non-leukaemogenic where possible
Low and intermediate risk patients
Intermediate risk: age 40-60 yrs and no high risk factors
Low risk: age <40 yrs and no high risk factors
Treat with aspirin and reverse/aggressively manage vascular risk factors
Enter patient into a clinical trial where open
Only give cytoreductive therapy:
i) in the context of a clinical trial
ii) or if symptomatic (e.g. progressive
splenomegaly, erythromelalgia)
iii) or other severe microvascular symptoms not improved with aspirin
iv) or uncontrolled bleeding associated with high platelet counts
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Therapy of Polycythaemia
Polycythaemia vera
• Venesection to maintain the Hct to <0.45.
• Aspirin 75 mg/d unless contraindicated.
• Cytoreduction should be considered if: poor tolerance of venesection; symptomatic or
progressive splenomegaly; other evidence of disease progression, e.g. weight loss, night
sweats; thrombocytosis.
• Choice of cytoreductive therapy, if indicated:
<40 years old: first line interferon, second line hydroxycarbamide
40–75 years old: first line hydroxycarbamide, second line interferon
>75 years old: first line hydroxycarbamide, second line 32P or intermittent low dose
Busulphan
Idiopathic erythrocytosis
• Venesection to reduce the Hct to <0.45 if Hct >0.54.
• Venesection to reduce the Hct to <0.45 if <0.54 and there is increased risk of thrombosis,
i.e. evidence of ischaemia, previous history of thrombosis, peripheral vascular disease,
diabetes or hypertension.
• Cytoreductive therapy is contraindicated
Refer to BCSH Guidelines for details
Therapy of Idiopathic Myelofibrosis
Risk assess using IPSS or current scoring system
Ruxulitinib is licensed for myelofibrosis and is recommended as first line therapy with
symptomatic splenomegaly and/or myelofibrosis related constitutional symptoms which are
impinging upon the quality of life and hepatomegaly and portal hypertension due to
myelofibrosis. NICE has recommended Ruxulitinib (TA 368) in adults with disease-related
splenomegaly or symptoms caused by primary myelofibrosis (also known as chronic
idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential
thrombocythaemia myelofibrosis, only if they have intermediate-2 or high-risk disease. It
will require CPC.
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 52 of 54
Open trials should be considered in all patients.
A trial of EPO may be given to patients who are symptomatically anaemic and have serum
EPO <120 U/l
Other options which may be considered:
• α-interferon or thalidomide may be efficacious in some cases
• Hydroxycarbamide for: platelets, WBCs or hypermetabolic symptoms
• Splenic irradiation for: hypermetabolic symptoms, leucopenia, symptomatic
splenomegaly or unfit for splenectomy
• Splenectomy should only rarely be considered due to the high complication rate but
indications may include symptomatic splenomegaly, hypersplenism, trauma or rupture
• Patients with a low or intermediate Dupriez score (Dupriez, et al 1996) receiving regular
red cell transfusion should be considered for iron chelation therapy after 25 transfused red
cell units.
• Allopurinol prophylaxis
• Encouraging data for RIC allogeneic stem cell transplantation are emerging. All patients
with IMF <65 years should be discussed with a transplant physician.
5.0 Dissemination
Ruxulitinib
Ruxulitinib 15mg bd Days 1-28 Ref: SPC Ruxulitinib BCSH guidelines – myelofibrosis 2012
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 53 of 54
This policy will be agreed by all consultant haematologists and clinical oncologists
managing patients with acute leukaemia . The guideline will form the basis for
development of the SACT regimen specific protocols. It will be available on the intranet for
use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and
delivery in patients with
6.0 MONITORING
Use of these guidelines will be monitored using audit.
7.0 EVIDENCE BASE / REFERENCES
Bibliography & references
NOTE these guidelines and protocols have been developed in conjunction with current
guidance from BSCH guidelines, protocols derived from current clinical trials along with
current recommendations from NICE, SMC and Northern Ireland Health Board. Clinicians
are reminded to refer to national guidelines and recommendations and specific trial
protocols for a more complete overview and reference.
8.0 CONSULTATION PROCESS
Consultant Haematologists and consultant Clinical Haematologists who manage acute
leukaemia, myelodysplastic/myeloproliferative disorders.
9.0 APPENDICES / ATTACHMENTS
10.0 EQUALITY STATEMENT
Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders Page 54 of 54
In line with duties under the equality legislation (Section 75 of the Northern Ireland Act 1998), Targeting Social Need Initiative, Disability discrimination and the Human Rights Act 1998, an initial screening exercise to ascertain if this policy should be subject to a full impact assessment has been carried out. The outcome of the Equality screening for this policy is:
Major impact Minor impact No impact.
SIGNATORIES (Policy – Guidance should be signed off by the author of the policy and the identified responsible director). Professor McMullin Date: Author Date: Director