Myeloproliferative diseases (MPDs) are clonal multipotential haemopoietic stem cell diseases, broadly characterized by:
• Proliferative behaviour, usually associated with:
• hypercellular bone marrow;
• increased numbers of one or more cell types in peripheral blood.
• Insidious onset.
• Chronic natural history, but tendency to:
• progress to bone marrow failure; or
• transform to acute leukaemia.
MPDs are predominantly adult diseases. Chronic myeloid leukaemia is rare and other MPDs exceedingly rare, in children.
Chronic myeloid leukaemia
• Although CML appears to be the same disease in molecular terms in patients of all ages (Myeloproliferative diseases, Chronic myeloid leukaemia, Aetiology p.[link]), it is much rarer in children than in adults, only accounting for 2–3% of childhood leukaemia.
• Incidence in children 0.6–1.2 per million person years.
• Slight male preponderance (1.2:1).
• Median age at presentation in paediatric age range is 12 years.
• Ionizing radiation is the only definitive causative agent.
• No definite genetic predisposition, although isolated cases have been reported in Down syndrome.
The molecular basis for CML is the BCR/ABL fusion gene, which codes for an abnormal tyrosine kinase (TK) protein product. In most patients this is visible cytogenetically, represented by the classical Philadelphia chromosome, with a t(9;22)(q34;q11) reciprocal translocation.
• 90–95% of children with CML have the Philadelphia chromosome (Ph+).
• The BCR/ABL fusion gene is present in ~50% of the remainder (2–5% overall) despite no visible Philadelphia chromosome.
• A very small number of paediatric CML patients are both Philadelphia and BCR/ABL negative.
Most children (and adults) present in chronic phase (CP), which is characterized by massive proliferation of morphologically normal and differentiated blood cells, including both mature granulocytes and to a lesser extent myeloid precursor cells, involving bone marrow, peripheral blood, spleen, and (less frequently) liver. Symptoms and signs are due to:
• Organ infiltration.
• Metabolic consequences of excessive myeloproliferation.
• ± features of hyperleucocytosis (Hyperleucocytosis pp.[link])
Most symptoms are explicable on the above basis, but nevertheless non-specific. Therefore, CML is sometimes diagnosed coincidentally (especially in adults) when a blood count is checked for other reasons, e.g. as a pre-operative check.
• Organ infiltration: bone pain, left upper abdominal fullness/discomfort.
• Metabolic consequences: systemic symptoms including fever, night sweats, lethargy, weight loss.
• ± Symptoms of hyperleucocytosis (e.g. neurological, visual, respiratory).
• ± Signs of hyperleucocytosis (e.g. focal neurological signs, papilloedema, retinal haemorrhages, tachypnoea).
The development of accelerated phase (AP) or blast crisis (BC) is usually accompanied by a progressive increase in systemic symptoms, whilst BC presents with additional symptoms and signs characteristic of acute leukaemia.
• CML is usually diagnosed in CP (for haematological features – see Myeloproliferative diseases, Chronic myeloid leukaemia, Investigation, Diagnosis p.[link]), and may remain in this phase (with or without treatment) for many years.
• AP is characterized by the presence of any one of a number of clinical, haematological or cytogenetic features:
• Clinical –
• increasing splenomegaly;
• development of a chloroma;
• presence of a previous BC.
• Haematological –:
• WCC rapidly rising (doubling in 5 days) or difficult to control;
• Hb <10g/dL or platelets <100 × 109/L, unresponsive to treatment;
• platelets >1000 × 109/L;
• blasts >10% but <30% in peripheral blood or bone marrow;
• blasts plus promyelocytes >20% in peripheral blood or bonemarrow;
• basophils plus eosinophils = 20% in peripheral blood.
• Cytogenetic abnormality in addition to Philadelphia chromosome.
• BC may occur in the context of either CP or more commonly AP, and is defined by >30% blasts in peripheral blood and/or bone marrow.
In CP CML:
• Marked leucocytosis with left shift.
• total WCC may reach 800 × 109/L;
• median WCC in childhood CML is ~250 × 109/L – higher than that seen in adults;
• severe hyperleucocytosis commoner in children than adults.
• Platelet count may be normal or show mild/moderate thrombocytosis (median 500 × 109/L).
• Mild normochromic, normocytic anaemia is common, but not invariable.
• Peripheral blood film shows the full range of differentiation of myeloid cells, including neutrophils, myelocytes, metamyelocytes, basophils, eosinophils:
• absolute basophilia is invariable, and absolute eosinophilia common (80% of patients);
• blasts may be seen, but usually <1–2%.
• ↑ Serum urate and LDH.
• ↓ Leucocyte alkaline phosphatase (LAP) (in contrast to ↑ LAP seen in leucocytosis 2° to infection), but now rarely used in clinical practice.
• Bone marrow aspirate/biopsy confirm marked hypercellularity:
• mostly granulocytic ± megakarocytic;
• despite hypercellularity, myeloid maturation unremarkable in appearance;
• blasts present but <10%.
• Cytogenetic analysis: usually performed on marrow, but feasible to analyse peripheral blood samples in some cases:
• standard karyotyping – t(9;22) i.e. Philadelphia chromosome, or variant, in >95%;
• fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) analysis nearly always demonstrates a BCR/ABL fusion gene.
• Other investigations performed at diagnosis should include:
• biochemical profile, including serum urate;
• coagulation profile;
• blood group;
• virology screen;
• HLA typing of patient and 1st degree relatives (parents, siblings).
Designation of disease phase (CP, AP, or BC) relies on a combination of clinical, haematological (blood and marrow) and cytogenetic features (Myeloproliferative diseases, Chronic myeloid leukaemia, Disease phase p.[link]).
Diagnostic difficulties are rare due to the characteristic cytogenetic findings. Possible differential diagnoses (which will all be Philadelphia or BCR/ABL negative, except for Ph+ acute leukaemia) include:
Chronic phase CML
• Leukaemoid reaction: splenomegaly usually absent or mild, infective/inflammatory source usually evident, LAP usually ↑.
• Juvenile myelomonocytic leukaemia (JMML): blood film usually shows a greater degree of monocytosis in JMML than in CML, whilst HbF is ↑ and skin involvement/lymphadenopathy common, in JMML but not CML.
• Other MPDs: granulocyte series is involved to a relatively much greater extent in CML than in other MPDs.
Blast crisis CML
• de novo acute leukaemia: can usually distinguished cytogenetically (no Philadelphia chromosome) and by lack of prior history of CP CML. BC CML is also typified by prominent splenomegaly and peripheral blood basophilia.
• de novo Ph+ acute leukaemia (Ph+ AL): can be much harder to distinguish, but nearly all children with Ph+ AL have atypical BCR/ABL rearrangements that produce a 190 kd TK protein, in contrast to the typical BCR/ABL rearrangements and 210 kd TK protein seen in CML.
General management at initial presentation
• Treat bleeding or infection if present.
• Ensure good hydration and start allopurinol to prevent tumour lysis syndrome. This may not be necessary in the rare patient with a low presenting white cell count (e.g. <20 × 109/L).
• Management of tumour lysis if present (rare) (Tumour lysis syndrome pp.[link]).
• Leucopheresis may be indicated:
• in hyperleucocytosis (especially in presence of symptoms or if WCC >300 × 109/L) (Hyperleucocytosis pp.[link]);
• to harvest autologous back-up stem cells for storage and possibly future use in the event of graft failure following HSCT (autologous marrow harvest may be performed at a later stage if leucopheresis is not performed at presentation).
Hydroxycarbamide (formerly called hydroxyurea [HOH]) is a short-acting S phase specific cytotoxic agent which normalizes blood count and reduces splenomegaly, but does not normalize cytogenetic abnormalities, nor modify the natural history of CML. Prior to the introduction of imatinib (Myeloproliferative diseases, Chronic myeloid leukaemia, Management, Initial treatment, Imatinib p.[link]), hydroxycarbamide was usually started at 15–30mg/kg orally once daily and the dose titrated to reduce WCC without excessive myelosuppression. Other side effects include skin rashes, but are uncommon.
Imatinib (IM) is a small molecule signal transduction inhibitor that acts by targeting specifically the BCR/ABL gene protein or other similar TKs. It is now the preferred initial treatment in most patients with CML, and it is anticipated that it will constitute effective long-term treatment for many.
• Usually started in newly diagnosed patients, or after withdrawal of hydroxycarbamide, at 260–340mg/m2 orally once daily with water (gastric irritant).
• Myelosuppression is common, managed by stopping IM if neutrophils <1 × 109/l or platelets <50 × 109/L, but since success of treatment appears to be reduced if low doses of IM are given, it appears preferable to support blood count (e.g. by transfusions or G-CSF) rather than stop IM or reduce dose repeatedly.
• Other side effects are common, including gastrointestinal symptoms (nausea, vomiting, diarrhoea), fluid retention ± oedema, cramps, bone pain, skin rashes, abnormal LFTs. In general, these should be managed symptomatically and dose reductions of IM avoided.
• Avoid concurrent use of paracetamol.
• Beware of potential interactions with drugs metabolized by CYP450 2D6 (e.g. codeine) or 3A4 (e.g. carbamazepine).
• Long-term IM has been used in adults for about 10 years, and is now being employed in an increasing number of children and adolescents, especially if a suitable well-matched allogeneic HSCT donor is not available.
• a small percentage of patients (<10%) achieve prolonged molecular remission but most relapse when IM is discontinued;
• however, no evidence yet that IM is curative.
• Response to treatment should be monitored very carefully using peripheral blood and bone marrow haematological and cytogenetic criteria (Chronic myeloid leukaemia, Response criteria p.[link]).
• If a complete molecular response is achieved (i.e. no detectable BCR/ABL transcripts using very sensitive methods) and maintained, medium-term evidence from adult studies and shorter-term experience in children suggests that long-term response is likely to be maintained and that it is appropriate to continue IM. However, almost all patients relapse when IM is discontinued.
• However, since IM was only introduced into clinical trials in adults in the late 1990s, information about long-term durability of response remains preliminary. Therefore, continued response monitoring is important, and HSCT should be considered if there is any loss of complete molecular response, or if molecular analysis demonstrates the presence of a BCR/ABL mutation associated with a higher risk of IM resistance.
• Historically, HSCT has been the mainstay of curative treatment strategies for children and adolescents with CML, and it remains the only treatment with a proven record of very long-term (i.e. >10 years) survival and apparent cure.
• Outcome of transplant is better (in particular, relapse rate is reduced) if HSCT performed in CP rather than more advanced disease (i.e. patients with previous AP or BC).
• Evidence from the pre-IM era shows that the outcome of HSCT is better if transplant is performed within 1 year of initial diagnosis. It is not yet known if this remains true for patients treated with IM.
• Most HSCT protocols employ either cyclophosphamide/total body irradiation (CyTBI) or busulfan/cyclophosphamide (BuCy) conditioning, with additional GvHD prophylaxis in unrelated donor transplants (Haemopoietic stem cell transplantation, Graft-versus-host disease prophylaxis p.[link]). CyTBI is usually preferred to BuCy for more advanced disease and for unrelated donor HSCT. There is little experience yet with the use of reduced-intensity conditioning for CML in children.
• Interferon-α (IFN-α) may be indicated in patients intolerant of IM and without a suitable HSCT donor. Most protocols give 3 MIU subcutaneously once daily with concurrent paracetamol to reduce ‘flu-like’ side effects. Compared to hydroxycarbamide, IFN-α increases the complete cytogenetic response rate and prolongs survival, and occasionally leads to complete molecular response and long-term survival. However, toxicity may prevent long-term treatment. The addition of cytosine arabinoside to IFN-α has not been shown to improve survival.
• Busulfan is no longer used in CML, even in adult practice.
• Newer TK inhibitors are being developed and introduced into clinical practice. Dasatinib may lead to improved response in some patients who are resistant to IM, but the durability of response is often poor. If feasible, such patients should undergo HSCT as soon as possible.
Imatinib or HSCT in chronic phase CML?
• Until the last few years, most children with CML and suitable HSCT donors (either related or unrelated) have been transplanted. Therefore, there is very little experience of even medium-term survival in children treated with IM.
• However, adult data from CP CML treated with IM is very encouraging, and most adults now receive IM as initial treatment, proceeding to HSCT only if intolerant of IM or if response to IM is suboptimal or not maintained.
• Therefore, many collaborative groups now recommend that children with CML should start initial treatment with IM, and either continue with this long-term (with current knowledge, this implies life-long) as long as a complete molecular response is maintained, or undergo HSCT ideally within the first 2 years after diagnosis.
• When fully informed of the potential benefits and risks of each treatment approach, individual patients and families may appropriately elect to follow either an IM (and monitor response) or a HSCT strategy.
Detailed response (and failure) criteria have been developed, primarily for adult patients but still applicable to children.
Different versions are available as experience (especially with IM) has evolved, but all are based on:
• Haematological response – normal blood count and film, resolution of splenomegaly.
• Cytogenetic response – based on karyotypic analysis of marrow; varies from none (>95% Ph+ cells) to complete (0% Ph+).
• Molecular response – based on PCR measurement of BCR/ABL/ABL ratio in peripheral blood.
Complications of treatment
Drug-related toxicity due to hydroxycarbamide or IM is usually manageable without stopping treatment, but IFN-α toxicity may be severe and necessitate discontinuation.
HSCT is associated with a risk of transplant-related mortality (~10–20% in HLA-identical sibling donor and ~30% in unrelated donor HSCT). (Haemopoietic stem cell transplantation, Complications pp.[link]).
• Although successful HSCT reduces the risk of progression to AP or transformation to BC considerably, relapse may occur in up to 25% of patients (over follow-up of up to 20 years). However, early (cytogenetic or ideally molecular) relapse may be treated very satisfactorily by donor lymphocyte infusions (DLI), albeit with a small risk of GvHD and marrow aplasia (Post-haemopoietic stem cell transplantation relapse p.[link]).
• Post-HSCT relapse may be:
• molecular – detected by PCR (performed >4 months post-transplant; analysis before this time may reveal a measurable but still falling BCR/ABL/ABL ratio);
• cytogenetic – detected by FISH or karyotype analysis;
• haematological – diagnosed by abnormal blood count or marrow appearance consistent with CML.
Estimates based on historical adult data suggest transformation rates to BC of 20–35% per year in patients treated with hydroxycarbamide or busulfan, and 10–20% per year during IFN-α treatment. Progression to AP or BC occurs in 1–3% of patients per year during the first 4 years of IM treatment.
• Interferon-α: 10 year overall survival in adult studies is ~25–50%, but almost all of these patients have molecularly detectable disease.
• Imatinib: adult data show 4–5-year overall survival of 90% and a transformation rate of 1–3% per year.
• HSCT: paediatric data show 3-year overall survival rates of 75–90% in HLA-identical sibling donor and 65% in unrelated donor HSCT. A mixed (but predominantly) adult study has shown a 20-year overall survival rate of 40% for HLA-identical sibling donor HSCT.
Other chronic MPDs of childhood
As a rule, chronic MPDs (other than CML) are diseases of older adults and exceptionally rare in children. Except for essential thrombocythaemia (ET), where recent paediatric literature is available, most information about their classification, presentation, treatment, and prognosis is derived from adult-based literature.
Recent investigations have revealed the presence of a mutation in the JAK2 TK gene (V617F) in 80–90% of adults with polycythaemia vera (PV) and 30–50% with ET or chronic idiopathic myelofibrosis (CIMF).
• Incidence 1 in 10 million children/year (60 times lower than in adults)
• Persistent isolated thrombocytosis (>600 × 109/L) without other cause (e.g. CML, PV, inflammatory response, hyposplenism).
• Platelet function abnormal.
• Thrombotic episodes, especially if platelet count >1500 × 109/L.
• Transformation, usually to AML or more rarely myelodysplasia (MDS) or myelofibrosis, may occur in ~1% of patients. It may be commoner in patients treated with chemotherapy.
• Management strategies modified from adult experience:
• observation only may be appropriate if platelet count <1000 × 109/L;
• consider low dose aspirin if platelet count <1500 × 109/L (care regarding risk of Reye's syndrome, but this appears to be lower with low dose aspirin, and is probably outweighed by risk of thrombosis due to thrombocytosis; written parent information about Reye's syndrome is available for parents);
• in patients with higher platelet counts, initial treatment with hydroxycarbamide will reduce thrombocytosis (which may then allow treatment with aspirin alone), followed by either –
• IFN-α, or if not tolerated;
• anagrelide (but long-term safety is unproven);
• consider HSCT only if refractory disease;
• spontaneous resolution of childhood ET has been reported.
• Increased red cell mass (haematocrit above age-related reference range), without a reason for 2° polycythaemia (e.g. chronic hypoxaemia, high affinity haemoglobin, raised erythropoietin).
• Plethoric complexion, headaches, dizziness, night sweats, pruritis.
• Low erythropoietin (differentiates PV from 2° polycythaemia).
• ± Thrombocytosis ± neutrophilia.
• JAK-2 V617F (or rarely other JAK-2 exon 12) mutations present.
• May be complicated by thrombosis or CNS ischaemia.
• Transformation to AML, MDS or myelofibrosis may occur.
• Management may involve:
• venesection to lower haematocrit (e.g. to <0.45);
• consider low dose aspirin;
• add IFN- α if not responding to above or if progressive disease.
• HSCT very rarely considered. Only if transformed to AML or if previous history of major thrombotic complications.
Chronic idiopathic myelofibrosis
• May be asymptomatic or present with systemic symptoms due to increased metabolic rate (night sweats, weight loss).
• Hepatosplenomegaly, may be massive.
• FBC variable, but typically → anaemia, thrombocytosis, leucocytosis.
• BM → variable cellularity (decreased in advanced disease), progressive fibrosis, often with prominent or bizarre megakarocyte proliferation.
• Diagnosis requires exclusion of other causes of marrow myeloproliferation and/or fibrosis, including CML, ET, PV, M7 AML, hypoplastic MDS and auto-immune disease.
• Transformation to AML in up to 30% of patients.
• Consider trial of steroids to exclude auto-immune disease.
• Advanced disease may merit HSCT.