Dear Sir,
Paroxysmal nocturnal haemoglobinuria (PNH) is characterised by chronic, uncontrolled complement activation leading to intravascular haemolysis causing anaemia in a proportion of patients. Its association with aplastic anaemia is well-known and also, although more rarely, with other conditions such as refractory anaemia (RA) and myelodysplastic syndromes (MDS)1,2. PNH and its inflammatory prothrombotic state are risk factors for splanchnic vein thrombosis, a serious and rare complication during the natural history of patients affected by the disease3.
Here we describe the case of a 42-year-old Caucasian woman referred to us in July 2007 with thrombocytopenia, anaemia, iron deficiency and a history of uterine fibromatosis.
Blood tests showed a white blood cell count of 5.4×109/L (neutrophils 3.5×109/L), haemoglobin 7.9 g/dL, mean corpuscular volume 110 fL, haematocrit 23%, platelet count 25×109/L, reticulocyte count 77×109/L, lactate dehydrogenase 1,313 U/L (normal values: 250–400 U/L), haptoglobin 20 mg/dL (normal values: 32–205 mg/dL), serum ferritin 10 μg/dL (normal values: 12–150 μg/dL) and transferrin saturation 9%.
On initial physical examination the patient was pale with pain in the epigastric area and splenomegaly. The abdominal computed tomography scan revealed spleno-portal and superior mesenteric vein thrombosis with cavernomatosis and confirmed splenomegaly with a 17 cm longitudinal diameter. Treatment was started with subcutaneous enoxaparin 1,200 IU/daily and iron supplementation. Bone marrow biopsy showed hypocellularity with dysplastic abnormalities, 2% of blast cells and a normal karyotype.
Glycosylphosphatidylinositol-deficient clones were detected in the peripheral blood with the absence of CD59 (14% of erythroid cells), CD66b (17% of granocytes) and CD14 (24% of monocytes), as determined by immunophenotyping (Figure 1). The patient was diagnosed as having PNH associated with MDS (RA according to the French-American-British classification) and the International Prognostic Scoring System (IPSS) score was intermediate-1. Treatment was started with prednisone 25 mg/daily. After 2 months, because of the persistent sideropenic anaemia, mainly due to symptomatic uterine fibromatosis, a hysterectomy was performed and the haemoglobin concentration increased to 11.9 g/dL.
Figure 1.
The events defined as “myelo” (based on the intensity and side scatter antigen CD45) are CD11b-positive in 99% of cases (right) while only a small proportion of them (17%) expresses the CD66b antigen (left).
The steroid was progressively withdrawn and heparin anticoagulation was changed to warfarin, maintaining the International Normalised Ratio between 2 and 3. Subsequently, the patient was followed up regularly every 3 months. Her haemoglobin remained stable around 11 g/dL and the PNH clone percentage also remained unchanged until June 2011 when mild anaemia (haemoglobin 10 g/dL) and thrombocytopenia (platelet count 25×109/L) were observed. The bone marrow biopsy revealed an increase in blast cell percentage to 13% and the karyotype showed monosomy of chromosomes 6 and 7, with evolution towards a MDS with a higher IPSS score. At that time the PNH clone involved about 9% of monocytes and granocytes.
The patient was treated with six cycles of azacytidine (75 mg/m2 daily for a week every 28 days), and once remission was obtained she underwent an allogeneic bone marrow transplant (in July 2012) from a fully HLA-matched unrelated donor. The transplant was tolerated well, no symptoms related to Graft-versus-Host disease occurred and full donor chimerism was obtained. Blood cell counts became normal as did the karyotype; the PNH clone disappeared. The anticoagulation was stopped definitively and abdominal ultrasound showed numerous portal vein branches and an efficient collateral circulation. To date, 36 months after transplantation, the patient is still in a good clinical condition (see Figure 2 for the entire clinical and laboratory course).
Figure 2.
Trend of the PNH clone, blast cell percentage, haemoglobin concentration and platelet count during the 7-year follow-up.
PNH: paroxysmal nocturnal haemoglobinuria.
The presence of PNH clones in different categories of MDS has only been reported in a limited number of studies, and some authors found that cells with a PNH-phenotype (PNH+) were only present in patients with RA, but not in patients with other MDS4. RA patients with a detectable PNH+ clone have an indolent clinical course as compared to RA PNH-negative patients. It was also seen that PNH+ cells were significantly increased in IPSS high-grade score MDS, such as refractory anaemia with excess of blasts, in transformation (AREB-t) and chronic myelomonocytic leukaemia. It was concluded that the presence of a larger amount of PNH+ cells in MDS was predictive of poor outcome4. Our patient presented with a small PNH clone in the context of bone marrow dysplasia and this condition was stable for some years without any transfusions being required.
Patients with limited PNH clones (e.g., aplastic anaemia/PNH, MDS/PNH or subclinical PNH) should not be treated unless they become symptomatic and, when required, therapy should be targeted to the underlying bone marrow disorder rather than to the asymptomatic PNH clone. In this patient the diagnosis of MDS was really difficult and made by exclusion, but we were able to recognise the MDS better when blast cells increased and the karyotype evolved. We can, therefore, assume the presence of a myelodysplastic clone since diagnosis.
Thrombosis is the main cause of death in PNH and should be treated promptly with anticoagulation and sometimes thrombolytic therapy depending on the location and the timing of the thrombus. In a study by Hall et al.5 the 10-year risk of thrombosis in patients with a PNH clone >50% in the granulocytes was 44%, compared to 5.8% for patients with a PNH clone <50%. Anticoagulation is only partially effective in preventing thrombosis in PNH patients and some authors consider thrombosis an absolute indication for initiating treatment with eculizumab. Unfortunately, at that time, the drug was not licensed for this indication by Italian health regulatory authorities. However, we did not observe any other thrombotic events during the entire follow-up either after evolution to MDS or after bone marrow transplantation.
In conclusion we think that this case once again confirms that when a PNH clone occurs concurrent with MDS, the prevailing cause of anaemia must be identified and the coexisting condition must be treated, while maintaining careful control of the evolution of the PNH clone.
Acknowledgements
This work was in part supported by the Associazione Italiana Leucemie Treviso (AIL Treviso) and Associazione Volontari Italiani Sangue per Progresso Ematologico (APE). Laura Candiotto is a fellow of AIL Treviso.
Footnotes
The Authors declare no conflicts of interest.
References
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