The severity of FIP1L1-PDGFRA-positive chronic eosinophilic leukaemia is associated with polymorphic variation at the IL5RA locus.

We have investigated the hypothesis that constitutional genetic variation in IL-5 signalling may be associated with the development or severity of FIP1L1-PDGFRA-positive chronic eosinophilic leukaemia (CEL) in humans. We genotyped six single-nucleotide polymorphisms (SNP) within or close to the IL5RA or IL5 genes in 82 patients with FIP1L1-PDGFRA-positive CEL plus, as controls, healthy individuals (n=100), patients with FIP1L1-PDGFRA-negative eosinophilia (n=100) or patients with chronic myeloid leukaemia (CML) (n=100). We found no association between SNP allele frequency between FIP1L1-PDGFRA-positive and control cases. However, for FIP1L1-PDGFRA cases, we found an association between the genotype at rs4054760, an SNP in the 5'-UTR of IL5RA and peripheral blood eosinophil count (P=0.026) as well as the presence or absence of tissue infiltration (P=0.032). Although these associations fell below the level of significance once corrected for multiple testing, no such association was seen in FIP1L1-PDGFRA-negative cases and no difference in allele frequencies for rs4054760 was seen in control populations across Europe. Furthermore, in an analysis of 112 patients with CML, IL5RA expression was strongly related to rs4054760 genotype (P<0.001). These data suggest that the variations in IL5RA expression are linked to constitutional IL5RA genotype and severity of FIP1L1-PDGFRA disease.

Report on slide session, British Society for Haematology, 43rd Annual Scientific Meeting, Glasgow, 2003.

Seven patients who had a diagnostic problem were presented at the British Society for Haematology, Annual Scientific Meeting in 2003. The likely diagnosis was discussed on the basis of a synopsis of the history and blood film and trephine biopsy features and forms the basis of this report. Diagnostic problems dealt with included lymphoproliferative and myeloproliferative disorders and haemolytic anaemia.

Lymphoid transformation in a CML patient in complete cytogenetic remission following treatment with imatinib.

We describe here a patient with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia who achieved a complete cytogenetic response following treatment with imatinib and then progressed abruptly to lymphoid blastic transformation. The sequence of events suggests that at least in some cases patients who respond well to imatinib may still harbor residual leukemia progenitor or 'stem' cells that are susceptible to acquisition of molecular events that underlie progression to advanced phase disease. The case highlights the need for molecular monitoring of responders and the need to develop strategies for reducing to a minimum or totally eradicating leukemia cells.

Acute isolated cerebral mucormycosis in a patient with high grade non-Hodgkins lymphoma.

A 57-year-old female in complete remission of grade IV non-Hodgkin lymphoma whilst on intensive chemotherapy, suddenly developed unilateral hemispheric stroke with a fatal outcome in 3 days. She was apyrexial and had received antifungal prophylaxis during her treatment. Post-mortem examination showed complete thrombosis of the internal carotid artery leading to infarction in the territory of the middle and anterior cerebral arteries. Microscopic examination of the brain showed involvement of intra-cranial vessel walls and brain parenchyma by mucormyces, with no evidence of systemic mucormycosis. Isolated cerebral mucormycosis is a rare occurrence, more commonly found in intravenous drug abusers, but can occur in patients with haematological malignancy.

The clinical significance of apoptotic cells in peripheral blood smears.

Apoptosis as introduced by Kerr and colleagues describes a distinct set of morphological features that represent programmed cell death. Apoptosis frequently arises owing to genetic programming, cytotoxic drugs and physical stimuli. In order to ascertain whether all of the natural triggers of apoptosis have been identified, we looked for the presence of apoptotic cells in all routine blood films throughout a 5-month period. Patients with known malignant disease or on chemotherapy were excluded from the study. Forty-nine blood films, from 10,000 examined in this period, showed apoptosis. The number of apoptotic cells ranged from the occasional cell to 20%. Apoptotic cells were either mainly lymphoid (34 of 49) or mainly myeloid (15 of 49). All 34 cases with lymphoid apoptotic cells were seen in patients with suspected infectious mononucleosis (IM). In patients with IM, the presence of large numbers of apoptotic cells was associated with a prolonged, severe clinical course. Myeloid apoptotic cells were found in a variety of conditions, including one patient who had persistent apoptosis and was found to have myelodysplasia. Unexplained persistent apoptosis in blood films requires further investigation.

Clonal eosinophilic disorders and the hypereosinophilic syndrome.

An increase in the blood eosinophil count may occur in a number of disease states including allergies, parasitic infections, vascular disease and as a reaction to the presence of malignant tumours. This article defines those disorders that are not purely reactive, and describes in detail the diagnosis and features of clonal eosinophilic disorders and the hypereosinophilic syndrome. The clonal disorders that are associated with eosinophilia are discussed, in particular the acute and chronic eosinophilic leukaemias and clonal eosinophilias in association with acute myeloid leukaemia, myeloproliferative disorders and myelodysplastic syndromes. Whether eosinophilia is produced by a clonal or reactive disorder, the end result can often be the same, i.e. end organ damage produced by sustained hypereosinophilia in the presence of eosinophil activation. When no cause for the eosinophilia leading to the end organ damage is found, this disease is termed 'idiopathic hypereosinophilic syndrome'. Its pathogenesis, clinical features and management are discussed with particular reference to the possibility of it being a T-cell-associated disorder.

Clinicopathological features of acute undifferentiated leukaemia with a stem cell phenotype.

Over a 4 1/2-year period, 141 patients with acute leukaemia had morphologic, immunophenotypic and cytochemical studies performed at King's College Hospital. Seven cases were noted to have blast cells which did not express myeloid or lymphoid antigens or cytochemical staining indicative of differentiation but were HLA DR and CD 34 positive. Based on these criteria we have used the term stem cell acute leukaemia to denote these patients. There were five women and two men with a median age of 61 years (16-86). Presentation marrows were heavily infiltrated with blasts (greater than 95% in 6/7) which were usually pleomorphic. Type 2 blasts. Auer rods and dysplastic features were absent. Two of six cases studied showed clonal karyotypic abnormalities. Four patients were treated with high dose chemotherapy. Three of these achieved a complete remission but relapsed at 3, 6 and 7 months respectively. The median survival of the group was 7 months (2-12). We conclude that the stem cell acute leukaemias are a distinct clinicomorphological group which appear to have a poor prognosis with conventional chemotherapy.

Autografting for patients with chronic myeloid leukaemia in chronic phase: peripheral blood stem cells may have a finite capacity for maintaining haemopoiesis.

We treated 14 patients with Ph-chromosome-positive chronic myeloid leukaemia still in chronic phase by autografting with blood-derived haemopoietic stem cells. Eleven patients were autografted electively after cytoreductive treatment with busulphan (16 mg/kg) and melphalan (60 mg/m2) and three were autografted after marrow cells from HLA-identical sibling donors had failed to engraft. In 13 patients haemopoiesis recovered; one failed to engraft and died 114 d after autografting. Two other patients became pancytopenic and received further stem cell transfusions at 3 and 40 months respectively after first autografting. One patient entered lymphoid transformation and died 14 months after autografting. Twelve patients survive at a median of 41 months (range 24-53) after autografting. Nine of the survivors have required further chemotherapy after autografting and four of the nine were electively autografted on a second occasion. Three patients surviving after autografting for 28, 43 and 53 months respectively have not required further chemotherapy. In two of these patients haemopoiesis is now predominantly Ph-negative. We conclude that autografting in chronic phase might prolong survival in some cases by reducing the size of the leukaemic stem cell population. The fact that initially successful grafts failed in two patients suggests that blood-derived stem cells may have a finite potential for self-replication.

Treatment of RAEB-t with intensive chemotherapy and GM-CSF.

A 55-yr old woman with refractory anaemia with excess of blasts in transformation developed prolonged bone marrow hypoplasia following two courses of mitozantrone and cytosine arabinoside. The administration of granulocyte-monocyte colony stimulating factor after two months of pancytopenia led to recovery of normal bone-marrow function, without any morphological evidence of myelodysplasia, which has persisted until the last blood count (6 months +).

Myelodysplastic relapse of de novo acute myeloid leukaemia with trilineage myelodysplasia: a previously unrecognized correlation.

We describe the occurrence of an unusual mode of relapse in six of 24 patients who presented with de novo acute myeloid leukaemia (AML) associated with trilineage myelodysplasia (TMDS). After the induction of complete remission (CR) by intensive chemotherapy in five patients and following bone marrow transplantation (BMT) in one, the myelodysplastic state, but not overt AML, recurred. Relapse of myelodysplasia occurred at a median of 147 weeks (50-520) from presentation and in two instances was followed a year later by AML. In five cases, myelodysplastic relapse was treated with low-dose cytosine arabinoside given alone or with other chemotherapeutic agents. Three patients remain in CR after 1, 2 and 5 years. The reappearance of myelodysplastic features in these six patients was strongly correlated with the presence of TMDS at presentation of the AML. It was not observed once in the 136 AML patients, treated similarly, who did not have associated TMDS at presentation (P less than 0.001). Thus, relapse with myelodysplasia is not an effect of chemotherapy as has been previously postulated.

Regression of intracerebral lesions in T prolymphocytic leukaemia treated with intravenous deoxycoformycin.

A case of T-prolymphocytic leukaemia (T-PLL) presenting with deafness and confusion is reported. Computerised tomography (CT) of the head showed several well-defined, rounded, high attenuation areas in the temporal, parietal and occipital regions of the brain substance that were suggestive of metastases. Treatment with weekly intravenous deoxycoformycin produced complete resolution of the CT abnormalities together with haematological evidence of disease regression 6 weeks after treatment was started.

Clinical and laboratory features of de novo acute myeloid leukaemia with trilineage myelodysplasia.

Primary myelodysplastic syndromes progress to acute myeloid leukaemia (AML) in about 30% of cases. We have sought evidence of pre-existing trilineage myelodysplasia (TMDS) using the FAB criteria (1982) in 160 consecutive cases of primary de novo AML. TMDS was found in 24 cases (15%) including two of 33 cases of M1 (6%), four of 40 cases of M2 (10%), none of 18 cases of M3, five of 31 cases of M4 (15%), six of 30 cases of M5 (20%), all of six cases of M6 and one of two cases of M7. The median presentation bone-marrow blast-cell count in the 24 AML/TMDS cases was 53% (30-90%) and 82% (45-100%) in the 136 cases of AML without TMDS. 60% of the AML/TMDS bone-marrow aspirates contained fewer than 60% of blasts compared with only 11% of those from AML without TMDS (P less than 0.001). In AML the occurrence of symptomatic cytopenias when the marrow blast-cell count is below 60% and the peripheral blood blast-cell count is below 20% is highly correlated with dysplastic haemopoiesis (P less than 0.001).

Phase II study of mitoxantrone and cytarabine in acute myeloid leukemia.

Thirty-eight patients with acute myeloid leukemia (AML) were treated with mitoxantrone (Mto) combined with cytarabine (Ara-C). Five patients had received no previous treatment for acute myeloid leukemia, seven were refractory to treatment with standard first-line chemotherapy, eight had relapsed during treatment, and 18 had relapsed after treatment was stopped. Eleven of these relapses were early (within 6 months of stopping treatment). Mto was given for 5 days by iv bolus injection at a dose of 10 mg/m2 to 12 patients and at 12 mg/m2 to 26. Ara-C was given at a dose of 1 g/m2 twice daily by a 2-hour infusion for 3 days to 37 patients. One patient received Ara-C at a dose of 500 mg/m2 twice daily for 3 days. Toxicity was acceptable except for cerebellar toxicity in two patients, which was irreversible in one. Twenty-two patients (56%) achieved complete remission (CR), and four achieved partial remission (10%). Seventy-five percent of the patients who had relapsed during treatment and 58% of those who had relapsed after treatment was stopped achieved CR. Eleven patients remain in CR at a median time of 10 months (range, 3-17) after treatment. In five patients remissions have lasted greater than 1 year, one in a patient treated in second relapse and one in a patient treated in third relapse. Mto and Ara-C appear to be effective salvage therapy in acute myeloid leukemia and should be considered for incorporation into first-line induction regimens.