Serum enzyme concentrations in untreated acute myeloid leukaemia

Summary Serum concentrations of lactate dehydrogenase (LDH), -hydroxybutyrate dehydrogenase (HBD), phosphohexose isomerase (PHI), leucine aminopeptidase (LAP), -glucuronidase (-gluc) and angiotensin-converting enzyme (ACE), were measured in 107 cases of untreated acute myeloid leukaemia which were classified by morphological, immunological and cytochemical criteria. The results show that serum LDH was increased in most cases, irrespective of leukaemic subtype, serum PHI and LAP were significantly higher in monocytic variants and serum -gluc and ACE levels were generally within normal limits. In addition, significant (p<0.05) relationships were found between serum LDH, PHI, LAP and -gluc concentrations and the numbers of circulating leucocytes.     

Heterogeneity of TdT+, HLA-DR+ acute leukaemia: immunological, immunocytochemical and clinical evidence of lymphoid and myeloid origin

15 cases of acute leukemia (AL) displaying a TdT+, HLA-DR+ phenotype were studied; surface immunoglobulins, T cell markers and the common acute lymphoblastic leukaemia (c-ALL) antigen were negative, as were peroxidase and non-specific esterase cytochemical reactions. All cases were extensively investigated by conventional immunofluorescence (IF) and immunoperoxidase (IP), with a panel of monoclonal antibodies (MoAb), using both light and electron microscopy, and for ultrastructural myeloperoxidase (MPO). 8 cases, which were OKB2+, BA1+, B4+, J5- and BA2- by IF, expressed the J5 antigen in IP. These cases were therefore re-classified as ALL with a weak expression of the C-ALL antigen. The other 7 cases showed an OKB2-, BA1-, B4+, BA2+ phenotype at IF and were also positive for 1 or more anti-myeloid MoAb. These features were confirmed by IP study. 4 patients also presented ultrastructural positivity to MPO. These cases were considered as proliferations of early precursor cells capable of expressing both myeloid and lymphoid features. This study, while demonstrating the heterogeneity of TdT+, HLA-DR+ AL, suggests that the cell origin of many cases may be defined by extensive immunotyping at both IF and IP level. The prognostic and therapeutic implications of these findings are discussed, also in view of the poor prognosis often observed in the more undifferentiated cases of AL.     

Childhood acute myeloid leukaemia

Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.     

Adult acute myeloid leukaemia

The curability of acute myeloid leukaemia (AML) in a fraction of adult patients was demonstrated a long time ago. Currently, the probability of cure is consistently above fifty per cent in patients with de novo disease expressing favourable-risk associated cytogenetic features. Even better, the cure rate exceeds 75% in the acute promyelocytic subtype since the introduction of retinoic acid-containing regimens. In the meantime, continuing progress in supportive care systems and stem cell transplant procedures is making myeloablative therapies, when needed, somewhat less toxic—and thereby more effective—than in the recent past. Therefore, evidence is accumulating to indicate an improved therapeutic trend over the years, with the notable exception of older (>55 years) patients with adverse-risk chromosomal aberrations and/or leukemia secondary to myelodysplasia or prior cancer-related chemotherapy and/or radiotherapy. This review conveys the many facets of this progress, focusing on diagnostic subsets, risk classes, newer biological issues and conventional as well as innovative therapeutic interventions with or without autologous/allogeneic stem cell transplantation.     

NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to monoblastic cases

Expression of NG2 has been reported in the majority of paediatric acute leukaemia (AL) cases with MLL rearrangement. We demonstrated 7. 1 positivity in 2/3 paediatric and 4/11 adult MLL rearranged acute myeloid leukaemia (AML) but in 0/28 adult AML without MLL rearrangement, thus extending the 100% specificity to adult cases. Positivity correlated with stage of maturation arrest since it was found in 0/6 immature AML but in 6/8 monoblastic cases. These data demonstrate that, if NG2 expression in AL is the (in)direct result of MLL rearrangement, such activation is restricted to a monoblastic population in AML. They also have practical implications for NG2 diagnostic screening strategies.     

Unexpected remission of acute myeloid leukaemia after GM-CSF

Summary. The administration of granulocyte-monocyte colony-stimulating factor (GM-CSF) was associated with complete clinical and haematological response in an adult patient with minimally differentiated acute myeloid leukaemia who presented with pneumonia and moderate neutropenia, but no blast cells in the peripheral blood. The response lasted 9 months. At relapse, a second GM-CSF course resulted in a very good partial remission lasting 5 months, although differences in the kinetics of haemoglobin, neutrophil and platelet recovery were noted. Subsequent recurrences were managed with chemotherapy, a complete remission being obtained twice more and lastly consolidated with myeloablative chemo-radiotherapy supported by a peripheral blood stem cell autograft. This report suggests that GM-CSF should be further investigated as a therapeutic agent in selected cases of AML.     

Independent prognostic variables in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is one of the most common haematological malignancies and is increasing in frequency due to an ageing population. Whilst remission will be achieved in up to 80% of those receiving intensive chemotherapy, the main variables precluding cure are the treatment-related mortality and relapse rates. Decisions on intensification, de-escalation and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task. Cytogenetic and molecular characterisation has already identified subgroups, such as acute promyelocytic leukaemia (APL) with t(15;17)/PML-RARA and AML with FLT3 mutation for which targeted therapies are available, and further molecularly defined groups who may be potential candidates for this approach are likely to be identified in the future. This review examines the range of established clinical and diagnostic parameters that should be used in assessing prognosis for a patient with AML and looks ahead to an expanding repertoire of potential variables that are currently under evaluation.     

Interleukin-3 priming in acute myeloid leukaemia patients

Summary Several studies have demonstrated that G-CSF, GM-CSF and, in particular, IL-3 can effectively recruit acute myeloid leukaemia (AML) blasts into the cell cycle, resulting in a significant increase in cytosine-arabinoside (Ara-C) mediated cytotoxicity in vitro. Since IL-3 has shown biological and clinical activity, we investigated the cell kinetic effects of rIL-3 and high-dose Ara-C/idarubicin in three patients with refractory AML selected for the presence of chromosome 7 monosomy; this enabled differentiation between the effects of IL-3 on leukaemic and on normal cells. The in vivo administration of rhIL-3 (250μ/m² d s.c. for 6–10 d) recruited AML blasts into the cell cycle in two of the three patients, and this effect resulted in an increase in in vitro growth of clonogenic cells (CFU-L) and of their S-phase fraction. The percentage of leukaemic cells with monosomy 7 increased only in the two cases who showed a proliferative response. Normal cells were not recruited, even when rhIL-3 was administered for up to 10 d. In vitro studies showed an increased Ara-C cytotoxicity on clonogenic AML cells, in particular with LL-3 plus GM-CSF, thus confirming the priming effects of IL-3 in the two responding cases.
The results of this study suggest that rhIL-3 can selectively recruit leukaemic cells into the cell cycle. Although leukaemic blasts can be sensitized to Ara-C, other mechanisms of primary blast resistance may limit the clinical benefit of kinetic-based approaches.     

Eosinophilia and granulocytic dysplasia terminating in acute myeloid leukaemia after 24 years

Eosinophilia of variable duration, and subsequent progression to granulocytic sarcoma and acute myeloid leukaemia, has been infrequently reported in the literature. We report a patient with eosinophilia and normal cytogenetics who, after 24 years, showed transformation to a granulocytic sarcoma of the brain. Haematological counts were normal but the marrow revealed the cytogenetic abnormality trisomy 8 in 25% of mitoses. Subsequently an AML-M2 developed, showing a complex karyotype including the trisomy 8 in all metaphases. FISH analysis combined with cytological examination identified the trisomy 8 in blasts, eosinophils and dysplastic granulocytes only. Thus progressive leukaemic transformation selectively involved the myeloid compartment.     

Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia

Allogeneic marrow transplantation using related marrow donors for myelodysplasia (MDS) and acute myeloid leukaemia (AML) arising from MDS results in 35–56% actuarial disease-free survival. Because the use of unrelated donors has not been well-characterized, we report on the outcome of 52 patients with MDS or MDS-related AML consecutively treated between 1987 and 1993 with unrelated donor marrow transplantation. The median age was 33 (range 1–53) years. 33 patients received chemotherapy and total body irradiation and the remainder busulfan and cyclophosphamide. The donors were phenotypically identical at the HLA-A, B and Dw/DRB1 loci in 34 cases and mismatched for one HLA locus in 17 cases and two loci in one case. Marrow was non-T-cell depleted and methotrexate with cyclosporine or FK506 was used for postgrafting immunosuppression. The 2-year disease-free survival, relapse, and non-relapse mortality rates were 38%, 28% and 48%, respectively. One patient who relapsed survives disease-free after withdrawal of immunosuppressive therapy. 16/19 survivors have a performance status of 90–100%. Patients with MDS in transformation or with AML had a significantly higher risk of relapse than patients with less advanced disease ( P  = 0.0014). Increased non-relapse mortality was significantly associated with higher age, longer disease duration before transplant, lower neutrophil count on admission and, unexpectedly, being seronegative for cytomegalovirus. We conclude that the outcome with transplantation using unrelated donors is similar to reported results using related donors and that a meaningful proportion of eligible patients with an otherwise incurable disease may be cured with this treatment. However, mortality from the transplant procedure is high and future studies should focus on reducing toxicity.     

P-glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival

P-glycoprotein (Pgp) expression, which is associated with the multi-drug resistance (MDR) phenotype, has been reported to be a useful predictor of treatment outcome in acute leukaemia. We have examined the expression of Pgp on acute myeloid leukaemia (AML) cells in 54 newly diagnosed patients, using a novel streptavidin-biotin complex (ABC) technique, 56% of patients at diagnosis were positive for Pgp with JSB-1, a monoclonal antibody that binds to an internal epitope of Pgp. All patients received intensive induction chemotherapy. Post-remission treatment consisted of futher chemotherapy ± bone marrow transplantation. Complete remission (CR) rates were significantly lower in the Pgp positive group than in the Pgp negative group (60%v 92%; P= 0.02). The overall survival for Pgp-positive patients was significantly shorter (329 v 534d, P= 0.004), disease-free survival was also reduced but the difference was not statistically significant (median 277 v 522d, P= 0.16). In this study CD34 expression was not predictive of response to chemotherapy nor was it associated with Pgp expression. Our results confirm the prognostic value of Pgp expression in AML at diagnosis and we suggest that Pgp could be a useful therapeutic target for reversing multi-drug resistance. Furthermore, our simple and sensitive method of detecting Pgp should enable widespread testing to be performed.