Acute myeloid/T‐lymphoblastic leukaemia (AMTL): a distinct category of acute leukaemias with common pathogenesis in need of improved therapy

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T‐lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T‐lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T‐cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T‐ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T‐ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T‐lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.     

Secondary acute lymphoblastic leukaemia is constitutional and probably not related to prior therapy

Very little is known about secondary acute lymphoblastic leukaemia (s‐ALL). This retrospective analysis studied a cohort of s‐ALL patients treated at a single centre between 1994 and 2013, while comparing therapy‐associated ALL (t‐ALL) and antecedent malignancy ALL (am‐ALL) patients. Thirty‐two patients with s‐ALL were identified. The overall incidence was 9·4% among ALL adults while T‐cell s‐ALL was rare (12% of s‐ALLs). The median time interval between two malignant diagnoses was 5·3 years (range: 0·1–28). In contrast to previous reports, most of the s‐ALLs were CD10 +  and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients (n = 23, 72%) received prior chemo‐/radio‐therapy for their first malignancy (t‐ALL) and only 9 (28%) did not (am‐ALL). No significant difference was found in the incidence of B‐/T‐ lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia‐positive ALL, nor in the rates of complete remission (P = 0·55) and OS (P = 0·97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s‐ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s‐ALL.     

Single agent thalidomide in patients with relapsed or refractory acute myeloid leukaemia

Thalidomide is a putative anti-angiogenesis agent that has significant anti-tumour activity in haematological malignancies with increased bone marrow angiogenesis, including multiple myeloma (MM) and myelodysplastic syndromes (MDS). Increased levels of the mitogen for angiogenesis, vascular endothelial growth factor (VEGF), correlate with worse survival in acute myeloid leukaemia (AML). A phase II trial of thalidomide was conducted in patients with relapsed- or refractory-AML previously treated with cytarabine-containing regimens. A total of 16 patients with refractory- or relapsed-AML were treated with thalidomide 200-800 mg orally daily (median dose 400 mg daily) for a median of 27 d (range, 3-94 d). Overall, one patient (6%) achieved complete remission (CR) lasting for 36 months, and two patients had a transient reduction in marrow blasts from 8% and 7% to less than 5% in both cases. There was no correlation between reduction in levels of angiogenesis markers and response. Toxicities related to thalidomide were significant, and precluded dose escalation beyond 400 mg orally daily in most patients. Although there appears to be some evidence of biological activity, single agent thalidomide is not an optimal choice of therapy for salvaging patients with relapsed- or refractory-AML. Thalidomide analogues with more potent immunomodulatory activities and more favourable toxicity profiles may offer more promise as anti-AML therapy.     

Two patients with haemophilia and acute leukaemia

Acute leukaemia is the commonest form of malignancy in childhood. The coincidental development of leukaemia in children or adults with haemophilia is extremely rare, although cases of leukaemia and other malignancies have been reported previously in HIV-positive subjects. Of a total of 440 people with haemophilia registered with our society, two were diagnosed with acute leukaemia last year. The development of leukaemia in a subject with haemophilia has previously been reported from our country in 1985, but the negative HIV status of these recent cases is very interesting. The first case involved a 14-year-old boy with moderate haemophilia A, who developed acute lymphoblastic leukaemia (ALL) [French-American-British (FAB) classification L2]. The second subject was a 16-year-old boy who had moderately severe haemophilia A with no previous family history, and developed acute nonlymphocytic (myelomonocytic) leukaemia (FAB-M4). Both patients received conventional chemotherapy and this report discusses the potential problems in management of such cases, including diagnosis and administration of chemotherapy in subjects with a pre-existing haemorrhagic disorder. Extensive cutaneous and mucosal bleeding, as well as bleeds in joints previously affected by haemarthrosis and alterations of haematological values were all initially suggestive of the development of inhibitors against factor VIII, but the appearance of blasts in the peripheral blood and bone marrow led to the definitive diagnosis. The risk of bleeding, due to the combination of both leukaemia and the consequences of the chemotherapy, was overcome by the administration of coagulation factor concentrates (daily initially followed by prophylactic doses after successful induction of remission in both patients). The young patient with ALL is now receiving the maintenance phase of the Children's Cancer Study Group 1961 protocol and is in the 15th month of follow-up, without any complications. The other case relapsed in the seventh month, developing enterobacter sepsis, and died. An important lesson to be learnt from these cases is that the possible diagnosis of leukaemia should not be overlooked in a patient with haemophilia and severe haemorrhagic problems, if the first-line differential diagnosis of inhibitor development against factor VIII (or IX) has been excluded.     

A Study of the Reproducibility of the Diagnostic Criteria for Acute Leukaemia

The Leukaemia Group of Middle Sweden recently started a new multicentre study of treatment of adult patients with acute leukaemia from 6 centres. The criteria for the diagnosis, subclassification, degree of leukaemic bone marrow infiltration, remission and relapse are to be used by the morphologists of 6 different pathology departments. The reproducibility of the criteria has been studied by 3 of the morphologists concerned, in a retrospective review of a strictly consecutive series of 79 adult patients treated at Södersjukhuset, Stockholm, Sweden, in the years 1978 to 1981. The results show that the reproducibility of the criteria and the concordance of the morphologists when using them increased when the criteria were made more detailed and precise.     

Acute liver failure as the initial manifestation of acute leukaemia

Abstract: Background/Aims: Haematological malignancies seldom cause clinically significant liver disease. Acute liver failure as the initial manifestation of acute leukaemia is very rare and carries a very poor prognosis. Methods/Results: Three cases of acute liver failure secondary to acute leukaemia are described. Each case presented initially as acute liver failure of uncertain cause. Specific treatment for the leukaemia was instituted; however, all three patients died as a consequence of the liver failure. We describe the clinical course and relevant investigations of these patients and discuss possible mechanisms of acute liver failure in this setting. Conclusion: Acute leukaemia presenting as acute liver failure has a very poor prognosis. Although a rare cause of acute liver failure, it should be considered in any patient presenting with acute liver failure with prodromal symptoms and a raised peripheral white cell count, lactate dehydrogenase and uric acid.     

Treatment of acute leukaemia in adult Jehovah's Witnesses

Since Jehovah’s Witness (JW) patients diagnosed with leukaemia refuse blood transfusions, they are often denied intensive chemotherapy for fear they could not survive myeloablation without blood transfusion support. Treatment of JW patients with acute leukaemia is challenging and carries a higher morbidity and mortality; however, the refusal of blood products should not be an absolute contraindication to offer multiple treatment modalities including haematopoietic stem cell transplantation. In this review we discuss their optimal management and describe alternative modalities to blood transfusions to provide sufficient oxygenation and prevent bleeding.     

Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias

The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-escalation trial of daily-infused clofarabine (CLO) followed by cyclophosphamide (CY) for four consecutive days (CLO-CYx4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1-5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 10(9) /l was 34 d, (range, 17-78). The overall response rate (ORR) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO-mediated enhancement of CY-induced DNA, which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO-CYx4 regimen was well tolerated and had activity in patients with RRAL, especially relapsed ALL. Therefore, CLO-CYx4 can be considered a salvage therapy for adults with RRALs, and warrants further investigations.     

The future role of monoclonal antibody therapy in childhood acute leukaemias

Leukaemia is the single most common childhood malignancy. With modern treatment regimens, survival in acute lymphoblastic leukaemia (ALL) approaches 90%. Only about 70% of children with acute myeloid leukaemia (AML) achieve long term survival. Patients who relapse have a dismal prognosis. Novel therapeutic approaches are needed to improve treatment outcomes in newly-diagnosed patients with a poor prognosis and for patients with relapsed/refractory disease that have limited treatment options. One promising approach in treating haematological malignancies has been the use of monoclonal antibodies to target cell surface antigens expressed on malignant cells. Most success with monoclonal antibody therapy in the treatment of haematological malignancies has come in the setting of adult B-cell non-Hodgkin lymphoma with the addition of the anti-CD20 monoclonal antibody rituximab to standard treatment regimens. In order to further advance treatment of haematological malignancies, novel monoclonal antibodies continue to be developed that target a variety of cell surface antigens. Several antibodies continue to be investigated in childhood leukaemias. This review will discuss the development of monoclonal antibodies that target a variety of cell surface antigens for the treatment of childhood ALL and the use of the anti-CD33 antibody gemtuzumab ozogamicin in the treatment of childhood AML.     

Serum Beta2-Microglobulin in Acute and Chronic Leukaemia

The serum concentration of beta₂-microglobulin (beta₂-m) was measured in 69 patients with acute or chronic lympho- and myeloproliferative disorders. Serum beta₂-m was found significantly increased in 12 out of 14 patients with chronic lymphatic leukaemia. The serum concentration was proportional to the estimated lymphatic infiltration of tissues but inversely related to the number of circulating lymphocytes. Cytostatic treatment was followed by a decrease in serum beta₂-m, but normalization of the serum concentration was not observed. 11 patients with chronic granulocytic leukaemia all had significantly elevated serum concentrations of beta₂-m and increased serum concentrations were also found in patients with acute leukaemias. Thus, 12 out of 25 patients with acute myeloid leukaemia and all of 5 patients with acute myelomonocytic leukaemia as well as 4 out of 5 patients with acute lymphatic leukaemia had increased serum beta₂-m levels. In acute leukaemia no correlation could be demonstrated between the blood lymphocyte concentration and serum beta₂-m. Also no significant changes in serum beta₂-m were found in either remission or relapse of the acute leukaemia. It is concluded that serum beta₂-m in patients with chronic leukaemia may reflect the total amount or turn-over of leukaemic cells in the body and that repeated determinations of serum beta₂-m in these patients might be useful as an estimate of the residual leukaemic cell mass after therapy. Apart from this the determination of serum beta₂-m seems to be of little, if any, clinical use in leukaemia.     

The role of gemtuzumab ozogamicin in acute leukaemia therapy

Gemtuzumab ozogamicin (GO) is an immunoconjugate that binds to CD33 on the surface of acute myeloid leukaemia (AML) blasts and, after internalisation, releases a cytotoxic drug, calicheamicin. GO is approved by the US Food and Drug Administration for the treatment of CD33-positive AML at first relapse in patients 60 years and older who are not candidates for other cytotoxic therapy. GO as a single agent has low antileukaemic activity. When given to patients meeting the criteria noted above, it produces a complete response (CR) rate of only 12%, with another 12% achieving CR with inadequate platelet recovery (CRp). The median survival of patients treated with GO monotherapy is 11.2 months. GO therapy at 9 mg/m(2) is complicated with hepatic veno-occlusive disease in 5-10% of patients, particularly prior to or following stem cell transplantation. GO at lower doses combined with chemotherapy as induction or postremission therapy is promising, however, and phase III trials are ongoing. GO is probably most active in acute promyelocytic leukaemia (APL). It is used for induction regimens in high-risk APL and for the elimination of minimal residual APL. Case reports suggest that GO also has activity in CD33-positive acute lymphoblastic leukaemia. In conclusion, single agent GO can induce responses in patients with CD33-positive AML in first recurrence. The future of GO is its use in combination with other cytotoxic agents. Ongoing clinical trials may better define the role of GO combinations, particularly in untreated AML.     

An infectious aetiology for childhood acute leukaemia: a review of the evidence

There are three current hypotheses concerning infectious mechanisms in the aetiology of childhood leukaemia: exposure in utero or around the time of birth, delayed exposure beyond the first year of life to common infections and unusual population mixing. No specific virus has been definitively linked with childhood leukaemia and there is no evidence to date of viral genomic inclusions within leukaemic cells. The case-control and cohort studies have revealed equivocal results. Maternal infection during pregnancy has been linked with increased risk whilst breast feeding and day care attendance in the first year of life appear to be protective. There is inconclusive evidence from studies on early childhood infectious exposures, vaccination and social mixing. Some supportive evidence for an infectious aetiology is provided by the findings of space-time clustering and seasonal variation. Spatial clustering suggests that higher incidence is confined to specific areas with increased levels of population mixing, particularly in previously isolated populations. Ecological studies have also shown excess incidence with higher population mixing. The marked childhood peak in resource-rich countries and an increased incidence of the childhood peak in acute lymphoblastic leukaemia (ALL) (occurring at ages 2-6 years predominantly with precursor B-cell ALL) is supportive of the concept that reduced early infection may play a role. Genetically determined individual response to infection may be critical in the proliferation of preleukaemic clones as evidenced by the human leucocyte antigen class II polymorphic variant association with precursor B-cell and T-cell ALL.