Cancer in relatives of children with myelodysplastic syndrome, acute and chronic myeloid leukaemia

Familial myelodysplastic syndrome (MDS) has been claimed to account for as many as one third of children with MDS, especially among those showing monosomy 7. The present study is the first to provide population-based estimates of the risk of haematological and other malignancies in relatives of children with MDS. The study was extended to include children with acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML). The index group consisted of 46 children with MDS, 62 with AML, and eight with CML, which is thought to represent all myeloid leukaemias in Danish children, 1980–91. By linkage to the Central Population Register we identified parents (230), siblings (231), grandparents (151), aunts and uncles (132) and cousins (140). Information on the cancer incidence was obtained from the Danish Cancer Registry. 27 cancers were observed versus 26.7 expected (relative risk 1.0). Leukaemia in relatives was observed in only one family. None of 11 children with MDS and monosomy 7 had family members affected by leukaemia. We found no evidence of an increased overall risk of cancer in the relatives. The risk of familial MDS may be considerably lower than previously estimated.     

Therapy‐related acute myeloid leukaemia and myelodysplastic syndrome in Victoria,Australia 2003–2014

Background

The burden of therapy‐related acute myeloid leukaemia (tAML)/therapy‐related myelodysplastic syndrome (tMDS) in Australia has not been characterised.

Aims

To provide insights into the incidence, associated cancers, latency and survival outcomes of patients with tAML/tMDS in Victoria, Australia, based on a state‐wide cancer registry and to assess if these features are different in tAML/tMDS compared with de novo AML/MDS.

Methods

We analysed adults aged ≥20 years at diagnosis of AML/MDS reported to the Victorian Cancer Registry (VCR) between 2003 and 2014.

Results

In total, 73 of 3120 (2.3%) AML cases were classified tAML. tAML patients were younger than non‐tAML patients at diagnosis (median age 66 vs 71 years, P = 0.000). Median overall survival was similar (6 months). Median latency to tAML was 82 months, with two incidence peaks at 1–4 and 7–8 years. In total, 59 of 73 patients had recorded cancers, the most frequent being non‐Hodgkin lymphoma (NHL, 32.2%) and breast cancer (16.9%). In total, 532 of 3120 (14.1%) additional AML cases had ≥1 prior cancer (confirmation of chemoradiotherapy unavailable). tAML incidence increased (0.0/100 000 persons in 2003, 0.5/100 000 persons in 2014), as did the incidence of non‐tAML with previous cancer (0.8/100 000 persons in 2003, 1.1/100 000 persons in 2014). In total, 101 of 4435 (2.3%) MDS cases were classified tMDS. Although tMDS incidence fluctuated (range 0–0.4/100 000 persons/year), the incidence of non‐tMDS with prior cancer rose (1.4/100 000 persons in 2003, 1.9/100 000 persons in 2014). Compared to tAML, the tMDS cohort was older (median age 70 vs 66 years, P = 0.007). Median latency to tMDS was 42.5 months. NHL was also the most common cancer preceding tMDS, but the second most common cancer was myeloma (17.8%). In total, 1287 of 5061 (20.3%) non‐tMDS patients had a prior cancer.

Conclusions

The burden of tAML/tMDS in Victoria is likely to be underestimated. Linkage between VCR and clinical registries is needed to provide more accurate insights.     

Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome

Wnt signaling activates the canonical pathway and induces the accumulation of non-phosphorylated beta-catenin (NPBC) in the nucleus. Although this pathway plays an important role in the maintenance of haematopoietic stem cells as well as in oncogenesis, the significance of nuclear NPBC remains unclear in malignant haematopoiesis. This study examined the expression of nuclear NPBC in bone marrow specimens from 54 and 44 patients with de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), respectively. On immunohistochemistry with an anti-NPBC antibody, the nuclei were positively stained in 22 and 18 of AML and MDS specimens, respectively. Staining of nuclear NPBC was associated with AML subtypes (M6 and M7), low complete remission (CR) rate, and poor prognosis. Nuclear NPBC was also associated with a high score when using the International Prognostic Scoring System (IPSS) for MDS and with −7/−7q and complex karyotypes. These findings suggest that in situ detection of nuclear NPBC by immunohistochemistry could provide new insights into the pathogenesis and prognosis of AML and MDS.     

Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS

The influence of Exisulind on the viability and apoptosis of CD34(+) stem cells from patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)/MDS was investigated. In eight out of 10 patient samples Exisulind reduced the fraction of viable cells by inducing apoptosis. We found evidence that Exisulind-mediated apoptosis depends on c-Jun NH(2)-terminal kinase (JNK) activation. Addition of a specific JNK-inhibitor to Exisulind-treated advanced MDS and AML/MDS cells partly abrogated apoptosis. We propose that Exisulind is tested in clinical phase I/II trials for the treatment of advanced MDS and AML/MDS.     

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome

Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic‐modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose‐escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly‐diagnosed AML, or intermediate‐ to high‐grade MDS. Thirty‐four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty‐nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m² daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose‐limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well‐tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation.     

Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in myelodysplastic syndromes and acute myeloid leukaemia

Mutations in the receptor tyrosine kinase (RTK/RAS) signalling pathway frequently provide a proliferative signal in myeloid malignancies. However, the role of RASSF1A, SHP-1 and SOCS-1, negative regulators of RTK/RAS signalling, has not been extensively investigated in the myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). This study employed methylation-specific polymerase chain reaction (MS-PCR) to determine if aberrant promotor methylation of RASSF1A, SHP-1 and SOCS-1 is involved in the pathogenesis of myeloid malignancies. Patients with MDS (n = 107), AML (n = 154) and juvenile myelomonocytic leukaemia (JMML, n = 5) were investigated, together with 15 normal controls. Primers were located in the promotor region of each gene as well as within exon 2 of SOCS-1. Methylation of RASSF1A was found in five of 55 (9%) MDS cases, but not in any of 57 AML cases studied. RASSF1A methylation was present in one case (20%) of JMML. SHP-1 methylation was present in 13 of 121 (11%) AML cases but was not found in MDS or JMML. SOCS-1 promoter methylation was present in eight of 74 (11%) MDS patients but was not seen in JMML or AML. Importantly, RAS mutations and RASSF1A and SOCS-1 methylation were mutually exclusive indicating that approximately 30% of MDS cases had a defect of the RTK/RAS pathway and its negative regulation. Finally, SOCS-1 exon 2 methylation may not be pathogenetically relevant, since it was detected in samples from normal individuals and did not correlate with promotor methylation.     

A novel translocation t(1;7)(p36;q34) in three patients with acute myeloid leukaemia

Studies of large numbers of patients have enabled the identification of relatively infrequent chromosome changes, such as inv(3)(q21;q26), t(6;9)(p23;q34) and t(8;16)(p11;p11), whose clinico-biological significance is gradually becoming clearer. Translocations involving chromosomes 1 and 7 are relatively rare in myeloid neoplasias, being found in far less than 1% of cases; the rearrangement that occurs most frequently consists of an unbalanced translocation [t(1;7)(p11; p11)], resulting in complete loss of 7q, associated with therapy-related or environmentally-induced high-risk myelodysplasia. We recently observed three cases of acute myeloid leukaemia (AML) with a previously unreported balanced translocation t(1;7) (p36;q34). Case 1 underwent autologous bone marrow transplantation and remains alive in CR; cases 2 and 3 relapsed after 10 and 4 months, respectively. The response to chemotherapy observed in our cases suggests that variable clinical features might be present in the broad cytogenetic category usually referred to as '7q abnormalities' and contributes to an interesting previous observation of prolonged disease-free survival in a subset of AMLs with 7q- as the isolated chromosome change.     

Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high‐risk myelodysplastic syndrome patients pre‐screened for low O6‐methylguanine DNA methyltransferase expression

Resistance to temozolomide is largely mediated by the DNA repair enzyme O⁶‐methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (β‐actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m²/d ×7 d. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR/CR with incomplete platelet recovery (CRp). Factors associated with a trend toward a higher response rate included MDS, methylated MGMT promoter and standard cytogenetic risk group. Induction and post‐remission cycles were well‐tolerated and most patients were treated on an outpatient basis. Patient who achieved CR/CRp had a superior overall survival compared to partial or non‐responders. In conclusion, targeted therapy based on pre‐selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.     

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.     

Secondary acute myeloid leukaemia with monosomy 7 in identical adult twins

We report the development of secondary acute myeloid leukaemia (AML) with monosomy 7 in identical twins, both at the age of 52 years. In the first twin, induction therapy resulted in complete remission (CR). At relapse 9 months later monosomy 7 was found. The patient died of sepsis 11 months after diagnosis. The other twin presented with leucopenia and thrombocytopenia and refractory anaemia (RA) was diagnosed. During follow-up, fluorescence in situ hybridization analysis demonstrated a monosomy 7 in 11% of the cells. Twenty-eight months following diagnosis the patient progressed to RA with excess blasts in transformation and induction chemotherapy was initiated without achieving CR. Three months later an allogeneic stem cell transplantation from a niece was performed, resulting in CR of the secondary AML.     

Shwachman-Diamond syndrome with late-onset neutropenia and fatal acute myeloid leukaemia without maturation: a case report

We report on a male patient affected by Shwachman Diamond syndrome (SDS) who presented an unusual delayed neutropenia and then developed a poorly differentiated acute myeloid leukaemia (M0-AML) with trilineage myelodysplasia in adulthood. Conventional cytogenetics revealed complex karyotypic changes (monosomies 20, 21, 22, additional 15p). The patient was treated with conventional chemotherapy but never reached complete remission of leukaemia and died 18 months after diagnosis. SDS is an inherited bone marrow failure syndrome with a high propensity to leukaemic transformation. Since neutropenia may be intermittent or with delayed onset, and leukaemic transformation may not occur until adulthood, full blood count should be regularly monitored in such patients.     

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high‐risk MDS

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS). Thirty‐four patients ≥60 years old (median age 70 years; range, 60–83) were randomized to receive tosedostat (120 mg on days 1–21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m²/d) or decitabine (20 mg/m²/d) every 35 d. Twenty‐nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS‐refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3‐internal tandem duplication mutations. Median follow‐up was 11·2 months (range, 0·5–22·3), and median survival was 11·5 months (95% confidence interval, 5·2–16·7). Twenty‐three patients (67·6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3–4 non‐haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.